Institute of Membrane & Systems Biology - Faculty of Biological ...

Institute of Membrane 

& Systems Biology 

Faculty of Biological Sciences

Institute of Membrane 

& Systems Biology 

Welcome to the Institute’s brochure. Its purpose is to provide an introduction to our 

research activity – what we do and why we do it. The brochure is intended for a broad 

spectrum of readers – approachable for those considering study at the University, 

informative for experts wishing to benefit from our research or invest in it. The Institute 

has two main reasons for existence – to educate and to discover. This brochure focuses 

mostly on the discovery side. Nevertheless, you should know that we also have extensive 

undergraduate and postgraduate education programmes running in parallel. 

These programmes are not separate from the research but inter-woven with it. Research informs the direction of teaching 

and, in many cases, causes it to be revised annually. It also provides a rich and modern experience in research discovery for 

undergraduates and postgraduates through projects in our research laboratories. We should also not forget that research is a 

central platform for the reputation of our University, which will influence the lives of most who study at it. 

The Institute is one of three research institutes in the Faculty. Its academic staff and research fellows have interests ranging from 

fundamental studies of the structures and functions of membrane proteins, to physiological questions in excitable systems 

including the mammalian cardiovascular, muscular, nervous and respiratory systems – all the way up to studies of health, exercise 

and disease in humans. The Institute provides an exciting and interactive environment for modern research relating to animal 

and human health, as well as access to “cutting-edge” research equipment, including moderate-to-high through-put protein, 

fluorescence and patch-clamp systems. Publication of research findings in leading international and high-profile scientific 

journals is a strong priority for all members of the Institute. Recent successes include papers in Nature Biotechnology, Molecular 

Cell, EMBO Journal and Proceedings of the National Academy of Science USA. Commensurate with this activity we have about 

four thousand square metres of newly refurbished laboratory space in the LIGHT Building and Centres for Integrative Membrane 

Biology and Sports & Exercise Science. We have constant interest in the next generation of researchers and invest major resources 

and effort in undergraduate and postgraduate education. Furthermore, space is available for recruitment of promising and 

established investigators and we would be pleased at any time to hear from talented and committed individuals wishing to join 

us. The Institute, Faculty and University as a whole operate a low-wall principle for research groupings, centres and institutes with 

the aim of stimulating cross-disciplinary research and integrative approaches to big scientific questions. This places the Institute 

within a powerful scientific environment that encourages and supports (along with its many sponsors) research and researchtraining 

at the highest level. 

Where ever you are in the world – for example at a school in Leeds, in a biotech firm or from a city on the other side of the 

globe, if you are interested in our research areas, please consider visiting us, joining us or investing in us. You would be most 

welcome. We are an ambitious, productive and open research centre in a big cosmopolitan city adjacent to some of the most 

beautiful countryside. You can contact any of our academics directly through e-mail. For enquiries about our undergraduate 

and postgraduate programmes, please see information on our web pages and make contact accordingly. 

Professor Jim Deuchars 

Director, IMSB 

Email: d.jones@leeds.ac.uk 

Tel: +44 (0)113 343 4272

Group 

Research 

Figure 2: Fibre orientation maps for apical slab of left 

ventricular free wall (left). The angle of inclination is 

colour-coded between -90 and +90 degrees (right). 

(Image Prof A. Holden) 

Cardiovascular 

& Sports Sciences 

The Group is part of the University’s 

Multidisciplinary Cardiovascular 

Research Centre (MCRC), which is a 

large cross-faculty research organisation 

providing a single academic framework 

to foster and promote cardiovascular 

research across the University. Our 

cardiovascular researchers have already 

benefited from substantial investment 

in the form of research fellowships and 

PhD studentships. This process of 

investment is continuing with the 

relocation, in May 2008, of many of the 

Group’s researchers to purpose built 

laboratory space. 

The Group serves to extend previous 

individual successes of its members, 

fostering new collaborative research 

directions, allowing Leeds to embrace the 

area of research in its broadest sense: 

Current themes range from molecular, 

cellular and computational approaches 

to sports-related subjects, encompassing 

aspects of health, fitness, exercise 

physiology, anatomy, biomechanics 

and motor control. Ultimately, these 

diverse approaches feed through to 

inform clinical practice and therapeutics. 

Research activities complement 

the Leeds Institute for Genetics and 

Health (LIGHT) and the Integrative 

Membrane Biology Research Group by 

fostering new and exciting cross-faculty 

research opportunities in areas such 

as cardiovascular epidemiology and 

protein structure studies. This strategy 

satisfies the University’s desire to 

establish coherent research units, whilst 

at the same time developing innovative 

graduate training programmes, thereby 

placing Leeds at the forefront of national 

and international cardiovascular and 

sports science research. 

During the past 5 years MCRC 

members have raised over £25M of 

external grant income. This includes 

funding from the British Heart 

Foundation (BHF), British Cardiac 

Association, MRC, Wellcome Trust, 

BBSRC, EPSRC, Department of Health 

and Industry. In addition to >100 

project grants, there are currently 5 

major programme grants. 

The quality and quantity of research 

output from MCRC continues to 

increase, with publications in the top 

cardiovascular journals (e.g. Circulation 

Research, Circulation, impact factors 

≥ 10) and quality multidisciplinary 

journals (e.g. Journal of Biological 

Chemistry, FASEB J). There is also 

an increasing number of high profile 

publications in Science, Nature, Nature 

Biotechnology and Molecular Cell. 

For more information: http://www.fbs. 

leeds.ac.uk/institutes/imsb/ 

Figure 1: Surface plot of a prolonged nuclear Ca2+ 

release event detected using line-scan confocal 

microscopy (Image Dr D. Steele) 

Figure 3: Tubulin (green) and microtubule-associated 

protein 4 (red) immunostaining in a control myocyte 

(lower) and a myocyte from a rat with streptozotocininduced 

type 1 diabetes (upper). Scale bar is 20 μm. 

(Image Dr S. Calaghan) 

Dr Derek Steele (Group leader) 

Prof Arun Holden 

Prof John Colyer 

Prof Ed White 

Dr Simon Harrison 

Dr Sarah Calaghan 1 

Dr Nicola Mutch 1 

Dr Keith Dilly 1 

Dr Olivier Bernus 1 

Dr Matthew Lancaster 2 

Dr Karen Birch 2 

Dr Harry Rossiter 2 

Dr Andrea Utley 2 

Dr Ronaldo Ichiyama 2 

Dr Jean Aaron 2 

Dr Neil Messenger 2 

1 

Recently appointed tenure track research fellows 

2 

Sports-related subjects 

Figure 4: Map of action potential conduction in sinoatrial 

node from 3 month old rat. Image from Dr S Jones

Group 

Research 

Integrative 

Membrane Biology 

The membranes that surround cells 

and the compartments within them 

play critical roles in almost all aspects 

of biology, ranging from the uptake 

of nutrients and perception of the 

environment to the transmission of 

information from one part of the body 

to another. 

The importance of membranes 

is highlighted by the finding that 

membrane proteins account for more 

than 20% of the human genome. 

Membrane dysfunction is involved in 

a panoply of common diseases and 

membrane proteins represent the 

targets of more than 50% of currently 

used therapeutic drugs. Our research 

in Integrative Membrane Biology aims 

at a fundamental understanding of 

the molecular mechanisms underlying 

these roles of membranes at the levels 

of cells, tissues and whole organisms. 

Importantly, we are trying to integrate 

the study of individual genes and 

membrane proteins with investigations 

of information flow within and 

between cells, in order to understand, 

for example, how the neural 

networks involved in brain function 

operate. To enable such a systems 

biology approach, we have strong, 

multidisciplinary research programmes 

in multiple areas, many involving 

collaborations with researchers not only 

within other Institutes and Faculties at 

Leeds, but worldwide. For example, at 

the molecular level, our researchers are 

collaborating with other groups in the 

UK and Europe to solve the structures, 

and thus understand the mechanisms, 

of membrane transporters, ion channels 

and hormone receptors (Figure 1). 

Figure 1: Model of the human membrane protein GLUT1, 

which transports glucose across the blood-brain barrier 

Work on these experimentallychallenging 

molecules has recently 

been enhanced by establishment 

of cutting-edge facilities for highthroughput 

protein production and 

crystallisation using robotic techniques. 

The detailed examination of the 

ligand binding sites of membrane 

proteins necessary to inform drug 

design has been made possible by the 

development of novel solid-state NMR 

techniques. In parallel, automated 

high-throughput electrophysiological 

and fluorescence approaches are being 

used to assay membrane function. At 

the cellular level, researchers studying 

the trafficking of membranes between 

cellular compartments, a process which 

plays critical roles in neurotransmission 

and in the response to hormones such 

as insulin, are using our state-of-the-art 

bioimaging facilities (Figure. 2). 

These include confocal, deconvolution 

and TIRF microscopes which can 

be used for real-time investigations 

on living cells. Current research on 

the role of membranes in tissue and 

whole organism function includes 

electrophysiology on complex neuronal 

networks and use of transgenic 

organisms. These investigations of 

normal physiology are complemented 

by studies on the role of membranes 

in disease, including Alzheimer’s 

disease, hypertension, cardiovascular 

disease, neuropathic pain, epilepsy 

and diabetes. Via such an integrative 

approach to membrane biology, we 

hope not only to gain an understanding 

of these key components of living 

organisms, but also to address some 

of the major healthcare problems in 

the UK. 

Figure 2: Surface location in a cultured human cell 

of a green fluorescent protein-labelled component of 

the exocyst complex, which plays a critical role in the 

secretory pathway of eukaryotes

Stephen Baldwin 

BA, MA (Cambridge) 

PhD (Cambridge) 

Postdoctoral research at Dartmouth Medical School, USA 

Professor of Biochemistry (1998-) 

Leader, Membrane Biology Research Group (200-) 

Associate Editor for UK and Europe, Molecular Membrane Biology (1993-2005) 

Contact: s.a.baldwin@leeds.ac.uk 

Molecular 

membrane biology 

We aim to understand how membrane 

proteins mediate the flow of molecules 

across cell membranes and how they 

are regulated by hormones. A better 

understanding should lead to the 

development of improved therapeutic 

drugs. Our current research falls into 

four main areas. 

Structural proteomics of membrane 

proteins. As part of the UK Membrane 

Protein Structure Initiative we are 

developing methods for the robotic 

high-throughput cloning, expression and 

functional characterization of membrane 

transporters and ion channels. In 

particular we are working on bacterial 

proteins related to important human 

proteins (see Figure 1). 

Folding of membrane proteins. We 

are also interested in how membrane 

proteins achieve their final, folded state. 

Current work is focused on an enzyme, 

PagP, from the outer membrane of 

Escherichia coli. We are using this 

protein as a model system to explore 

protein folding. 

Figure 1: Binding of the neurotransmitter glutamate to a 

human neuronal transporter, modelled on the structure 

of a bacterial homologue 

Figure 2: Immunofluorescent imaging of adenosine 

transporters (green) in a muscle cell from rat heart 

Adenosine transporters as therapeutic 

targets. Adenosine regulates many 

processes, including cardiac output, 

neuronal signalling and sleep. 

Adenosine transporters are also the 

route of uptake of anti-cancer and 

chemotherapeutic drugs. Members of 

the transporter family responsible for 

adenosine transport in most human 

tissues were first identified and cloned 

in our laboratory (see Figure 2). We are 

studying these proteins to understand 

their biological roles and develop new 

drugs for the treatment of, for example, 

chronic pain and malaria. 

Role of the exocyst in vesicular 

trafficking. The exocyst is a multiprotein 

complex essential for 

membrane-trafficking processes. 

We are using a combination of cell and 

structural biological approaches (see 

Figure 3) to understand the molecular 

mechanism of this complex and how it 

contributes to defects in trafficking seen 

in disease states. 

Figure 3: Model of the exo70 component of the 

mouse exocyst complex, showing its extended, 

four-domain structure 

Funding: Wellcome Trust; British Heart 

Foundation; Government agencies; 

MRC; BBSRC; Invitrogen; Astra-Zeneca 

Overseas collaborators: James Young, 

Carol Cass (Canada) 

More information: 

http://www.bmb.leeds.ac.uk/staff/sab/ 

Representative Publications 

Baldwin, SA, Yao SYM, Hyde RJ et al. 

(2005) Functional characterisation of novel 

human and mouse equilibrative nucleoside 

transporters (hENT3 and mENT3) located in 

intracellular membranes. Journal of Biological 

Chemistry 280: 15880–15887. 

Barnes, K, McIntosh, E, Whetton, AD, Daley, 

GQ, Bentley, J & Baldwin, SA (2005) Chronic 

myeloid leukaemia: an investigation into 

the role of Bcr-Abl-induced abnormalities in 

glucose transport regulation. Oncogene 24: 

3257–3267. 

Fielding, AB, Schonteich, E, Matheson, J et 

al. (2005) Rab11-FIP3 and FIP4 interact with 

Arf6 and the Exocyst to control membrane 

traffic in cytokinesis. EMBO Journal 24: 

3389–3399.

Alan Bateson 

BSc (Brunel) 

PhD (Kings College, London) 

Postdoctoral research at MRC Molecular Neurobiology Unit, Cambridge 

Assistant/Associate Professor in Pharmacology, Neuroscience and Psychiatry, University of Alberta, Canada 

Senior Lecturer (2001-); Chair, Canadian Institutes of Health Research Pharmacology and Toxicology Grants 

Committee (2003-2006); Council Member, British Association for Psychopharmacology, (2004-2008); Meetings 

Secretary, British Association for Psychopharmacology, (2007-2010) 

Contact: a.n.bateson@leeds.ac.uk 

Regulation and expression 

of ion channels 

My research centres on the mechanisms 

that regulate the expression and 

function of ion channels, particularly 

in the nervous system. 

GABA A 

receptors are ligand-gated ion 

channels responsible for the majority 

of fast-synaptic inhibition in the central 

nervous system (CNS). They are 

important drug targets for a variety of 

conditions including anxiety and sleep 

disorders, and some forms of epilepsy. 

Benzodiazepines, such as diazepam 

(Valium), act at GABA A 

receptors by 

potentiating the actions of GABA. 

Tolerance and dependence develops 

following long-term benzodiazepine 

exposure. We have examined the 

mechanism by which such exposure 

produces a change in GABA A 

receptor 

expression (Figure 1). Understanding 

these mechanisms may allow the 

identification of better drugs or different 

drug targets. 

Figure 1: Schematic illustrating the mechanism by 

which GABA A 

receptor activation alters its own expression 

following chronic exposure to receptor activation or 

modulation. 

We recently found that GABA A 

receptors 

functionally associate with L-type Ca 2+ 

channels. Thus, activation of excitatory 

GABA A 

receptors early in development 

causes a depolarization-linked Ca 2+ 

entry via L-type Ca 2+ channels. Further, 

a novel inhibition of L-type Ca 2+ channel 

function was revealed by repeated 

GABA A 

receptor activation. We also 

demonstrated a role for Ca 2+ entry via 

L-type Ca 2+ channels in the regulation of 

GABA A 

receptor gene expression. 

Figure 2: Cultured cerebellar granule neurons (CGNs). 

(A) Bright-field image. (B) CGNs filled with the Ca 2+sensitive 

dye Fluo4 (C) CGNs stimulated by GABA. (D) 

CGNs stimulated by high [K + ]. 

In collaboration with Dr Anne King 

(Leeds) we have used biolistic (gene 

gun) gene delivery to examine the 

regulation of expression of the 

preprotachykinin-A gene promoter in 

cultured spinal cords. This methodology 

allows transcriptional analysis in intact 

tissue without the time and expense of 

constructing transgenic mouse lines. 

TRP channels are widely expressed, 

including the CNS where they regulate 

neuronal growth cones. In collaboration 

with Professor Beech (Leeds) we 

discovered that TRPC5 is activated 

by lysophospholipids and other lipids 

which may have significance for 

neuronal development and function. 


Bahnasi, YM, Wright, HM, Milligan, CJ, Dedman, 

AM, Zeng, F, Hopkins, PM, Bateson, AN, Beech, 

DJ (2008) Modulation of TRPC5 cation channels 

by halothane, chloroform and propofol. British 

Journal Pharmacology 153: 1505-1512. 

Flemming, PK, Dedman, AM, Xu, SZ et al. (2006) 

Sensing of lysophospholipids by TRPC5 calcium 

channel. Journal of Biological Chemistry 281: 

4977–4982. 

Brazier, SP, Mason, HA, Bateson, AN & Kemp, 

PJ (2005) Cloning of the human TASK-2 

(KCNK5) promoter and its regulation by 

chronic hypoxia. Biochemical and Biophysical 

Research Communications 336: 1251–1258. 

Hilton, KJ, Bateson, AN & King, AE (2004) A 

model of organotypic rat spinal slice culture 

and biolistic transfection to elucidate factors 

that drive the preprotachykinin-A promoter. 

Brain Research. Brain Research Reviews 46: 

191–203. 

Bateson, AN (2002) Basic pharmacologic 

mechanisms involved in benzodiazepine 

tolerance and withdrawal. Current 

Pharmaceutical Design 8: 5–21.

David Beech 

BSc 1st Class Honours Pharmacology (Manchester) 

PhD Pharmacology (University of London) 

Postdoctoral research, University of Washington, USA 

Professor (2000–) 

Head of the Multidisciplinary Cardiovascular Research Centre (MCRC) 

Member of the Medical Research Council Population and Systems Medicine Board 

Member of the Wellcome Trust-DBT India Alliance’s Early Fellowships Selection Committee 

Contact: d.j.beech@leeds.ac.uk 

Ion channels in vascular disease 

General purpose 

The overall aim of the lab is to make 

fundamental discoveries relating to 

trans-membrane calcium and sodium ion 

movements in mammalian cells, especially 

regarding ion channels in cells of human 

vascular diseases and associated conditions. 

The lab aims to reveal molecular mechanisms 

and to determine how they integrate into 

cells and are regulated by chemical factors. It 

aims to use the information to develop novel 

therapeutic strategies. The lab’s current 

specific interests lie in chemical regulation 

of newly-discovered calcium-permeable 

channels that play roles in tissue remodeling 

of vascular disease and cancer. Channels of 

interest include the TRP channels and Orai 

channels. 

Discoveries and innovations 

TRPC1 is a key driver of remodelling; 

chemical reduction of the turret by 

extracellular redox protein is a mechanism 

for channel opening; TRPC channels are 

transducers for responses to lipid factors, 

including sphingosine-1-phosphjate 

and oxidized phospholipids; TRPM3 is a 

functional vascular smooth muscle ion 

channel conferring reciprocal regulation 

by neurosterids and cholesterol; STIM1 

is a functional plasma membrane ion 

channel subunit of vascular cells; TRPM2 is 

a molecular basis of calcium-activated nonselective 

cation channels; NCS1 is a calciumsensor 

of TRPC5; REST transcription factor is 

a switch for ion channel gene regulation in 

remodelling; Kv1 channels control arterial 

tone; there are non-contractile subcellular 

calcium domains of arterial smooth muscle 

cells; regulatory and molecular features 

of vascular K-ATP channels are nucleotide 

diphosphates and Kir6.1; robotic multiwell 

patch-clamp recording for academic 

research; patch-clamp methods for intact 

microvessels; extracellular blocking 

antibodies and design strategies for use 

in academic research and pharmaceutical 

drug development; routine use of fresh 

human diseased tissue samples for ion 

channel studies. 

Example current projects 

• Integrated functions of TRPC channels in 

vascular smooth muscle cells 

• TRPM3 and sulphated steroid responses of 

vascular smooth muscle cells 

• Oxidized phospholipid ionic transduction 

mechanism of human vascular cells 

Above are images from our lab: Ion channel blocking 

antibodies; Robotic patch-clamp for primary cells 

(Nanion); Novel calcium channels of vascular smooth 

muscle cells; Chemical screening and vascular TRPM3. 

Funding: Wellcome Trust, British Heart 

Foundation, Medical Research Council, 

BBSRC, AstraZeneca, Nanion 


http://www.cardiovascular.leeds.ac.uk/ 

staff/Beech/ 

Lab members: Ion Channel Retreat 2010 (DJ Beech is 6th 

from the right) 


AL-Shawaf E et al (2010) Acute stimulation of 

calcium-permeable TRPC5-containing channels by 

oxidized phospholipids. ATVB In Press 

Naylor J et al (2010) Pregnenolone sulphate- and 

cholesterol-regulated TRPM3 channels coupled to 

vascular smooth muscle secretion and contraction. 

Circulation Research In Press 

Milligan CJ et al (2009) Robotic multi-well planar 

patch-clamp for native and primary mammalian 

cells. Nature Protocols 4: 244-255. 

Li J et al (2008) Interactions, functions and 

independence of plasma membrane STIM1 and 

TRPC1 in vascular smooth muscle cells. Circulation 

Research 103: e97-104. 

Xu S et al (2008) TRPC channel activation by 

extracellular thioredoxin. Nature 451: 69-72. 

Kumar B et al (2006) Up-regulated TRPC1 channel 

in vascular injury in vivo and its role in human 

neointimal hyperplasia. Circulation Research 98: 

557–563 

Xu S et al (2006) A sphingosine-1-phosphate 

activated calcium channel controlling vascular 

smooth muscle cell motility. Circulation Research 

98: 1381-1389. 

Xu S et al (2005) Generation of functional 

ion channel tools by E3-targeting. Nature 

Biotechnology 23: 1289-1293. 

Cheong A et al (2005) Down-regulated REST 

transcription factor is a switch enabling 

critical potassium channel expression and cell 

proliferation. Molecular Cell 20: 45–52. 

McHugh D et al (2003) Critical intracellular Ca 2+ - 

dependence of Transient Receptor Potential 

Melastatin 2 (TRPM2) cation channel activation. 

Journal of Biological Chemistry 278: 11002-11006. 

Xu S & Beech DJ (2001) TrpC1 is a membranespanning 

subunit of store-operated Ca 2+ channels 

in native vascular smooth muscle cells. Circulation 

Research 88: 84-87.

Olivier Bernus 

MSc, PhD (Ghent, Belgium) 

Postdoctoral research, SUNY Upstate Medical University, USA 

Tenure-Track Independent Research Fellow (2007-) 

Contact: o.bernus@leeds.ac.uk 

Three-dimensional organization of cardiac 

electrical activity during arrhythmias 

My research focuses on the 

mechanisms underlying life-threatening 

cardiac arrhythmias leading to sudden 

cardiac death, the largest cause of 

death in the industrialized world. 

Every heartbeat is triggered by electrical 

waves of excitation propagating through 

the cardiac muscle from sinus node to 

the ventricles. Abnormal propagation 

of this wave severely compromises 

the mechanical function of the heart 

and represents a major cause of 

arrhythmias. Reentry, during which 

a wave of excitation repeatedly 

activates the cardiac muscle, is such 

a type of abnormal propagation and 

occurs during dangerous arrhythmias 

such as fibrillation. My laboratory 

utilizes both computational and 

experimental techniques to visualize 

the propagation of electrical waves 

through myocardium and understand 

the mechanisms underlying reentry 

and associated arrhythmias. 

There is compelling clinical evidence 

that acute myocardial ischemia 

occurring after coronary occlusion is 

one of the most important causes of 

ventricular arrhythmias. Recently, we 

discovered a novel mechanism for 

arrhythmogenesis during early regional 

ischemia using a realistic computational 

model of ischemic myocardium. 

In this model, reentry occurred as a 

result of calcium-mediated alternating 

conduction blocks in the ischemic 

border zone. Based on this hypothesis, 

we have designed an experimental 

model of regional ischemia and are 

currently investigating arrhythmogenesis 

in this model. 

Optical imaging using voltage-sensitive 

dyes has become a powerful tool to 

study electrical propagation in cardiac 

tissue. However, poor transparency of 

tissue has enforced surface or subsurface 

imaging and prevents the use 

of conventional optical methods to 

visualize the electrical waves through 

the thickness of the cardiac muscle. 

My laboratory works on the application 

of novel optical tomographical 

methods and laser scanning to probe 

deeper layers of the cardiac muscle 

and unravel the three-dimensional 

wave patterns underlying cardiac 

arrhythmias. 

Funding: Research Foundation – 

Flanders (Belgium), IWT (Belgium) 

Overseas collaborators: Arkady 

Pertsov (USA), Sasha Panfilov (The 

Netherlands), Henri Verschelde 

(Belgium) 


http://users.ugent.be/~obernus 

Figure 1: Reentry in a computational model of the human 

ventricles. 

Figure 2: Three-dimensional reconstruction of a linear 

object using biaxial laser scanning in an experimental 

phantom of biological tissue. 


Wellner, M, Bernus, O, Mironov, SF, Pertsov 

AM (2006) Multiplicative tomography of 

cardiac electrical activity. Phys. Med. Biol. 

51:44, 29-4446. 

Khait, VD, Bernus, O, Mironov, SF, Pertsov AM 

(2006) A Method for the Three-Dimensional 

Localization of Cardiac Electrical Activity using 

Optical Imaging. J. Biomed. Opt. 11:034007. 

Bernus, O, Zemlin, CW, Zaritsky, R et al 

(2005) Alternating Conduction in the Ischemic 

Border Zone as Precursor of Reentrant 

Arrhythmias: a Simulation Study. Europace 7: 

93-104. 

Bernus, O, Wilders, R, Zemlin, C et al. (2002) 

A computationally efficient electrophysiological 

model of human ventricular cells, Am. J. 

Physiol. - Heart and Circulatory Physiology 

282:H2296-H2308.

Karen Birch 

BSc (Hons) Movement Science: Liverpool University (1990) 

PhD Exercise Physiology: Liverpool John Moores University (1995) 

Lecturer and Senior Lecturer in Exercise Science, Manchester Metropolitan 

University (1993-2002) 

Senior Lecturer in Exercise Physiology, University of Leeds (2002-) 

Member of Physoc, ACSM. 

Female reproductive hormones, 

exercise and cardiovascular disease 

Figure 1: Cardiopulmonary exercise test 

My research group comprises a team 

of researchers with an intense focus 

on investigation of the interplay 

between female reproductive hormone 

fluctuation, exercise and cardiovascular 

health and function. This work involves 

collaboration with the LIGHT, Vascular 

Medicine at the LGI and the Academic 

Dept. Obstetrics and Gyneacology, 

St James’s University Hospital. The 

techniques utilised by the team include 

cardiopulmonary exercise tests, 

echocardiography for assessment of 

left ventricular structure and function, 

doppler ultrasonography for assessment 

of haemodynamics and endothelial 

function and applanation tonnometry 

for assessment of arterial stiffness. 

• The hormone oestrogen has potent 

effects upon the vasculature that are 

seen to influence haemodynamics. 

These effects are often tempered by 

the ovarian steroid progesterone. 

We have investigated the influence 

of oestrogen and progesterone 

fluctuations throughout the menstrual 

cycle and oral contraceptive cycle 

upon post-exercise hypotension. 

Having indicated the lack of effect 

of exogenous hormones (Birch et 

al., 2002: Experimental Physiology) 

we have recently been the first 

group to highlight that, rather than 

increase the magnitude of postexercise 

hypotension, oestrogen and 

progesterone appears to buffer the 

hypotension in the late follicular and 

mid luteal phases of the menstrual 

cycle (Esformes et al. 2005: Medicine 

and Science in Sports and Exercise 

and ACSM Annual Congress, 2005). 

The impact of fluctuating hormones 

upon health and performance in 

premenopausal women has been 

highlighted further in an invited 

clinical review for the British Medical 

Journal (Birch, 2005) and a Chapter in 

the British Medical Association ABC of 

Sports Medicine. 

• Loss of the ovarian hormones at 

the menopausal transition has 

been shown to increase the risk of 

cardiovascular disease and type 2 

diabetes in women. This has been 

highlighted in a key note, by invitation 

by the Physiological Society, at both 

the British Association of Science 

Annual Congress, Dublin, (2005) 

and the Association for Science 

Education (2005). With funding 

from Heart Research UK we have 

assessed the impact of a six month 

exercise training programme upon 

risk factors for cardiovascular disease 

in postmenopausal women with and 

without type 2 diabetes. These results 

have been presented at EuroPrevent 

(a European Society of Cardiology 

Congress) in Athens (2006) and Madrid 

(2007) and the annual Congress of 

Figure 2: Ultrasound assessment of flow 

mediated dilation 

ACSM (2007) in New Orleans. The most 

exciting results of these studies were 

that exercise training can improve 

endothelial function independently of 

changes in any other CVD risk factors 

in these women. We have recently 

received BHF funding to explore this 

finding further by assessing the impact 

of exercise training upon endothelial 

progenitor cell function and number. 

Funding: European Commission FP5, 

Nuffield Foundation, Heart Research UK, 

British Heart Foundation 


http://www.leeds.ac.uk/sports_science/ 

staff/kb.htm 


Cubbon RM, Murgatroyd SR, Ferguson C, 

Bowen TS, Rakobowchuk M, Baliga V, Cannon D, 

Rajwani A, Abbas A, Kahn M, Birch,,KM, Porter KE, 

Wheatcroft SB, Rossiter HB, Kearney MT (2010) 

Human exercise-induced circulating progenitor 

cell mobilization is nitric oxide-dependent and is 

blunted in South Asian men. Arterioscler Thromb 

Vasc Biol, 30(4): 878-884. 

Oxborough D, Batterham AM, Shave R, Artis N, 

Birch KM, Whyte G, Ainslie PN, George KP (2009) 

Interpretation of two-dimensional and tissue 

Doppler-derived strain (epsilon) and strain rate 

data: is there a need to normalize for individual 

variability in left ventricular morphology? Eur J 

Echocardiogr, 10(5): 677-682. 

Esformes JI, Norman F, Sigley J, Birch KM (2006) 

The influence of menstrual cycle phase upon 

postexercise hypotension Med Sci Sports Exerc 

38(3): 484-491. 

Birch KM (2005) ABC of sports and exercise 

medicine - Female athlete triad British Medical 

Journal, 330: 244-246.

Sarah Calaghan 

BSc, PhD (Leeds) 

Postdoctoral Research, Dept of Biochemistry & Molecular Biology, Dept of Physiology, University of Leeds 

British Heart Foundation Research Fellow (2000-2003) 

School of Biomedical Sciences University Research Fellow (2006-) 

Institute of Membrane and Systems Biology 

Contact: s.c.calaghan@leeds.ac.uk 

Control of signalling 

in the cardiac cell 

The heart pumps blood around 

the body, delivering nutrients to 

and removing waste products from 

every organ. Its function is finely 

tuned to respond to the demands of 

the body. My research focuses on 

the mechanisms which control the 

behaviour of individual cardiac muscle 

cells in the heart in response to a variety 

of stimuli. This information can be used 

to understand the function of the heart 

in both health and disease. 

The way that the heart functions in 

a healthy individual is a result of a 

balance between the stimulatory 

sympathetic nervous system and the 

inhibitory parasympathetic system. 

These 2 systems work through different 

receptors (β-adrenoceptors and 

muscarinic receptors), but many of 

the components of the downstream 

signalling pathways are the same. I am 

interested in how cellular signalling 

is controlled to allow these receptors 

to produce such diverse functional 

responses. One structure that 

contributes to this is the caveola, which 

is a small flask shaped pocket in the 

cell membrane (Figure 1). Caveolae can 

concentrate or exclude components of 

signalling pathways so as to modulate 

both the efficiency and fidelity of 

signal transduction. Our work has 

revealed a central role for caveolae in 

compartmentalisation of cyclic AMP 

signalling in the adult cardiac myocyte 

following β2 adrenoceptor stimulation. 

We are currently exploring the effect of 

drugs (statins) and diet (polyunsaturated 

fatty acids) on caveolar organisation, 

and the potential impact of this on 

cAMP-dependent signalling. 

The heart possesses a unique intrinsic 

ability to regulate its force of contraction 

in response to circulatory demand. For 

example, during exercise, the amount of 

blood returning to the heart increases 

and stretches the cardiac muscle. 

This acts as a stimulus for increased 

contraction, allowing the chambers of 

the heart to expel this greater volume 

of blood. Some of the processes which 

link stretch to increased contraction 

are not understood. I have identified a 

number of elements (stretch-activated 

channels, the NaH exchanger) which 

contribute to the slow phase of force 

increase following stretch both in single 

cardiac myocytes. Recent work from the 

laboratory has shown that caveolae are 

reservoirs of extra membrane recruited 

upon stretch in the cardiac myocyte. This 

has implications for membrane tension, 

stretch-activated channel function 

and thereby the mechanotransductive 

response of the heart. 

Figure 1: A caveola in the cell membrane (courtesy of 

Tim Lee, Faculty of Biological Sciences) 

Figure 2: A cardiac cell from a model of type 1 diabetes 

stained to show the microtubular cytoskeleton 

Cardiac function is adversely affected by 

many different diseases. For example, 

cardiovascular complications are a major 

cause of disability and death in patients 

with diabetes. We have identified a 

novel change in the microtubular 

network (Figure 2), that may contribute 

to adverse alterations in cardiac cell 

function in a model of type 1 diabetes. 

Funding: British Heart Foundation, 

Medical Research Council 

Overseas collaborators: 

Bob Harvey (Reno, US), Jean-Yves Le 

Guennec (France), Chris Howarth (UAE) 


Kozera L, White E, Calaghan S (2009) Caveolae 

act as membrane reserves which limit 

mechanosensitive I(Cl,swell) channel activation 

during swelling in the rat ventricular myocyte. 

PLoS One 4: e8312 

Calaghan SC, Kozera L, White E (2008) 

Compartmentalisation of cAMP-dependent 

signalling by caveolae in the adult cardiac 

myocyte. J Mol Cell Cardiol 44: 85-92 

Shiels H, O’Connell A, Qureshi MA, Howarth FC, 

White E, Calaghan S (2006) Stable microtubules 

contribute to cardiac dysfunction in the 

streptozotocin-induced model of type 1 diabetes 

in the rat. J Mol Cell Biochem 294: 173-180 

Calaghan SC, White E (2004) Activation of 

Na + -H + exchange and stretch-activated channels 

underlies the slow inotropic response to stretch 

in myocytes and muscle from the rat heart. J 

Physiol 559: 205-214

John Colyer 

BSc; CNAA; MPhil, London 

PhD, Southampton 

Post-doctoral work, University of Calgary, Canada 

British Heart Foundation lecturer, University of Leeds (1991-99) 

Senior lecturer (1999-2007) 

Professor of Biotechnology, University of Leeds (2007-) 

Founder of Fluorescience Ltd (biotech/drug discovery company) (1998) Badrilla Ltd. (2004) 

Natural & Therapeutic Control 

of Cardiac Function 

The performance of many biological 

events is controlled through the transient 

chemical modification of components, 

or the partnering of new components 

in a cell. Where and when these events 

take place is key to the process of 

control, and errors in these processes 

can lead to human disease. In my lab 

we are interested in the development of 

technologies which permit observation of 

these short-lived chemical events, and 

the application of these technologies 

to understand normal and abnormal 

cardiac performance (Figure 1). 

The chemical adaptation of a small 

number of influential proteins changes 

the performance of the heart to meet 

the demands of exercise and stress, 

but this process fails following cardiac 

damage leading to life threatening 

loss of performance of the heart. We 

have developed tools to examine these 

events by immunoassay, and within 

the company Badrilla Ltd., we are 

developing quantitative immunoassays 

based on novel proprietary calibration 

standards (Figure 2). 

Figure 2: Calibration standards for quantitative immunoassays 

We are also developing novel 

experimental strategies for cardiac 

therapy. Having identified influential 

components in cardiac biology, we 

have engineered a strategy in which 

the diseased component (a protein) 

is removed by molecular intervention 

and replaced with a designer version 

of the component which corrects the 

malfunction. This strategy is being 

developed with a cardiac protein 

component, but has applications 

across medicine & biotechnology. 

Funding: MRC 


Jones, P.P., Bazzazi, H., Kargacin, G.J. 

& Colyer, J. (2006) Inhibition of cAMPdependent 

protein kinase under conditions 

occurring in the cardiac dyad during a Ca2+ 

transient. Biophysical Journal 91, 433-443 

Carter, S., Colyer, J., Sitsapesan, R. (2006) 

Maximum phosphorylation of the cardiac 

ryanodine receptor at serine-2809 by protein 

kinase A produces unique modifications to 

channel gating and conductance not observed 

at lower levels of phosphorylation. Circ. Res. 

98, 1506-1513 

Johnson B.R.G., Bushby, R.J., Colyer, J., & 

Evans, S.D. (2006) Self assembly of actin 

scaffolds at ponticulin containing supported 

phospholipids bilayers. Biophysical Journal 90, 

L21-23L 

Rodriguez, P., Bhogal, M.S. & Colyer, J., 

(2003) Stoichiometric phosphorylation of 

cardiac Ryanodine Receptor on serine-2809 

by protein kinase A and calmodulin-dependent 

kinase II. J. Biol. Chem. 278, 38593-38600 

Figure 1: Use of fluorescently labelled Coiled coil 

peptides to monitor phosphorylation

Jim Deuchars 

BSc Physiology, IIi, Glasgow (1988) 

PhD Physiology with Prof. KM Spyer, University of London (1992) 

Postdoc with Prof. AM Thomson, University of London (1992-1997) 

Lecturer in Physiology, Leeds, (1997) Professor 

Contact: J.Deuchars@leeds.ac.uk 

Central neuronal circuits influencing cardiovascular 

control – from neuronal characteristics to pathway 

discovery and function 

This research is a team effort, areas 

of which I lead in conjunction with 

Sue Deuchars. We investigate the 

organisation and function of the parts 

of the brain and spinal cord that 

contribute to control of the autonomic 

nervous system. This branch of the 

nervous system undertakes tasks 

to keep our body functioning, such 

as control of blood pressure, heart 

rate, breathing and digestion. The 

current team comprises postdoctoral 

and postgraduate researchers who 

use CNS slice electrophysiology, 

neuronal tracing, molecular biology, 

immunohistochemistry and light 

and electron microscopy. This 

interdisciplinary approach allows us to 

examine issues from several angles, 

leading to us being able to: 

l Identify new CNS regions that may 

be involved in autonomic control, for 

example a nucleus in the brainstem 

that receives afferent input from 

neck muscle proprioceptors and 

which projects to the nucleus tractus 

solitarius, a region pivotal in central 

autonomic neurocircuitry (Edwards 

et al., 2007., J Neurosci. 2007 

27(31):8324-33). 

l provide evidence that the major 

group of inhibitory neurotransmitter 

receptors, GABA receptors, can be 

made up components from 2 (A, C) 

of the 3 (A,B,C) sub-types (Milligan et 

al., 2004, J. Neurosci, 24:9241-50). 

l reveal the distribution and function 

of ion channels contributing to the 

properties of specific groups of nerve 

cells involved in autonomic neuronal 

circuits – both in the brainstem 

(Dallas et al., 2005, J.Physiol. 

562:655-72) and the spinal cord 

(Deuchars et al., 2001, Neurosci., 

106, 433-446). In each area these 

channels appear to mark a cell type 

with specific roles in influencing 

autonomic nervous activity. In one 

study (Dallas et al., 2005), we applied 

antibodies as ion channel specific 

modulators to identify the specific 

channel proteins contributing to 

neuronal behaviour (see Figure 1). 

Funding: Wellcome Trust; British Heart 

Foundation; Government agencies 

MRC, BBSRC. 


http://www.fbs.leeds.ac.uk/staff/profile. 

php?staff=JDeu 

Figure 1: A summary of the many different types of 

neuronal proteins which antibodies have been used to 

target functionally, reviewed in Dallas, Deuchars and 

Deuchars (2005), J. Neurosci. Meths. 146(2):133-48 

Figure 2: the Kv3.3 potassium channel subunit (red) 

is localised to presynaptic terminals with SV2 (yellow is 

co-localised). 


Edwards IJ, Dallas ML, Poole SL, Milligan CJ, 

Yanagawa Y, Szabo G, Erdelyi F, Deuchars 

SA, Deuchars J.(2007). The neurochemically 

diverse intermedius nucleus of the medulla 

as a source of excitatory and inhibitory 

synaptic input to the nucleus tractus solitarii.J 

Neurosci. 2007 Aug 1;27(31):8324-33 

Dallas, M.L., Atkinson, L., Milligan, C.J., 

Morris, N.P., Lewis, D.I., Deuchars, S.A. and 

Deuchars, J. (2005). Localisation and function 

of the Kv3.1b subunit in the rat medulla 

oblongata: focus on the nucleus tractus 

solitarius. Journal of Physiology, 562(Pt 

3):655-72 

Deuchars, S.A., Milligan, C.J., Stornetta, R.L. 

and Deuchars, J. (2005). GABAergic neurones 

in the central region of the spinal cord: a novel 

substrate for sympathetic inhibition. Journal of 

Neuroscience, 25(5):1063-70 

Milligan, C.J.; Buckley, N.J.; Garret, M., 

Deuchars, J. and Deuchars, S.A. (2004). 

Evidence for inhibition mediated by coassembly 

of GABAA and GABAC receptor 

subunits in native central neurones. Journal 

of Neuroscience

Susan Deuchars 

BSc (Cardiff) 

PhD (University of London) 

Independent Research Fellow (1997–2005) 

Academic Fellow (2005-, 60% FT) 

Editorial Board Autonomic Neuroscience: Basic and Clinical 

Convenor for CRAC Special Interest Group, The Physiological Society (2001-2007) 

Contact: s.a.deuchars@leeds.ac.uk 

Unravelling autonomic circuits 

in brainstem and spinal cord 

The sympathetic and parasympathetic 

branches of the autonomic nervous 

system control most of the essential 

homeostatic processes. Many 

clinical conditions are associated 

with abnormal autonomic function, 

such as hypertension and associated 

cardiovascular problems. One underexplored 

avenue for treatment is the 

manipulation of areas of the central 

nervous system involved in sympathetic 

and thus cardiovascular control. 

I lead an enthusiastic team in 

conjunction with Jim Deuchars to 

investigate properties of neuronal 

circuits that underlie control of the 

cardiovascular system. 

Figure 1: Spinal cord interneuron 

One focus of our research is 

characterizing the role of interneurons 

(small local cells in the spinal cord) 

in the sympathetic circuits: where 

they are located, which neurons link 

to these cells, what neurotransmitters 

they contain and how they talk to other 

cells. We have discovered a novel group 

of interneurons that directly inhibit 

sympathetic neuronal activity and may 

be important in mediating stress-related 

changes in sympathetic outflow. 

We have also provided the first 

characterization of other interneurons 

involved in sympathetic control 

and described a role for a specific 

potassium channel in shaping their 

firing properties. These ion channels 

are not present in other sympathetic 

neurons and may help to shape the 

pattern of outflow from the spinal cord. 

Since sympathetic outflow may be 

severely compromised during stressful 

events such as ischaemia, it is vital 

to understand how sympathetic 

activity may be regulated by specific 

modulators (such as adenosine) that 

are released during these events. 

We have highlighted how activation 

of functionally diverse adenosine 

receptors may act in a novel synergistic 

way to cause an overall decrease in 

sympathetic preganglionic activity. 

This mechanism may be crucial in 

reducing potentially dangerous levels of 

excitability in these neurons, which are 

a key component in the maintenance of 

cardiovascular homeostasis. 


Foundation. 

Overseas collaborators: Ida Llewllyn- 

Smith (Flinders, Adelaide), Ruth 

Stornetta (University of West Virginia) 


www.fbs.leeds.ac.uk/staff/profile. 

php?staff=SAD 

Figure 2: Specific ion channels in interneurons enable 

them to fire at a fast frequency 


Deuchars, S.A. (2007) Multi-tasking in the 

spinal cord - do “sympathetic” interneurones 

work harder than we give them credit for? 

Journal of Physiology 580(Pt 3):723-9. 

Deuchars, SA, Milligan, CJ, Stornetta, RL & 

Deuchars, J (2005) GABAergic neurons in 

the central region of the spinal cord: a novel 

substrate for sympathetic inhibition. Journal of 

Neuroscience 25: 1063–1070. 

Brooke, RE, Deuchars, J & Deuchars, 

SA (2004) Input specific modulation of 

neurotransmitter release in the lateral horn 

of the spinal cord via adenosine receptors. 

Journal of Neuroscience 24: 127–137. 

Deuchars, SA, Brooke, RE, Frater, B 

& Deuchars, J (2001a) Properties of 

interneurones in the intermediolateral 

cell column of the rat spinal cord: role of 

the potassium channel subunit Kv3.1. 

Neuroscience 106: 433–446. 

Deuchars, SA, Brooke, RE & Deuchars, J 

(2001b) Adenosine A1 receptors reduce 

release from excitatory but not inhibitory 

synaptic inputs onto lateral horn neurons. 

Journal of Neuroscience 21: 6308–6320.

Keith Dilly 

BSc (Coventry University) 

MPhil (Liverpool University) 

PhD (University of Maryland, MD, USA) 

Postdoctoral Research, University of Maryland Biotechnology Institute, MD, USA 

Postdoctoral Research, Columbia University, NY, USA 

Postdoctoral Research, University of Washington, WA, USA 

Tenure Track Independent Research Fellow, University of Leeds 

Contact: k.w.dilly@leeds.ac.uk 

Calcium signaling 

in the heart 

My research is focused on 

understanding the electrical activity and 

mechanical function of the heart. 

To work as an efficient pump the 

heart must beat in a coordinated 

fashion. Cardiac muscle contraction 

is stimulated by electrical activity 

of the cardiac action potential. 

This complex pathway, known as 

excitation-contraction (E-C) coupling 

can be disrupted resulting in reduced 

pumping efficiency of the heart and 

heart failure. My research focuses on 

how electrical activity and mechanical 

function of the heart are coordinated 

and regulated – how changes in cardiac 

calcium signaling under normal and 

pathophysiological conditions may result 

in heart failure and how molecular 

mechanisms may prevent such defects. 

Furthering our understanding may 

provide useful therapeutic targets for 

the treatment of heart failure. 

Figure 1: Greater Ca 2+ signaling in Endo than in Epi 

cardiac myocytes 

Figure 2: Intimate localization of KCNQ1 and β 2 

-AR 

shown by acceptor bleaching FRET. 

We recently discovered regional 

differences in E-C coupling and calcium 

signalling in the heart. We also showed 

these regional differences in calcium 

signalling and E-C coupling result in 

differential activation of the calcineurin- 

NFAT pathway. This in turn causes 

differential expression of a cardiac 

potassium channel gene involved 

in electrical excitability of cardiac 

tissue. We are intent on discovering 

the mechanisms responsible for 

controlling this excitation-transcription 

coupling pathway, which may prove to 

be a ubiquitous signalling pathway of 

excitable tissues. (Figure 1). 

Sympathetic nervous system-mediated 

control of cardiac function results 

from activation of the β-adrenergic 

signalling pathway and numerous 

downstream effector molecules. Cellular 

compartmentalization of the response 

to adrenergic signalling is in part the 

result of localized A-kinase anchoring 

proteins. Recently we demonstrated 

localization of adrenergic signalling 

to specific cardiac potassium channels. 

(Figure 2). We are interested in further 

understanding localization of 

protein kinase A signalling within 

cardiac muscle. 

We recently found a rare fatal heart 

condition (LQT 4) can be caused by 

disruption of a protein (ankyrin-B) that 

anchors ion channels within cardiac 

cells. Mutation of ankyrin-B results in 

disrupted sub-cellular organization, 

altered cardiac calcium signaling and 

susceptibility to arrhythmia and sudden 

death with exercise or β-adrenergic 

stimulation. (Figure 3). 

Figure 3: Steady state action potentials recorded from 

AnkB (+/-) ventricular myocytes. 


Rossow, C.F., K.W. Dilly and L.F. Santana. 

Differential calcineurin/NFATc3 activity 

underlies the mouse Ito transmural gradient. 

(2006). Circ Res. May 26;98(10):306-13. 

Dilly, K.W., Charles F. Rossow, James S. 

Meabon, Jennifer L. Cabarrus and Luis F. 

Santana. Mechanisms underling variations in 

excitation-contraction coupling across the left 

ventricular free wall. (2006). J.Physiol. Apr 

1;572(pt1):227-41. 

Dilly, K.W., Kurokawa J., Terrenoire C., 

Reiken S, Lederer W.J., Marks A.R. and 

Kass R.S. Overexpression of β2-adrenergic 

receptors cAMP-dependent protein kinase 

phosphorylates and receptor/channel colocalization. 

(2004). J.Biol.Chem. Sep 24; 

279(39): 40778-97. 

Mohler, Peter J., Jean-Jacques Schott, 

Anthony O. Gramolini, Keith W. Dilly, Silvia 

Guatimosim, William H. duBell, Long-Sheng 

Song, Karine Haurogné, Florence Kyndt, 

Mervat E. Ali, Terry B. Rogers, W. J. Lederer, 

Denis Escande, Herve Le Marec, Vann Bennett. 

Ankyrin-B mutation causes type 4 long QT 

cardiac arrhythmia and sudden cardiac death. 

(2003). Nature. Feb 6; 421(6923): 634-9.

Dan Donnelly 

BSc Biological Chemistry, University of Leicester (1988) 

PhD, University of London 1992, supervisor Prof TL Blundell 

Post doc with Prof J.B.C. Findlay (1991-1995) 

Lecturer (1995-2004) & Senior Lecturer (2004-), University of Leeds 

Contact: d.donnelly@leeds.ac.uk 

G Protein-Coupled 

Receptors 

My research group studies the structure 

& function of G protein-coupled 

receptors - one of the most diverse 

and ubiquitous families of integral 

membrane proteins. GPCRs play a 

pivotal role in many cellular signalling 

pathways and are prime targets for 

the development of therapeutic agents 

designed to either block or activate the 

receptors. The aim of this laboratory is 

to elucidate the mechanism by which 

these receptors bind their ligands 

and transduce the signal across the 

plasma membrane. 

The control of the body’s blood sugar 

level requires keeping an intricate 

balance between the levels and 

actions of the two opposing pancreatic 

hormones, insulin and glucagon. While 

low glucose levels result in glucagon 

secretion from pancreatic alpha cells, in 

the high glucose situation the action of 

glucose on pancreatic beta cells results 

in increased plasma insulin levels. 

However, high blood glucose levels are 

not solely responsible for increased 

insulin secretion. Two hormones, 

glucagon-like peptide-1 (GLP-1) and 

glucose-dependent-insulinotropic 

polypeptide (GIP), are responsible 

sensing food intake and consequently 

sensitizing the pancreatic beta cells’ 

insulin secretory system to glucose. 

Using truncated and mutated receptors 

alongside modified peptide ligands, our 

group has defined a two-stage model for 

peptide binding at the GLP-1 receptor 

(Al-Sabah & Donnelly, 2003; Lopez de 

Maturana et al. 2003). 

The GLP-1 work in my laboratory 

is currently funded by an Industrial 

Partnership award from BBSRC & 

AstraZeneca, part of which involves 

the design & synthesis of small 

molecules ligands (Dr. Colin Fishwick, 

School of Chemistry). 

As part of a collaboration with GSK, our 

group also study the calcitonin receptorlike 

receptor (e.g. Miller et al., 2010) and 

the receptors for parathyroid hormone 

(e.g. Mann et al., 2008). 

Current Funding: BBSRC; GSK, 

AstraZeneca 

Past Funding: Novo Nordisk, Knoll, Royal 

Society, BBSRC, Wellcome 

Trust, British Heart Foundation 

and Diabetes UK. 



php?staff=DD 

Figure 1: Schematic figure of how GLP-1 bind to its 

receptor (left) and a competition binding experiment 

using three different ligands at the GLP-1 receptor 

expressed in HEK-293 cells (right). 


Mann RJ, Nasr NE, Sinfield JK, Paci E, Donnelly 

D (2010) The major determinant of exendin-4/ 

GLP-1 differential affinity at the rat GLP-1 

receptor N-terminal domain is a hydrogen bond 

from SER-32 of exendin-4. Brit. J. Pharmacol doi: 

10.1111/j.1476-5381.2010.00834.x 

Miller PS, Barwell J, Poyner DR, Wigglesworth 

MJ, Garland SL, Donnelly D (2010) Non-peptidic 

antagonists of the CGRP receptor, BIBN4096BS 

and MK-0974, interact with the calcitonin 

receptor-like receptor via methionine-42 and 

RAMP1 via tryptophan-74. Biochem Biophys Res 

Commun 391(1): 437-442 

Mann R, Wigglesworth MJ, Donnelly D (2008) 

Ligand-receptor interactions at the parathyroid 

hormone receptors: subtype binding selectivity is 

mediated via an interaction between residue 23 

on the ligand and residue 41 on the receptor. Mol 

Pharmacol 74(3): 605-613 

Al-Sabah S, Donnelly D (2003) A model for 

receptor-peptide binding at the glucagon-like 

peptide-1 (GLP-1) receptor through the analysis 

of truncated ligands and receptors British Journal 

of Pharmacology 140: 339-346 

Lopez de Maturana R, Willshaw A, Kuntzsch 

A, Rudolph R, Donnelly D (2003) The isolated 

N-terminal domain of the glucagon-like 

peptide-1 receptor binds exendin peptides 

with much higher affinity than GLP-1 Journal of 

Biological Chemistry 278: 10195-10200

John Findlay 

B.Sc. (1st Hons.): Biochemistry, University of Aberdeen (1968) 

Ph.D: Biochemistry, University of Leeds (1972) 

Post-doctoral: Harvard University, USA 

Professor of Biochemistry: University of Leeds (1990-) 

Contact: j.b.c.findlay@leeds.ac.uk 

The Membrane Protein 

and Proteomics Group 

The main interest of this laboratory is to 

examine the structure and mechanism 

of action of membrane proteins. 

Research focuses on receptor systems 

(G protein coupled receptors (GPCRs) 

and membrane receptors for lipocalins), 

ion channels (proton-transporting 

channels and ligand-regulated Cachannel), 

the proteomics of mast 

cell and stem cell differentiation 

and bioinfomatics. There are also 

investigations into mutations in GPCRs 

and proteins of the visual system 

which give rise to human disease. 

The principle techniques used, 

dependent on the exact project, include 

protein chemistry, electrophysiology, 

molecular biology, protein mutation 

and expression, general membranology 

and biophysical analysis (NMR, X- 

ray, EM). There are a number of 

ongoing collaborations with other 

groups in Leeds, elsewhere in the UK 

and abroad. The laboratory houses 

a protein chemistry facility which 

includes automated protein sequencing 

and robotic proteomics utilizing mass 

spectrometry. 

Current projects include: 

l Studies of the Structure:Function 

of G protein coupled receptors 

including aspects of their folding, 

assembly and quarternary structure. 

l The development of new biosensor 

and assay systems by exploiting 

native and novel GPCRs expressed in 

reporting systems of various kinds. 

This project will not only develop 

novel sensor / assay systems but will 

reveal how novel specificities arise in 

GPCR structures 

l 

l 

l 

l 

Structure:Function of lipocalin 

receptors, their expression, 

reconstitution and functional 

characteristics. 

The role and mechanism of action of 

the RBP-receptor system and its role 

in Type2 Diabetes 

The proteomics of embryonic and 

adult stem cells and the pathways 

involved in differentiation to mature 

cell types. 

Drug discovery projects to address 

insulin resistance and genetic 

disease in membrane proteins 

Funding: Research supported by 

BBSRC, Wellcome Trust, EC, MRC, 

Government Depts. 

More Information: 

www.fbs.leeds.ac.uk/staff/findlay/ 

Figure 1: A model of the proposed role of RBP, CRBP 

and their receptor in the uptake of retinol (vitamin A) into 

the cell 


Wrigley J D J, Ahmed T, Nevett C L, Findlay 

J B C. Peripherin/rds influences membrane 

vesicle morphology. J Biol Chem , Vol 275, 

No18, 13191-13194 2000. 

Bhogal N, Blaney FE, Ingley PM, Rees and 

Findlay JBC. The proximity of the extreme 

N-terminus of the NK2 tachykinin receptro to 

Cys167 in the putative fourth transmembrane 

helix. Biochemistry, 43, 3027-3038, 2004 

Blades MJ, Ison JC, Ranasinghe R, Findlay JBC. 

Automatic generation and evaluation of sparse 

protein signatures for families of protein structural 

domains. Protein Science 14,13-23, 2005 

Clare DK, Orlova EV, Finbow MA, et al. An 

expanded and flexible form of the vacuolar 

ATPase membrane sector. Structure, 14 (7), 

1149-1156 (2006) 

Redondo C, Vourapolou M, Evans J and Findlay 

JBC. The identification of the Retinol Binding 

Protein interaction site and functional state of 

RBPs for the membrane receptor. Invited by 

FASEB J. (2007). In Press.

Nikita Gamper 

MS (St. Petersburg State University) 

PhD (Institute of Evolutionary Physiology and Biochemistry, St. Petersburg) 

Postdoctoral research, Tübingen University, Germany 

and UT Health Science Center at San Antonio, TX, USA 

Lecturer in Neuroscience (2005-) 

Contact: n.gamper@leeds.ac.uk 

Ion channels and regulation 

of cellular excitability 

Separation of electrical charges on the 

cell membrane is necessary for cell-tocell 

communication. Such separation 

is achieved by a coordinated work of 

different ion channels, transporters and 

pumps. Accordingly, dysfunction of 

ion channels causes human disease, 

including epilepsy and sudden 

cardiac death. We use cutting-edge 

biophysical, biochemical, molecular 

and cell-biological approaches to study 

ion channels and their involvement in 

regulation of cellular excitability. 

One focus of our research is the Kv7 

K + channels that control neuronal 

excitability and are involved in cardiac 

arrhythmias, epilepsy and deafness. 

In one project we recently showed the 

oxidative modification and upregulation 

of neuronal M channels by reactive 

oxygen species (ROS). Since ROS are 

produced during hypoxia or ischaemia 

in the brain, oxidative modification of M 

channels represents a mechanism for 

‘neuronal silencing’ in the precarious 

time when neurons may die. We study 

oxidative modification using cloned Kv7 

channels expressed in an immortalized 

cell line and native M channels 

in cultured primary neurons and 

organotypic hippocampal slice cultures. 

Other Kv7-related projects are focused 

on the regulation of channel trafficking, 

assembly at the plasma membrane and 

retrieval for degradation. We also study 

regulation of Kv7 channels by their 

auxiliary subunits. 

We are also interested in the regulation 

of neuronal ion channels by G-proteincoupled 

receptors (GPCRs), and how the 

specificity of GPCR-triggered signalling 

is achieved in a single neuron. The 

project is based on the recent discovery 

of signalling specificity among Gq/11- 

coupled receptors in the regulation of 

neuronal ion channels. Although coupled 

to similar signalling pathways, different 

receptor types have different effects. 

Recently we proposed a hypothesis 

of receptor-specific phospholipid 

signals (Figure 1) to account for such 

remarkable specificity, but further work 

is needed. We plan to study receptorspecific 

regulation of K + and Ca 2+ 

channels in sensory neurons, where 

such regulation is critical for pain 

sensation. Figure 2 shows measurement 

of bradykinin receptor activation by 

the translocation of a GFP-tagged 

membrane-localized PIP 2 

-sensitive 

probe, delivered to sensory neurons 

of trigeminal ganglia by a biolistic 

‘Gene Gun’. 

Funding: AHA 

Figure: 2 


Gamper, N, Li, Y & Shapiro, SM (2005) 

Structural requirements for subunit-specific 

modulation of KCNQ K + channels by Ca 2+ / 

Calmodulin. Molecular Biology of the Cell 16: 

3538–3551. 

Gamper, N, Reznikov, V, Yamada, Y, Yang, J 

& Shapiro, MS (2004) PIP 2 

signals underlie 

receptor-specific G q/11 

-mediated modulation of 

N-type Ca 2+ channels. Journal of Neuroscience 

24: 10980–10992 (see also subsequent 

review by Delmas, Coste, Gamper & Shapiro 

(2005) Neuron 47: 179–182). 

Gamper, N & Shapiro, MS (2003) Calmodulin 

mediates Ca 2+- dependent modulation of 

KCNQ2/3 potassium channels. Journal of 

General Physiology 122: 17–31. 

Huber, SM, Uhlemann, A-C, Gamper, NL, 

Duranton, C, Kremsner, PG & Lang, F (2002) 

Plasmodium falciparum activates endogenous 

Cl - channels of human erythrocytes by 

membrane oxidation. EMBO Journal 21: 

22–30. 

Figure: 1

Michael Harrison 

BSc Hons, PhD (Leeds) 

Lecturer in Biochemistry 

Contact: M.A.Harrison@leeds.ac.uk 

Structure and function 

of proton pumps 

The current focus of my work is on the 

vacuolar H + -ATPase, a large protein 

complex that uses energy from ATP 

to pump protons across biological 

membranes. This ‘acid pump’ is found in 

virtually all eukaryotic cells, playing key 

roles in the function of endomembranes. 

In osteoclastic bone cells, some kidney 

epithelial and some tumour cells, it is 

also found at the plasma membrane, 

where acts to pump acid out of the cell. 

Loss-of-function mutations in the genes 

encoding subunits of the V-ATPase 

can result in kidney disease, hereditary 

deafness or the bone thickening disease 

osteopetrosis, and because of its 

involvement in the processes of bone 

resorption and tumour metastasis, the 

V-ATPase has also attracted attention as 

a possible drug target. 

My interest in this key protein covers 

several areas: in structural biology, my 

lab is characterising the structures of the 

individual polypeptides that make up the 

V-ATPase and the contacts, both static 

and dynamic, that they make with each 

other. This is allied to advanced methods 

in electron microscopy which can provide 

detailed images of individual V-ATPase 

molecules trapped in different states 

(see picture). We are also asking questions 

about the site of binding and mechanism 

of action of V-ATPase inhibitors, answers 

to which may help in the design of new, 

more specific inhibitors with therapeutic 

potential. 

In the area of cell biology, work in the lab 

is focused on two questions: Firstly, how 

is the V-ATPase regulated in response to 

physiological demands? Secondly, how is 

location of the V-ATPase within the cell 

controlled? Relocation to the plasma 

membrane occurs during maturation 

of the osteoclasts and in some forms of 

tumour cell in response to extracellular 

signals, requiring changes in the 

interactions between V-ATPase and the 

cytoskeleton. The signalling mechanisms 

that control this process remain 

uncertain, but understanding them may 

be a crucial factor in the design of new 

drugs that prevent bone degeneration. 

Figure 2 (clockwise from top right): 

Osteoclasts dissolve bone as part of the 

normal cycle of skeleton repair. Cultured 

in the laboratory, they will attack the 

surface of bone wafers, providing a bone 

diseases model. Osteoclasts dissolve 

bone by forming an ‘acid bath’ on its 

surface – this requires the activity of the 

V-ATPase. Both natural and synthetic 

compounds inhibit the V-ATPase by 

binding to a specific region at the 

interface between two key membrane 

subunits. As a consequence, such 

compounds can act to block the process 

of bone resorption. 

Funding: Work in the lab is currently 

supported by BBSRC, and in the past by 

the European Union and Wellcome Trust. 

Figure 1 

Figure 2 


Jones RPO, Durose LJ, Phillips C, Keen JN, 

Findlay JBC & Harrison MA (2010) A site-directed 

cross-linking approach to the characterization of 

subunit E-subunit G contacts in the vacuolar H + - 

ATPase stator. Mol. Memb. Biol. in press 

Muench SP, Huss M, Song CF, Phillips C, 

Wieczorek H, Trinick J & Harrison MA (2009) 

Cryo-electron microscopy of the vacuolar ATPase 

motor reveals its mechanical and regulatory 

complexity. J. Mol. Biol. 386: 989-999 

Kóta Z, Páli, T, Dixon N, Kee T, Harrison M, Findlay 

JBC, Finbow ME & Marsh D (2008) Incorporation 

of transmembrane peptides from the vacuolar 

H + -ATPase in phospholipid membranes: spinlabel 

electron paramagnetic resonance and 

polarised infrared spectroscopy. Biochemistry 47: 

3937-3949 

Dixon N, Pali T, Kee TP, Ball SK, Harrison MA, 

Findlay JBC, Nyman J, Väänänen K, Finbow ME 

& Marsh D (2008) Interaction of spin-labelled 

inhibitors of the vacuolar H + -ATPase with the 

transmembrane V o 

-sector. Biophys. J. 94: 506–514 

Duarte AMS, Wolfs CJAM, Van Nuland NAJ, 

Harrison MA, Findlay JBC, Van Mierlo CPM & 

Hemminga MA (2007) Structure and localization 

of an essential transmembrane segment of the 

proton translocation channel of yeast H + -V- 

ATPase. Biophys. Biochim. Acta (Biomembranes) 

1768: 218-227 

Clare DK, Orlova EV, Finbow ME, Harrison MA, 

Findlay JBC & Saibil HR (2006) An expanded and 

flexible form of the vacuolar ATPase membrane 

sector. Structure 14: 1149-1156

Simon Harrison 

BSc (Leeds), PhD (Glasgow) 

Postdoctoral work with Prof D Bers, University of California (1986-1989) 

Convenor of HCM special interest group of the Physiological Society (2003-) 

Senior Lecturer (1999-) 

Contact: s.m.harrison@leeds.ac.uk 

Heart function in health 

and disease 

My research interests lie in 

understanding the mechanisms of 

normal excitation-contraction coupling 

in the heart, how these processes are 

regulated and how a variety of ‘disease 

states’ (hypertrophy, sepsis, etc) affect 

the strength of contraction of the heart. 

High blood pressure or ‘hypertension’ 

affects 10 million people in the 

UK (http://en.wikipedia.org/wiki/ 

Hypertension). In hypertensive patients 

the heart has to work harder to pump 

blood around the body and this 

causes the walls of the heart to thicken 

(hypertrophy). Eventually hypertrophy 

can lead to heart failure and associated 

with this progression are changes at 

the cellular level in the way heart cells 

contract. We have been studying the 

mechanisms associated with altered 

contraction and calcium regulation in 

normal and hypertrophied heart cells. In 

collaboration with Prof Ed White’s group 

we also compare ‘bad’ hypertrophy 

(above) with ‘good’ hypertrophy which 

occurs in athletes involved in endurance 

training. We aim to understand why 

bad hypertrophy leads to heart failure 

whereas good hypertrophy does not. 

Sepsis (http://en.wikipedia.org/wiki/ 

sepsis) is a potentially life-threatening 

condition associated with the release 

of inflammatory cytokines like tumour 

necrosis factor (TNF). These cytokines 

have direct inhibitory effects on the 

heart and contribute to cardiovascular 

complications. We have shown that 

combinations of TNF and interleukin-1ß 

dramatically increase the leakiness of the 

internal store of calcium so that it cannot 

contribute properly during the heart 

beat. In the right hand panel of Figure 1 

Figure 1 

the increased number of bright spots 

(‘sparks’) compared to the left hand 

panel represents increased leak of 

calcium from the store induced by these 

cytokines (see 2010 paper Cell Calcium). 

One consequence of severe sepsis is 

cell necrosis or death, and the contents 

of dying cells can be released into the 

vicinity of healthy cells. We are currently 

investigating the effects of histones (the 

normal function of which is to organise 

DNA in the nucleus) on cardiac function. 

Our initial experiments suggest that 

histones H3 and H4 induce very 

deleterious effects on the regulation 

of cytosolic calcium and therefore 

contractility in isolated ventricular 

myocytes. We aim to characterise their 

effects and identify a novel means of 

inhibiting these proteins which may 

prove therapeutically useful in patients 

suffering from severe sepsis. 

Funding sources for these projects 

include: The British Heart Foundation, 

Wellcome Trust, Royal Society and the 

Medical Research Council. 


Duncan DJ, Yang Z, Hopkins PM, Steele DS & 

Harrison SM (2010) TNF-α and IL-1β increase 

Ca2+ leak from the sarcoplasmic reticulum and 

susceptibility to arrhythmia in rat ventricular 

myocytes. Cell Calcium 47: 378-386 

Stones R, Billeter R, Zhang H, Harrison SM & 

White E (2009) The role of transient outward 

K+ current in electrical remodelling induced by 

voluntary exercise in female rat hearts. Basic 

Research in Cardiology 104: 643-652. 

Stones R, Natali A, Billeter R, Harrison SM & White 

E (2008) Voluntary exercise-induced changes 

in β2-adrenoceptor signalling in rat ventricular 

myocytes. Experimental Physiology 93: 1065- 

1075 

Fowler MR, Naz JR, Graham MD, Orchard CH & 

Harrison SM (2007) Age and hypertrophy alter 

the contribution of sarcoplasmic reticulum and 

Na+/Ca2+ exchange to Ca2+ removal in rat left 

ventricular myocytes. Journal of Molecular and 

Cellular Cardiology 42: 582-589

Peter Henderson 

BSc, PhD (Bristol); MA, ScD (Cambridge) 

Postdoctoral research, University of Madison, USA, Lecturer, University of Leicester (1973-75) 

Lecturer, University of Cambridge (1975-90), Visiting Research Professor, Jichi, Japan (1982-83) 

Reader, University of Cambridge (1990-92), Professor of Biochemistry and Molecular Biology 

University of Leeds (1992-), Canadian Commonwealth Research Fellow (1993), Dean of Research 

Faculty of Biological Sciences (1998-2002), Leverhulme Senior Research Fellow (2003-05) 

Scientific Director, European Membrane Protein consortium (EMeP) (2005-) 

Contact: p.j.f.henderson@leeds.ac.uk 

Membrane transport 

and antibiotic action 

I am interested in how cells transport 

nutrients, wastes and antibiotics 

across the essentially impermeable 

cell membrane. 

All cells are bounded by a lipid 

bilayer membrane that is inherently 

impermeable to the majority of 

hydrophilic solutes required for cell 

nutrition and to many of the waste 

products and toxins that must be 

excreted. Accordingly, the membrane 

contains proteins, the sole function of 

which is to catalyse the translocation of 

substrates through the membrane. The 

structure-activity relationships of these 

proteins are difficult to elucidate because 

they are of low natural abundance in the 

membrane; they are very hydrophobic; 

and, even when purified, they are very 

difficult to crystallize, which is just the 

beginning of determining their molecular 

mechanism of operation. 

As approximately 5-15% of all proteins, 

revealed by the current efforts in genome 

sequencing, are membrane transport 

proteins vital for the capture of nutrients 

(Figure 1), and hence the first stage 

in cell growth, there is an urgent need 

in the new millennium to determine 

their structures. Their additional roles 

in antibiotic resistance, toxin secretion, 

respiration, and ATP synthesis in bacteria 

(Figure 1), and neurotransmission, 

kidney function, intestinal absorption, 

tumour growth and other diverse cell 

functions in man presage a major 

investigative effort to elucidate their 

molecular mechanisms of action. 

We concentrate on bacterial transport 

proteins homologous to human 

transporters, and employ recombinant 

DNA methods to amplify their expression 

and genetically engineer ‘tags’ to 

facilitate purification and make mutants 

that illuminate their activities. A wide 

range of physical techniques are then 

applied, including fluorimetry, circular 

dichroism, mass spectrometry, EPR, 

X-ray crystallography and NMR. 

We have cloned over 50 transport 

proteins. Many, especially transporters 

of antibiotics and sugars, have been 

purified. Several form 3d crystals and 

diffract, and structures should result 

soon. We attract collaborators from 

abroad, and have well funded projects 

with scientists in Europe and in Glasgow, 

London and Southampton. 

Funding: BBSRC, EPSRC, EU, 

Wellcome Trust, Novartis 

Overseas collaborators in Belgium, 

France, Japan, Germany, Holland, 

Norway, Portugal, Sweden. 

Figure 1: General scheme of bacterial transport reactions 


Suzuki, S and Henderson, P.J.F. (2006) 

“The hydantoin transport protein from 

Microbacterium liquefaciens” J. Bacteriol. 

188, 3329-3336. 

Clough, J., Saidijam, M., Bettaney K.E., 

Szakonyi, G., Meuller, J., Suzuki, S., Bacon, 

M., Barksby, E., Ward, A., Gunn-Moore, F., 

O’Reilly, J., Rutherford, N.G., Bill, R.M. 

and Henderson, P.J.F. (2006) “Prokaryote 

membrane transport proteins: amplified 

expression and purification”. Structural 

genomics of membrane proteins (ed. 

Lundstrom, K.) pp.21-42. CRC Press, USA. 

Saidijam, M., Benedetti, G., Ren, Q., Zhiqiang, 

X., Hoyle, C.J., Palmer, S.L., Ward, A., 

Bettaney, K.E., Szakonyi, G., Meuller, J., 

Morrison, S., Pos, M.K., Butaye, P, Walravens, 

K., Langton, K., Herbert, R.B., Skurray, R.A., 

Paulsen, I.T., O’Reilly, J., Rutherford, N.G., 

Brown, M.H., Bill, R.M. and Henderson, P.J.F. 

(2006) “Microbial Drug Efflux Proteins of the 

Major Facilitator Superfamily”, in Current Drug 

targets 7, pp. 793-811. 

Patching, S.G., Herbert, R.B., O’Reilly, J., 

Brough, A.R. and Henderson, P.J.F. (2004) 

“Low 13C-background for NMR-based studies 

of ligand binding using 13C-depleted glucose 

as carbon source for microbial growth”. J. Am. 

Chem. Soc. 126, 86-87.

Arun Holden 

BA (Oxford, UK) 

PhD (Alberta, Canada) has been at Leeds since 1971, and is currently Professor of Computational Biology, 

and Deputy Director, Centre for Nonlinear Studies, and is an editor of several nonlinear science journals 

and two book series on Nonlinear Science. 

Contact: arun@cbiol.leeds.ac.uk 

Computational 

Biology 

(a) The Computational Biology laboratory 

constructs detailed computer models 

of muscular organs - the beating heart, 

and the pregnant uterus - that are based 

on data from membrane, cell and tissue 

experiments, and from clinical data. 

These models are validated by their 

prediction of normal organ behaviour, 

and abnormal behaviours seen in 

disease. They are applied to dissect, 

in space and time, physiological and 

pathological mechanism, to prescreen 

drugs, and to contribute to the drug 

design and discovery process, and the 

design of physical interventions. 

(b) Most of our research has been in the 

construction of cardiac virtual tissues, 

and these are now being applied to 

biomedical problems. Application areas 

include the normal pacemaking of the 

heart and its pharmacological control; 

the genetic engineering of pacemaking 

activity in the ventricles, as an alternative 

to implanted electronic pacemakers; 

the initiation and control of re-entrant 

arrhythmias in the atria and ventricles; 

the effects of drugs on propagation 

phenomena within the heart; and the 

effects of electrical and very large 

magnetic fields on the behaviour of the 

in situ heart. The same methodology, of 

developing and applying virtual tissues, 

is being applied to model uterine activity 

and possible mechanisms in premature 

and normal labour. 

(c) An important new development has 

been the extraction of structural data, 

(geometry, cell orientation) from diffusion 

tensor magnetic resonance imaging of 

tissues; this allows the reconstruction of 

a 3-D detailed digital map of an organ in 

a few days, rather than the months-years 

necessary for histological reconstruction. 

Funding: Computational Biology Leeds 

is funded by project, programme and 

network grants from the BBSRC, EPSRC, 

MRC, BHF, EU and Sun Microsystems 

Figure 1: Reconstructed geometry of gravid human 

uterus, side view 

Figure 2: Simulation of electrical activity producing a 

contraction in a near full term uterus, front view 

Figues 3 & 4: Reconstructed ventricular geometry, 

and visualsiation of electrical activity during 

simulated fibrillation 

Figure 4 


Tong WC, Holden AV. (2005) Induced 

pacemaker activity in virtual mammalian 

ventricular cells, Lecture Notes in Computer 

Science, 3504: 226-235 

Zhang HG, Garratt CJ, Zhu JJ, et al. (2005) 

Role of up-regulation of I-K1 in action 

potential shortening associated with atrial 

fibrillation in humans. Cardiovascular Research 

66 (3): 493-502 

Holden AV. (2005) The sensitivity of the 

heart to static magnetic fields. Progress in 

Biophysics and Molecular biology, 87: 

289-320 

Aslanidi OV, Clayton RH, Lambert JL, 

Holden AV. (2005) Dynamical and cellular 

electrophysiological mechanisms of ECG 

changes during ischaemia. J.Theoretical 

biology 237: 369-381.

Ronaldo Ichiyama 

BSc Lic Universidade Estadual de Campinas (Brazil) 

MSc, PhD University of Illinois at Urbana-Champaign (USA) 

Postdoctoral Fellow University of California Los Angeles (USA) 

Contact: r.m.ichiyama@leeds.ac.uk 

More information: http://www.fbs.leeds.ac.uk/staff/profile.php?tag=Ichiyama_RM 

Structural and Functional Plasticity in the CNS activity 

dependent plasticity in the spinal cord 

Neural Control of Movement 

The mechanisms related to the neural 

control of movement in mammalian 

systems are largely unanswered, simply 

because the intricacies of interneuronal 

communication and computations 

necessary to produce coordinated, 

voluntary movements are of such 

complexity that we have only begun 

to understand them. Relative to the 

overwhelming complexity of the 

supraspinal control of movement, the 

spinal neural circuits provide a simpler 

model to investigate motor control 

issues. This does not, however, imply 

that spinal control of movement in 

mammalian species is a simple model. 

My research has focused on the changes 

within the spinal cord that occur after 

a complete spinal cord transection and 

on the activity-dependent plasticity 

in the spinal neural circuits associated 

with locomotor training after the spinal 

cord injury. We have used behavioural, 

immunohistochemical, electron 

microscopic and electrophysiologic 

methods to investigate those issues. 

The combined results strongly suggest 

that the biochemical, structural, and 

electrophysiological properties of 

motoneurons change dramatically 

within the spinal cord isolated from the 

brain, which are altered by locomotor 

training. Understanding these processes 

in detail will provide critical insight into 

the mechanisms involved in the control 

and learning of movements within 

spinal cord neural circuits. 

Neural Control of Cardiorespiratory 

Function in Exercise 

Another interest in my lab is the neural 

control of cardiovascular function 

related to movement production and 

exercise. During muscular activity, two 

basic mechanisms control cardiovascular 

adjustments: a central command and 

a reflex arising from the contracting 

muscles, which is dependent on 

medullary centers. I have investigated 

issues related to both of those 

mechanisms. We have implicated higher 

cortical centers (insular cortex) in the 

central command circuitry. In addition, 

I have demonstrated that specific 

locomotor and cardiovascular control 

areas in the brain change with exercise 

training. The posterior hypothalamus 

nucleus, the mesencephalic locomotor 

region, periaqueductal grey, nucleus 

of the tractus solitarius and the 

rostral ventrolateral medulla showed 

diminished, possibly more efficient, 

activation profiles (cfos) in exercised 

than in non-exercised rats in response to 

a single bout of controlled exercise. 

Spinal Cord Injury, Neural 

Regeneration and Functional 

Recovery 

After a spinal cord injury, the remaining 

unaffected spinal tissue changes to 

a great extent. A successful neural 

regenerative strategy will have to 

overcome not only all the obstacles 

that the injury site itself presents (glial 

scaring, physical gap, etc.) but also 

a new environment that has formed 

below the level of the lesion. We 

hypothesize that the beneficial effects 

of locomotor training will potentiate the 

effects of regenerative strategies. We 

have combined locomotor training with 

different potential neural regenerative 

strategies, with both positive and 

surprising results. Given the nature of 

spinal cord injuries, we firmly believe 

that only a combination strategy will be 

effective in regenerating and forming 

functional synaptic reconnections after 

an injury. 

We have developed a technique to 

epidurally stimulate the spinal cord, 

which produces alternating and 

coordinated steps in completely 

spinalized adult rats. This technique 

allows us to study the control of 

locomotion in an in vivo adult 

mammalian preparation, which was not 

possible previously. We have used this 

technique to investigate reflex control 

mechanisms in the intact spinal cord and 

also after a complete spinal transection. 

Motoneurones (green) activated (red nuclei) during locomotion, 

visualized by immunofluorescence techniques. 


Maier IC*, Ichiyama RM*, Courtine G* et al. (2009) 

Differential effects of anti-Nogo –A antibody 

treatment and treadmill training in rats with 

incomplete spinal cord injury. Brain 132:1426-40 

*these authors contributed equally 

Ichiyama R et al. (2009) Enhanced motor function 

by training in spinal cord contused rats following 

radiation therapy. PLoS One 4(8): e6862 

Courtine G et al. (2009) Transformation of 

nonfunctional spinal circuits into functional 

states after the loss of brain input. Nature 

Neuroscience 12(10): 1333-1342 

Ichiyama RM et al. (2008) Step Training Reinforces 

Specific Spinal Locomotor Circuitry in Adult 

Spinal Rats. Journal of Neuroscience 28(29):7370- 

7375 

Ichiyama RM et al. (2008) Dose Dependence of 

the 5-HT Agonist Quipazine in Facilitating Spinal 

Stepping in the Rat with Epidural Stimulation. 

Neuroscience Letters 438 (3): 281-285

Lars Jeuken 

BSc/MSc, Utrecht University, the Netherlands (1990-1995) 

PhD, Leiden University, the Netherlands (Promotor: Prof. G.W. Canters) (1995-1999) 

Postdoctoral research, University of Oxford, UK (Supervisor: Prof. F.A. Armstrong) (1999-2002) 

Postdoctoral research, (Supervisor: Prof. S.D. Evans) (2002), BBSRC David Phillips Research Fellow, University of Leeds, 

UK (2002-2007) 

Senior Lecturer, University of Leeds, UK (2007-) 

Contact: l.j.c.jeuken@leeds.ac.uk 

Transmembrane charge transport 

and biological electron transfer 

The lab is active in the development of 

new tools to elucidate charge transport 

mechanisms of membrane proteins and 

enzymes. Charge transport through 

membranes is an ubiquitous and key 

process in – for instance - metabolism, 

photosynthesis, active membrane 

transport and signal transduction. 

The ultimate aim is to understand the 

charge transport activities of membrane 

proteins in mechanistic and – where 

structural information is available - 

molecular detail. A method developed 

at the University of Leeds allows a 

biological membrane (containing the 

protein of interest) to be ‘tethered’ 

to a solid surface which can act as 

an electrode (i.e. solid supported 

membranes). Using electrochemical 

systems based on this technique we 

are trying to create a generation of 

electrodes that are widely applicable to 

a range of membrane proteins. 

We are also interested in the 

mechanisms of action of redox proteins 

and enzymes, both membrane and 

glubular. Redox proteins function 

in transporting electrons between 

proteins and oxidase and reduce a 

wide range of substrates. By optimising 

electrode design and combining 

electrochemistry with fluorescence 

techniques we aim to obtain functional 

information about reaction mechanisms 

for transmembrane enzymes, like 

cytochrome c oxidase, and globular 

enzymes, like the copper-containing 

nitrite reductase. 

Objectives 

One objective is to design and create 

novel electrodes that can be used 

to study a wide range of membrane 

proteins. In order to do this we need to 

understand the structural properties of 

electrodes that can electrically interact 

with the membrane proteins. By 

thorough surface characterisation using 

microscopy and spectroscopy we hope 

to improve existing electrode designs. 

Secondly, we use these new tools to 

study catalytic mechanisms of redoxactive 

and transport proteins in their 

native environment. 

More information: http://www.fbs.leeds. 

ac.uk/staff/profile.php?tag=Jeuken_LJC 


Kendall JKR, Johnson BRG, Symonds PH, 

Imperato G, Bushby RJ, Gwyer JD, van Berkel 

C, Evans SD, Jeuken LJC (2010) Effect of the 

Structure of Cholesterol-Based Tethered Bilayer 

Lipid Membranes on Ionophore Activity. 

ChemPhysChem 11: 2191-2198. DOI: 10.1002/ 

cphc.200900917 

Jeuken LJC (2009) Electrodes for integral 

membrane enzymes. Nat. Prod. Rep. 26: 1234- 

1240. DOI:10.1039/B903252E 

Weiss SA, Bushby RJ, Evans SD, Henderson 

PJF, Jeuken LJC (2009) Characterisation of 

cytochrome bo3 activity in a native-like surfacetethered 

membrane. Biochem. J. 417: 555-560. 

DOI:10.1042/BJ20081345 

Jeuken LJC, Weiss SA, Henderson PJF, Evans SD, 

Bushby RJ (2008) Impedance Spectroscopy of 

Bacterial Membranes: Coenzyme-Q Diffusion in a 

Finite Diffusion Layer. Anal. Chem. 80: 9084-9090. 

DOI:10.1021/ac8015856 

Wijma HJ, Jeuken LJC, Verbeet MP, Armstrong 

FA, Canters GW (2007) Protein Film Voltammetry 

of Copper-containing Nitrite Reductase reveals 

Reversible Inactivation. J. Am. Chem. Soc. 129: 

8557-8565. DOI: 10.1021/ja071274q 

Jeuken LJC, Connell SD, Henderson PJF, Gennis 

RB, Evans SD, Bushby RJ (2006) Redox Enzymes 

in Tethered Membranes. J. Am. Chem. Soc. 128: 

1711-1716

Lin-Hua Jiang 

BSc and MSc, East China Normal University, P.R. China 

PhD with D Wray, University of Leeds 

Postdoc with RA North, University of Sheffield 

Wellcome Trust University Award (2004) 

Contact: L.H.Jiang@leeds.ac.uk 

Structure, function and regulation 

of ion channels 

Our research aims to understand 

molecular mechanisms determining the 

expression, function and regulation of 

Ca2+ permeable ion channels and their 

roles in cellular Ca2+ signalling, with 

particular interest in ATP-gated P2X 

receptors and TRP channels. 

P2X receptors are homo/hetero-trimers 

and function as extracellular ATPgated 

channels with multifarious roles, 

including fertility, pain sensation, taste 

and immune response. We are working 

at two leading forefronts. One is to 

understand where the ATP-binding 

site is, how ATP binding is coupled to 

channel opening and how the open 

pore permeates cations and the other is 

to elucidate the molecular or structural 

basis specifying interactions of P2X7 

receptors with selective antagonists 

and modulators so as to search for 

specific and potent human P2X7 

receptor antagonists for therapeutic 

use in rheumatoid arthritis and other 

inflammatory diseases. 

Figure 1 

TRPM2 is a melastatin-related member 

of transient receptor potential channel 

superfamily. TRPM2 channel is homotetrameric 

assembly and opens upon 

binding of intracellular ADP-ribose. 

TRPM2 channel activation also occurs 

in response to oxidative stress, and 

thus TRPM2 channel act as a cellular 

redox potential sensor. Important 

physiological and particularly 

pathophysiological roles have emerged, 

extending from insulin release, cytokine 

production, endothelial barrier 

dysfunction, to neuronal destruction. 

In collaboration with Prof. DJ Beech 

and other colleagues at Leeds, we are 

studying the molecular mechanisms 

controlling TRPM2 channel expression, 

assembly, function and regulation and 

its role in the pathogenesis of oxidative 

stress-related diseased conditions 

such as neurodegenerative and 

cardiovascular diseases. 

Funding: BBSRC, Wellcome Trust, Royal 

Society and Alzheimer’s Research Trust. 


Browne LE, Jiang L-H and North RA (2010) New 

structure enlivens interest in P2X receptors. 

Trends Pharmacol. Sci. 31: 229-237 

Roger S, Mei Z, Baldwin JM, Bradley H, Dong L, 

Baldwin SA, Surprenant A and Jiang L-H (2010) 

Single nucleotide polymorphisms that were 

identified in affective mood disorders affect ATPactivated 

P2X7 receptor functions. J. Psychiatr. 

Res. 44: 347-355 

Milligan CJ, Li J, Sukumar P, Majeed Y, Dallas 

ML, English A, Emery P, Porter KE, Smith AM, 

McFadzean I, Beccano-Kelly D, Bahnasi Y, Cheong 

A. Naylor J, Zeng F, Liu X, Gamper N, Jiang L-H, 

Pearson HA, Peers C, Robertson B and Beech DJ 

(2009) Robotic multi-well planar patch-clamp for 

native and primary mammalian cells. Nat. Protoc. 

4: 244-255 

Liu X, Ma W, Surprenant A and Jiang L-H (2009) 

Identification of extracellular domain residues of 

rat P2X7 receptor involved in functional inhibition 

by acidic pH. Br. J. Pharmacol. 156: 139-142 

Li J, Sukumar P, Milligan CJ, Kumar B, Ma Z, 

Munsch MC, Jiang L-H, Porter KE and Beech BJ 

(2008) Interactions, functions and independence 

of plasma membrane STIM1 and TRPC1 in 

vascular smooth muscle cells. Circ. Res. 103: 

e97-104 

Xia R, Mei Z, Mao H, Yang W, Dong L, Bradley H, 

Beech DJ and Jiang L-H (2008) Identification of 

pore residues engaged in determining divalent 

cationic permeation in transient receptor 

potential melastatin subtype channel. J. Biol. 

Chem. 283: 27426-27432 

Xu SZ, Sukumar P, Zeng F, Li J, Jairaman A, 

English A, Naylor J, Ciurtin C, Majeed Y, Milligan 

CJ, Bahnasi YM, Al-Shawaf E, Porter KE, Jiang 

L-H, Emery P, Sivaprasadarao A and Beech DJ 

(2008) TRPC channel activation by extracellular 

thioredoxin. Nature 451: 69-72 

Liu X, Surprenant A, Mao HJ, Roger S, Xia R, 

Bradley H and Jiang L-H (2008) Identification of 

key residues coordinating functional inhibition 

of P2X7 receptors by zinc and copper. Mol. 

Pharmacol. 73: 252-259

Anne King 

BSc (Aberdeen) 

PhD (Southampton) 

MRC Post-doctoral Research Fellowship, St Bartholomews HMC, London 

Wellcome Trust Research Fellow, University College London 

Lecturer & Senior Lecturer, University of Leeds 

Reader, Institute Membrane & Systems Biology Affiliations, Neuroscience, Integrative & Membrane Biology 

Contact: a.e.king@leeds.ac.uk 

Spinal Mechanisms of Somatosensation, 

Pain and Analgesia 

The focus of our work is modulation 

of somatosensory processing in the 

spinal dorsal horn with an emphasis 

on synaptic transmission between 

peripheral sensory afferents and 

target spinal neurons that underpin 

nociception (pain). From a clinical 

perspective, the effective treatment of 

chronic debilitating pain represents a 

huge scientific challenge. An important 

aspect of our research, undertaken 

with industrial collaborators, is to 

identify novel targets for development 

of new-generation analgesics. Our work 

provides an understanding of the basic 

neurobiology and neuropharmacology 

of pain at the level of spinal cord and 

periphery, building a platform for drug 

discovery and therapeutic advances for 

clinical pain management. Current work 

includes the following. 

(1) Adenosine and nucleoside 

transporters in spinal cord: the 

nucleoside adenosine has potent antinociceptive 

actions that may contribute 

to the body’s endogenous analgesic 

(pain-relieving) system. Its intracellular 

and extracellular distribution is critically 

dependent on CNT and ENT transporter 

proteins. We are currently defining the 

function and distribution of ENT and 

CNT nucleoside transporter subtypes 

in normal spinal cord and in models of 

persistent (inflammatory) pain. 

(2) Rhythmicity in spinal dorsal horn 

sensory processing: rhythmicity 

underpins many basic central nervous 

system functions, such as sensory 

binding and motor output. In the dorsal 

horn, we are characterizing synaptic 

(GABA-ergic) and non-synaptic (gapjunction) 

mechanisms of synchronized 

dorsal-horn ensemble activity in vitro 

and determining novel modulatory 

influences of analgesic drug families 

(3) The trigeminal system and orofacial 

pain: the mechanisms of usedependent 

synaptic plasticity in the 

trigeminal system that occur as a 

consequence of prolonged neuronal 

activation (e.g. chronic dental and facial 

pain). In this joint project with Professor 

Boissonade (Sheffield) the aim is to 

investigate stimulation–transcription 

coupling and the signalling cascades 

that are activated following prolonged 

nociceptive afferent input. We are 

examining these mechanisms in the 

trigeminal nucleus using molecular 

markers (Fos, pERK, CREB) of neuronal 

activation and plasticity. 

Figure 1 Schematic model for regulation 

of ‘pain signaling’ by ENT1 nucleoside 

transporters in spinal dorsal horn. In 

substantia gelatinosa (SG), glutamate 

(GLU) excites ‘nociceptive’ neurons 

that signal ‘pain’ inputs. Adenosine 

(ADO) elicits anti-nociception via presynaptic 

receptors (A1R), an effect 

that is mimicked by blocking the ENT1 

transporter. The opioid receptor (MOR) 

induces release of ADO via modulation 

of ENT1. 

Funding: Wellcome Trust, BBSRC, 

GlaxoSmithKline. 


www.fbs.leeds.ac.uk/staff/king/ 

Figure 1 


Governo, RJM, Deuchars, J, Baldwin, SA & 

King, AE (2005) Localisation of the NBMPRsensitive 

equilibrative nucleoside transporter 

ENT1 in the rat dorsal root ganglia and lumbar 

spinal cord. Brain Research 1059: 129–138. 

Asghar, AU, Cilia La Corte, PF, LeBeau, 

FE et al. (2005) Oscillatory activity within 

rat substantia gelatinosa in vitro: a role for 

chemical and electrical neurotransmission. 

Journal of Physiology (London) 562: 183–198. 

Worsley, MA, Todd, AJ & King, AE (2005) 

Serotoninergic-mediated inhibition of 

substance P-sensitive deep dorsal horn 

neurons: a combined electrophysiological and 

morphological study in vitro. Experimental 

Brain Research 160: 360–367. 

Ackley, MA & King, AE (2005) Adenosine 

contributes to μ-opioid synaptic inhibition in 

rat substantia gelatinosa in vitro. Neuroscience 

Letters 376: 102–106.

Matthew Lancaster 

BSc (Leeds) 

PhD (Liverpool) 

Postdoctoral research at Leeds 

Lecturer in Exercise Physiology (2003-) 

Contact: m.k.lancaster@leeds.ac.uk 

Cardiac Ageing Leads to 

Cardiac Problems 

My group’s research is directed towards 

understanding what happens to our 

hearts as we age. Age is the single 

biggest risk factor for developing cardiac 

problems but unlike several other known 

risk factors for cardiac problems such 

as diet and blood pressure ageing is 

currently unavoidable, unfortunately 

you can’t just give up ageing! By 

studying ageing of the heart though 

we are seeking to identify the specific 

mechanisms whereby ageing renders the 

heart susceptible to problems and assess 

the potential for suitable interventions to 

optimise ageing of the heart. 

Two major issues affecting the ageing 

heart are a steadily reducing maximal 

heart rate associating with a reduction 

in maximal functional capacity and 

accompanying this an increasing 

susceptibility to cardiac arrhythmias. 

These heart rhythm control problems 

can lead to an increasing intolerance to 

exercise/exertion and also mean the large 

majority of artificial pacemaker implants 

are performed in patients over the age 

of 65 because their normal cardiac 

pacemaker appears to have begun to fail. 

Every beat of the heart begins in a cell 

such as that shown in figure 1. We have 

shown that with ageing the electrical 

coupling of these cells to the rest of the 

heart begins to deteriorate and they 

also begin to change their expression of 

several ion channels that are normally 

responsible for their electrical activity. 

Disconnected and dysfunctional this is 

why we believe the pacemaker of the 

heart begins to fail with age. Knowledge 

of this is already beginning to raise 

questions regarding how we treat cardiac 

conditions in patients with an aged heart 

but we are also expanding this work 

investigating the effects of restoring 

connections and modifying excitability in 

an attempt to restore youthful function. 

Of course it’s unfortunately not just the 

cardiac pacemaker that ages we have 

found plenty of ageing related changes 

happening elsewhere in the heart. Some 

of these such as changes in intracellular 

calcium regulation could predispose to 

arrhythmias and damage in the event of 

a heart-attack. We have been looking at 

how to limit or reverse age-associated 

problems using exercise, acute or 

life-long. The effects have been pretty 

interesting with exercise affecting the 

aged heart more than the young heart in 

terms of changes in gene expression but 

unfortunately not all these changes may 

be beneficial and regrettably exercise 

does not prove to reverse ageing of the 

heart. Continuation of this work will 

however offer further insight and how to 

prevent ageing of the heart turning into 

failing of the heart. 

Funding: Wellcome Trust and the 

Strategic Promotion of Ageing Research 

Capacity, a BBSRC/EPSRC joint venture 

Overseas collaborators: Haruo Honjo 

(Japan) 


www.fbs.leeds.ac.uk/staff/lancaster/ 

Figure 1: A typical pacemaker cell. 


Jones SA, Yamamoto M, Tellez JO, Billeter-Clark 

R, Boyett MR, Honjo H & Lancaster MK (2008) 

Distinguishing properties of cells from the 

myocardial sleeves of the pulmonary veins; a 

comparison of normal and abnormal pacemakers. 

Circulation: Arrhythmia & Electrophysiology 1: 

39-48 

Jones SA, Boyett MR., Lancaster MK. (2007) 

Declining into failure: The age-dependent loss of 

the L-type calcium channel within the sinoatrial 

node. Circulation 115: 1183-90 

Lancaster MK, Jones SA, Harrison SM & Boyett MR 

(2004) Intracellular Ca 2+ and pacemaking within 

the rabbit sinoatrial node: heterogeneity of role 

and control. Journal of Physiology 556: 481–494 

Jones SA, Lancaster MK & Boyett MR (2004) 

Ageing-related changes of connexins and 

conduction within the sinoatrial node. Journal of 

Physiology 560: 429–437 

Honjo H, Inada S, Lancaster MK et al. (2003) 

Sarcoplasmic reticulum Ca 2+ release is not a 

dominating factor in sinoatrial node pacemaker 

activity. Circulation Research 92: 41–44

Jonathan Lippiat 

BSc (Leicester) 

PhD (Leicester) 

Postdoctoral research at Oxford 

Junior Research Fellow, Linacre College Oxford, Lecturer (2004-) 

Contact: j.d.lippiat@leeds.ac.uk 

Electrophysiology and molecular 

biology of ion channels 

Our research explores the molecular 

and cellular properties of ion 

channels, how they can be targeted 

by drugs, and why particular genetic 

variations cause disease. A number of 

laboratory techniques are employed: 

electrophysiology, protein biochemistry, 

DNA manipulation, optical imaging 

and FRET. 

CLC-5 chloride channel 

These proteins are found in the kidney 

and are involved in the reabsorption of 

protein, minerals and vitamins back into 

the body from the glomerular filtrate. 

Loss of functional CLC-5 channels 

by inherited genetic mutation causes 

Dent’s disease, resulting in kidney 

stones and eventual kidney failure. 

Our studies will help understand why 

very small changes in particular regions 

of the chloride channel structure 

(Figure 1) can affect protein function 

and result in disease. 

Intracellular ion-regulated 

potassium channels 

We are studying a family of ion 

channels activated by intracellular 

ion concentrations, enabling them to 

regulate cellular events. Members of 

this family of channels are differentially 

sensitive to calcium, magnesium, 

sodium (Figure 2) and chloride ions. 

Pharmacology 

Ion channels are interesting targets 

for drug action in a wide range of 

diseases. Activation of potassium 

channels in smooth muscle cells would 

have a relaxing effect and may have 

applications in the treatment of blood 

pressure, asthma and incontinence. In 

the brain, activation of these channels 

would reduce neuronal activity and 

could help treat epilepsy or stroke. 

Our research helps to identify which ion 

channels are valid drug targets for the 

treatment of particular diseases. 

Modulation by 

protein interaction 

Ion channels are rarely isolated 

structures in cell membranes, 

but associate with other proteins. 

Interactions affect how the channels 

behave and their drug sensitivity. One 

protein can have different physiological 

roles in different cell types, and 

particular protein assemblies present 

more cell-specific drug targets. We are 

investigating how different ion-channel 

proteins co-assemble and which 

other types of protein interact with ion 

channels to alter their properties. 

Funding: Wellcome Trust, BBSRC 

Figure 1: Model of a CLC Cl − channel structure. 

Figure 2: Single Na +- activated K + channels. 


Toye, AA, Lippiat, JD, Proks, P et al. (2005) 

A genetic and physiological study of impaired 

glucose homeostasis control in C57BL/6J 

mice. Diabetelogia 48: 675–686. 

Proks, P, Antcliff, JF, Lippiat, J, Gloyn, 

AL, Hattersley, AT & Ashcroft, FM (2004) 

Molecular basis of Kir6.2 mutations associated 

with neonatal diabetes or neonatal diabetes 

plus neurological features. Proceedings of 

the National Academy of Sciences USA 50: 

17539–17544. 

Tsuboi, T, Lippiat, JD, Ashcroft, FM & Rutter, 

G (2004) ATP-dependent interaction of the 

cytosolic domains of the inwardly rectifying 

K + channel Kir6.2 revealed by fluorescence 

resonance energy transfer. Proceedings of 

the National Academy of Sciences USA 101: 

76–81.

David Marples 

BA in Physiological Sciences (Oxford) (1984) 

MA, BM. BCh. (Oxford) (1990) 

D.Phil in Physiology (Oxford) (1990) 

House jobs (surgery in High Wycombe & medicine in Oxford) (1990/91) 

Post-Doc with A Taylor (Oxford) (1991-1993) 

Assistant Professor with Søren Nielsen, Aarhus, Denmark (1993-1996) 

University Research Fellow, Leeds (1996-2001) 

Lecturer, University of Leeds (2001-2006) 

Senior Lecturer, University of Leeds (2006-) 

Contact: d.d.r.marples@leeds.ac.uk 

Aquaporin water channels 

and the kidney in health and disease 

My research group is interested in how 

the regulation of the expression and 

distribution of aquaporins in the kidney 

helps us to maintain a normal body fluid 

composition, and how these processes 

are disrupted in disease. Ultimately, 

we hope to be able to correct these 

pathological disorders, and maybe use 

the defects therapeutically, for example 

to generate novel diuretics. 

Aquaporin 2 (AQP2) water channels 

are found in the principal cells of the 

renal collecting duct. They shuttle to 

the cell surface in response to 

antidiuretic hormone, allowing the 

reabsorption of water, and production 

of a concentrated urine. This acute 

response is modulated by changes in 

AQP2 expression, for example due to 

chronic water deprivation. 

Defects in the acute trafficking of 

AQP2 cause nephrogenic diabetes 

insipidus (NDI), in which patients 

produce huge volumes of urine. This 

disrupts their lives very badly, and 

can lead to dehydration and brain 

damage, especially in babies. We are 

looking for alternative ways to drive this 

trafficking, and so overcome the defect. 

Some drugs alter AQP2 expression: 

for example, lithium greatly decreases 

its expression, leading to NDI. We are 

studying the factors which regulate 

AQP2 expression. This may help us 

treat patients with this type of NDI by 

increasing AQP2, and may allow us 

to decrease AQP2, to increase water 

loss in fluid-retaining states such as 

congestive heart failure. 

Other aquaporins (1, 3, 4, 6, 7, 8, and 

11) are also found in the kidney: with 

the exception of AQP1 their roles are 

much less well understood. We plan to 

study some of these aquaporins, and 

see if they can also be useful in treating 

human disease. 

Aquaporins are also found in many other 

places in the body: we are studying this 

in collaboration with other groups in the 

UK and abroad. 

A second topic of interest is the 

organisation of microtubules in 

epithelia, and their role in vesicle 

trafficking, including that of AQP2 in 

collecting duct cells. 

Figure 1: AQP2 shuttling. In the top, control panel, AQP2 

(shown in red) lies within the cells. After ADH (bottom 

panel), it is in the plasma membrane, together with the 

green membrane marker. 

Figure 2: Effect of Lithium on AQP2 expression : 

AQP2 is decreased by about 95% 

Funding: MRC, Kidney Research UK 



php?staff=DDRM 


Baggaley E, Nielsen S, Marples D (2010) 

Dehydration-induced increase in aquaporin-2 

protein abundance is blocked by nonsteroidal 

anti-inflammatory drugs. American Journal of 

Physiology 298: F1051-F1058 

Lutken SC, Kim SW, Jonassen T, Marples D, 

Knepper MA, Kwon TH, Frokiaer J, Nielsen S 

(2009) Changes of renal AQP2, ENaC, and NHE3 in 

experimentally induced heart failure: response to 

angiotensin II AT(1) receptor blockade. American 

Journal of Physiology 297: F1678-F1688 

Floyd RV, Mason SL, Proudman CJ, German AJ, 

Marples D, Mobasheri A (2007) Expression and 

nephron segment-specific distribution of major 

renal aquaporins (AQP1-4) in Equus caballus, the 

domestic horse American Journal of Physiology, 

293: R492-R503 

Shaw S & Marples DDR (2005) N-ethylmaleimide 

causes aquaporin-2 trafficking in the renal inner 

medullary collecting duct by direct activation of 

protein kinase A. American Journal of Physiology, 

288: 832 – 839 

Mobasheri A, Marples DDR (2004) Expression 

of the AQP-1 water channel in normal human 

tissues: a semiquantitative study using tissue 

microarray technology. American Journal of 

Physiology 286: C529-C537 

Christensen BM, Marples DDR, Kim YH, Wang WD, 

Frokiaer J, Nielsen S (2004) Changes in cellular 

composition of kidney collecting duct cells in rats 

with lithium-induced NDI. American Journal of 

Physiology 286: C952-C964 

Shaw S & Marples DDR (2002) A rat kidney tubule 

suspension for the study of vasopressin-induced 

shuttling of AQP2 water channels. American 

Journal of Physiology 283: F1160-F1166

Neil Messenger 

BSc (Salford) 

PhD (Salford) 

Postdoctoral research, University of Salford 

Lecturer in Sport Biomechanics, University of Brighton 

Lecturer in Sport and Exercise Biomechanics (1995-) 

Contact: n.messenger@leeds.ac.uk 

Biomechanics of 

lower limb function 

The principle research undertaken in this 

programme examines the biomechanical 

aetiology of overuse injury in sport and 

exercise and we are also interested in the 

mechanical adaptation to locomotion 

under various external conditions or 

novel environments. 

Overuse injuries of the lower limb are 

common in most sports and can, in 

extreme cases, result in the complete 

withdrawal of an athlete from their 

chosen activity. These injuries affect 

athletes across the full spectrum of 

performance levels, from elite to 

recreational, and have a significant impact 

on sport and exercise participation. It has 

long been postulated that an individual’s 

susceptibility to such injuries is in part 

due to their particular musculoskeletal 

structure and the coupling of limb motion 

across a number of joints. In particular 

these injuries have been associated with 

malfunction of the subtalar joint and its 

supporting structures. This joint has often 

been described as a torque converter 

in the transition of motion above the 

support foot during repetitive activities 

such as running. However, recent work 

has shown that, although this mechanism 

is apparent in both running and walking, 

the rigidity of the coupling is less than 

previously thought and that interaction 

between the forefoot and the lower 

limb is as important as that between the 

rearfoot and the lower limb. Future work 

seeks to develop a more complete model 

of these interactions. 

Many gait irregularities are functions of 

poor or improper control of locomotion. 

The consequences of these, as in trips and 

falls in the elderly, can be devastating. 

Sport provides a useful model for the 

analysis of the control mechanisms 

used to maintain effective and efficient 

gait as it provides a number of well 

defined environments in which to 

investigate perturbations to and stresses 

on the locomotor apparatus. Current 

research focuses on: the effect of surface 

interaction and footwear: limb segment 

coordination in gait: the control of 

balance in activities such as archery. 

Figure 1: Still image from computer animation of 

human walking: bonecolour depth indicates 


http://www.leeds.ac.uk/sports_science/ 

staff/nm.htm 


Pohl MB, Messenger N & Buckley JG (2006) 

Changes in foot and lower limb coupling due 

to systematic variations in step width. Clinical 

Biomechanics 21: 175–183 

Bailey M, Maillardet FJ & Messenger N (2003) 

Kinematics of cycling in relation to anterior knee 

pain and patellar tendonitis. Journal of Sports 

Sciences 21: 649–657 

Eubank C & Messenger N (2000) The frequency 

and causes of injury in squash - conference 

communication Journal of Sports Sciences 18: 

13–14. 

Messenger N, Patterson WD & Brook DB (2000) 

The Science of Climbing and Mountaineering. 

Human Kinetics, Champaign IL

Paul Millner 

BSc (Leeds) 

PhD (Leeds) 

Postdoctoral research, Purdcue University, USA and Imperial College, London 

Reader in Biotechnology (2006-) 

Contact: p.a.millner@leeds.ac.uk 

Biosensors, Biocatalysis 

and Affinity systems 

Biosensor design: Enzyme based 

sensors: we are engaged in work aimed 

at optimisation and stabilisation of 

acetylcholine esterase (AChe) based 

electrochemical biosensor chips 

for detection of organophosphate 

pesticide residues in food and water 

(EC Project SAFEGARD). Our aim is 

to effect efficient immobilisation of 

AchE and other industrially important 

enzymes to carbon and metal 

electrode surfaces and to improve 

their storage and operational stability. 

In addition, we are developing a range 

of immunosensors. These include 

biosensors for GM-material in food 

stuffs (EC Project IMAGEMO), based 

on affinity immobilisation of tagged 

antibodies to mixed self assembled 

mixed monolayers and sensors for 

antibiotics, cancer markers and 

other analytes (www.immunosensors. 

com) based on antibodies attached 

to electropolymerised pyrrole layers. 

In particular, we are interested in the 

nanoscale structure of the sensor 

surface and the mechanism underlying 

generation of the amperometric or 

impedance signal. 

Biocatalysis: the development of 

improved, cheap and biodegradeable 

supports for the attachment of 

enzymes for biocatalysis is of increased 

importance, since it is simpler to 

dispose of the support matrix after 

synthesis than carry out cleanup. 

We have developed matrices based on 

carageenan, a natural biodegradeable 

polysaccharide isolated from red 

seaweeds and current EC projects 

SANTS and COMBIO are concerned 

with using biosilicates and polymeric 

nanoparticles as enzyme supports 

for biocatalysis. 

Funding: Our work is sponsored 

by the EC, under Framework 6, 

and the HOSDB. 

Figure 2: scanning electrochemical image of microarray 

electrode design P10 (courtesy of Dr G Johnson, Uniscan 

Instruments Ltd) 


Vakurov A, Simpson CE, Daly CL, Gibson TD, 

Millner PA (2005) Acetylecholinesterase-based 

biosensor electrodes for organophosphate 

pesticide detection. II. Immobilization 

and stabilization of acetylecholinesterase 

Biosensors and Bioelectronics 20, 2324- 

2329. 

Weiss S, Millner P,Nelson A (2005). 

Monitoring protein binding to phospholipid 

monolayers using electrochemical impedance 

spectroscopy. Electrochimica Acta - 50, 4248 

- 4256. 

Hays H,Millner PA, Prodromidis MI 

(2006). Development of capacitance based 

immunosensors on mixed self-assembled 

monolayers. Sensors & Actuators: B. 

Chemical.114, 1064-1070. 

Hleli S, Martelet C, Abdelghani A, Bessueille 

F, Errachid A, Samitier J, Hays HCW,Millner 

PA, Burais N, Jaffrezic-Renault N (2006). 

An immunosensor for haemoglobin based 

on impedimetric properties of a new mixed 

self-assembled monolayer Materials Sci.and 

Engineering C.26, 322-327.

Hugh Pearson 

BSc Pharmacology, University of London 

PhD Pharmacology, University of London 

Postdoctoral Research, University of London 

Lecturer, University of Leeds 

Contact: h.a.pearson@leeds.ac.uk 

The role of ion channels 

in Alzheimer’s disease 

Alzheimer’s disease is becoming an 

increasing large clinical problem as 

the average age of our population gets 

higher. An estimated 5-10% of the 

population over the age of 65 develop 

Alzheimer’s disease (AD) and this figure 

increases even further in more elderly 

age groups. A hallmark of AD is the loss 

of neurones in the cortex and memory 

forming areas of the brain such as the 

hippocampus. We have been studying 

the effects of an AD-related peptide, 

amyloid protein (Aß) on voltage-gated ion 

channel currents in cultured neurones 

using the whole-cell patch clamp 

technique (see publications). 

The effects on ion channel currents have 

also been correlated with the Aß-induced 

cell death. To do this we use a variety of 

neurotoxicity assays, some biochemical 

such as the MTT, TUNEL or LDH 

release assays, and some morphological, 

where we fix and stain cells and look 

for changes in membrane and nuclear 

structure. We also use fluorescent assays 

to monitor cell death/survival following 

challenge with Aß. Related to this project 

are studies regarding the effect of free 

radicals on ion channel activity and 

cell survival. 

A project recently funded by the 

Alzheimer’s Research Trust is looking at 

potential side effects of novel Alzheimer’s 

disease treatments. We have shown 

that Aß is not just a toxic peptide, but 

may also have a physiological role in 

the brain. This suggests that drugs that 

prevent Aß production may have serious 

side effects on brain function. We are 

using cell death assays and biochemical 

studies to investigate this possibility. 

Funding: Medical Research Council, 

BBSRC, Alzheimer’s Research Trust, 

Wellcome Trust 

Figure 2: Amyloid ß protein expression in cultured 

neurones from cerebellum). 


Pearson HA, Peers C (2006). Physiological 

roles for amyloid peptides. J. Physiol. 575: 

5-10 

LD Plant, NJ Webster, JP Boyle, M Ramsden, 

DB Freir C Peers, HA Pearson. (2006) Amyloid 

β peptide as a physiological modulator of 

neuronal ‘A’-type K+ current Neurobiology of 

Aging 27: 1673-1683 

Atkinson L, Boyle JP, Pearson HA, Peers C. 

Chronic hypoxia inhibits Na+/Ca 2+ exchanger 

expression in cortical astrocytes. (2006) 

Neuroreport. 17:649-652. 

LD Plant, JP. Boyle , IF Smith, C Peers & HA 

Pearson (2003). The production of amyloid 

β peptide is a critical requirement for the 

viability of central neurones. J. Neurosci. 

23:5531-5535 activated current (Ih) in the 

medial septum/diagonal band complex in the 

mouse. Brain Research 1006: 74–86. 

Yeung, SYM, Thompson, D, Wang, Z, Fedida, 

D & Robertson, B (2005) Modulation of Kv3 

subfamily potassium currents by the sea 

anemone toxin BDS: Significance for CNS and 

biophysical studies. Journal of Neuroscience 

25: 8735–8745 

Figure 1: Fluorescence based Live/Dead assay in a 

neuronal cell line

Harry B. Rossiter 

BSc (Birmingham) 

MSc (King’s College, University of London) 

PhD (St. George’s Hospital Medical School, University of London) 

Fellow of The American College of Sports Medicine 

Editorial Board, The European Journal of Applied Physiology 

Wellcome Trust International Prize Travelling Research Fellow, UC San Diego (2001-2003) 

National Institutes of Health National Research Service Award, UC San Diego (2003-2005) 

Lecturer in Exercise Physiology (2005-) 

Contact: h.b.rossiter@leeds.ac.uk 

Exercise bioenergetics 

in health and disease 

Research in our labs focuses on the 

mechanisms controlling and limiting oxygen 

transport and utilisation during exercise. 

The ability to sustain muscular exercise is 

a key determinant of health and mortality 

in ageing and chronic disease (Myers et al. 

New Eng J Med 46:793-801, 2002). As such, 

we investigate the effective integration of 

the cardio-pulmonary and neuromuscular 

systems that conflate to allow muscular 

exercise to be sustained - with a special 

focus on the nonsteady-state. 

To achieve this we use a multi-scale systems 

biology approach. 

Figure 1: Cardiopulmonary Exercise Testing (CPET) with 

tissue oxygenation in chronic heart failure. 

Patient Studies 

In the Exercise Physiology Laboratory we use 

state-of-the-art CPET by mass spectrometry 

and turbinometry for alveolar gas exchange, 

12-Lead ECG, and tissue oxygenation 

monitoring to investigate exercise responses 

in patients with chronic heart failure (CHF) 

and chronic obstructive pulmonary disease 

(COPD). We collaborate with Dr Klaus Witte 

(pictured; Fig 1), Consultant Cardiologist at 

Leeds General Infirmary, which is one of the 

largest teaching hospitals in the UK serving 

a population of >0.75M. Our focus is on 

the mechanisms contributing to systems 

limitations in order to better understand 

their relationships with mortality, and to 

design strategies for the amelioration of 

exercise intolerance. 

Human Performance 

Exercise intolerance extends throughout 

the spectrum of human performance. This 

strand of our research focuses on exercise 

responses in health, ageing and elite 

athletes (in collaboration with UK Sport) 

to provide a better understanding of the 

dynamic integration of physiological 

systems for the optimisation of human 

performance. We use non-invasive 

techniques for muscle and whole-body 

investigation of exercise dynamics, such 

as: Magnetic resonance spectroscopy and 

imaging (Fig 2); Dopplar ultrasound for 

blood flow; Near-infrared spectroscopy of 

tissue oxygenation; and muscle structure 

and metabolism from biopsy samples. 

In Vivo Models 

To probe deeper into tissue and organelle 

function we use animal models of exercise 

and chronic disease: Pulmonary structure 

and function in models of COPD is 

investigated using combined magnetic 

resonance imaging and molecular 

biological techniques (Fig 3); Muscle 

morphology and mitochondrial function 

is probed in models of ageing and CHF; 

Cardiovascular and skeletal muscle 

interactions are investigated using selfand 

pump-perfused muscle models. 

Figure 2: 3T magnetic resonance spectroscopy and 

imaging of quadriceps mitochondrial function, acid-base 

status, and recruitment patterns during exercise. 

Figure 3: 3D models of murine lung structures from 80μm 

isotropic magnetic resonance images at 7 Tesla. 

Systems Biology of Exercise 

Multi-scale measurements are integrated 

in computational models combining, 

muscle metabolism, circulatory dynamics 

and pulmonary responses during exercise 

transients. These quantitative models aim 

to elucidate the emergent properties of 

the integrated physiological systems in 

limiting exercise tolerance. 

Funding: Biotechnology & Biological 

Sciences Research Council UK, Medical 

Research Council UK, The Wellcome Trust 

UK, National Institutes of Health USA; 

Leeds MCRC. 

More information: http://www. 

cardiovascular.leeds.ac.uk/staff/ 

Rossiter_H/index.htm 


Cubbon RM et al. (2010) Human exercise-induced 

circulating progenitor cell mobilization is nitric 

oxide-dependent and is blunted in South Asian men. 

Arteriosclerosis, Thrombosis and Vascular Biology 

30: 878-884 

Rossiter HB et al. (2008) Doxycycline treatment 

prevents alveolar destruction in VEGF-deficient 

mouse lung. Journal of Cellular Biochemistry 104: 

525-535 

Endo MY et al. (2007) Thigh muscle activation 

distribution and pulmonary VO2 kinetics during 

moderate, heavy and severe intensity cycling 

exercise in humans. American Journal of Physiology 

293: R812-R820 

Rossiter HB et al. (2006) A test to establish maximal 

O2 uptake despite no plateau in the O2 uptake 

response to ramp incremental exercise. Journal of 

Applied Physiology 100: 764-770

Asipu Sivaprasadarao 

BSc, MSc (Andhra University, Visakhapatnam, India) 

PhD (Leeds; Commonwealth Fellow 1987) 

Lecturer/Senior Lecturer in Biomedical Sciences (1993-2006) 

Reader in Membrane Biology (2006-2007) 

Professor of Membrane Biology (2007-) 

Contact: a.sivaprasadarao@leeds.ac.uk 

Potassium channels 

in health and disease 

Research in my laboratory is focused 

on ion channels, a family of membrane 

proteins that control the flow of ions 

across the cell membrane. Ion channels 

play crucial roles in a wide range of 

physiological processes including 

transmission of nerve impulses, 

heartbeat, muscle contraction, hormone 

secretion, cell proliferation and 

apoptosis. Consequently, defects in the 

function of ion channels lead to diseases 

such as epilepsy, cardiac arrhythmias, 

kidney dysfunction and diabetes. 

As such, ion channels represent 

important drug targets. Our goals are to 

understand (i) how ion channels work 

at the molecular level and (ii) how they 

are made and transported to and out 

of their site of action. To address the 

first question, we use techniques in 

molecular biology, electrophysiology 

and protein chemistry, and monitor 

conformational changes associated with 

the function of channels. This approach 

has allowed us to make important 

discoveries on how ion channels sense 

changes in voltage (for example, see 

refs 1,2 and Figure 1). To address the 

second question, we combine the above 

techniques with approaches in cell 

biology. These integrated approaches 

have led to several new findings: for 

example, we have demonstrated that a 

genetic mutation in the ER exit signal of 

the pancreatic K ATP 

channel (a potassium 

channel that regulates insulin secretion) 

underlies congenital hyperinsulinism (ref 

3, Figure 2), while an inherited mutation 

in the internalization signal contributes 

to neonatal diabetes (ref 4). Building 

on this expertise, we have begun 

expanding our research into other ion 

channels including the hERG potassium 

channel, sodium channels and TRP 

channels in order to understand their 

role in health and disease. Once the 

molecular and cellular mechanisms are 

revealed, we aim to screen chemical 

libraries and cell penetrating peptides 

(ref 3; Figure 2) to identify novel 

compounds with therapeutic potential. 

Funding: Wellcome Trust, MRC, BHF, 

BBSRC, GlaxoSmithKline, Millipore 

Figure 1: Structure of the voltage sensing domain of KvAP 

showing reduced membrane thickness around S3 and S4, 

as determined by the site-directed cysteine accessibility 

approach. 

Figure 2: Top: In healthy individuals K ATP 

channels traffic 

to the cell surface (red), but in neonatal diabetes they fail 

to do so due to a mutation in an ER exit signal. Bottom: 

a designer peptide bearing the exit signal prevents cell 

surface expression of the channel- a property that could 

be exploited to stimulate insulin secretion. 


Elliott DJS, Neale EJ, Aziz Q, Dunham JP, Munsey 

TS, Hunter M, Sivaprasadarao A (2004) Molecular 

mechanism of voltage sensor movements in a 

potassium channel EMBO J 23: 4717-4726 

Neale EJ, Rong H, Cockcroft CJ, Sivaprasadarao A 

(2007) Mapping the Membrane-aqueous Border 

for the Voltage-sensing Domain of a Potassium 

Channel. Journal of Biological Chemistry 282: 

37597-37604 

Taneja TK, Mankouri J, Karnik R, Kannan S, 

Smith AJ, Munsey T, Christesen HB, Beech DJ, 

Sivaprasadarao A (2009) Sar1-GTPase-dependent 

ER exit of KATP channels revealed by a mutation 

causing congenital hyperinsulinism. Hum Mol 

Genet 18: 2400-2413 

Mankouri J, Taneja TK, Smith AJ, Ponnambalam 

S, Sivaprasadarao A (2006) Kir6.2 mutations 

causing neonatal diabetes prevent endocytosis 

of ATP-sensitive potassium channels. EMBO J 25: 

4142-4151

Derek Steele 

BSc (Glasgow) 

PhD (Glasgow) 

Postdoctoral research at Glasgow 

Lecturer (1996-2000) 


Cardiovascular Group Leader, Institute of Membrane & Systems Biology (2005-) 

Contact: d.steele@leeds.ac.uk 

Ryanodine receptor function in 

skeletal and cardiac muscle disease 

Most of my work addresses the role of 

the sarcoplasmic reticulum (SR) Ca 2+ 

channel (ryanodine receptor, RyR) in 

cardiac and skeletal muscle. In cardiac 

and skeletal muscle, electrical excitation 

of the surface membrane causes Ca 2+ 

release from the SR and contraction of 

myofilaments. We study SR Ca 2+ release 

in normal cells and aberrant Ca 2+ 

release in disease (ischaemia, inherited 

cardiomyopathies). Our recent work on 

cardiac muscle has addressed the role 

of the t-tubules in excitation–contraction 

coupling, changes in SR Ca 2+ 

regulation associated with ischaemia 

or anoxia (e.g. ATP depletion) and 

the cardioprotective effects of volatile 

anaesthetics. Recently we described 

long-lasting Ca 2+ -release events that 

may be involved in regulation of 

gene transcription or expression. In 

a collaborative project (with Noriaki 

Ikemoto and Graham Lamb) we are 

using peptides to induce and study 

abnormal RyR2 gating associated 

with inherited arrhythmias. This 

‘peptide probe’ technique is based 

on the hypothesis that in normal 

RyR2 channels interaction between 

the N-terminal and central domains 

stabilizes the channel (Figure 1). 

Mutations in these regions can induce 

abnormal Ca 2+ release and consequent 

arrhythmias. Our work on skeletal 

muscle addresses the development of 

fatigue and malignant hyperthermia, 

an inherited condition associated 

with potentially fatal increases in 

core body temperature, triggered 

by exposure to volatile anaesthetics 

(Figure 2). The abnormality is known 

to be caused by mutations in RyR1, 

which result in sustained Ca 2+ release 

and contraction during anaesthesia. 

Working with clinicians and geneticists 

(St James’s Hospital, Leeds) we have 

shown that reduced Mg 2+ inhibition of 

RyR1 is a common feature of many 

channel mutations and may explain 

the abnormal response to anaesthetics. 

Ongoing work involves characterization 

of novel RyR1 mutations and 

development of non-invasive DNAbased 

screening. 

Figure 1: Proposed interaction between the N-terminal 

and central RyR2 domains. 

Figure 2: Image sequence showing a propagated 

Ca2+ wave induced by halothane in a mechanically 

skinned human skeletal muscle fibre from a patient with 

malignant hyperthermia 


Foundation, Department of Health 

Overseas collaborators: Noriaki Ikemoto, 

Graham Lamb (Australia 



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Yang, Z, Harrison, SM & Steele, DS (2005) 

ATP-dependent effects of halothane on 

SR Ca2+ regulation in permeabilized atrial 

myocytes. Cardiovascular Research 65: 

167–176. 

Yang, Z & Steele, DS (2005) Characteristics 

of prolonged Ca2+ release events associated 

with the nuclei in adult cardiac myocytes. 

Circulation Research 96: 82–90. 

Duke, M, Hopkins, PM, Halsall, JP & Steele, 

DS (2004) Mg 2+ dependence of halothaneinduced 

Ca 2+ release from the sarcoplasmic 

reticulum in skeletal muscle from humans 

susceptible to malignant hyperthermia. 

Anesthesiology 101: 1339–1346. 

Yang, Z, Pascarel C, Steele, DS, Komukai, 

K, Brette, F & Orchard, CH (2002) Na+-Ca 2+ 

exchange activity is localized in the T-tubules 

of rat ventricular myocytes. Circulation 

Research 91: 315–322.

Andrea Utley 

BA (Hons) Human Movement Studies (1984) 

PGCE Physical Education (1985) 

PhD University of Leeds (1998) 

Lecturer, School of Education, University of Leeds, (1993-1997) 

Senior Lecturer. Motor Control and Learning, Leeds Metropolitan University (1997-1999) 

Senior Lecturer, Director Centre for Sport and Exercise Sciences, Institute of Systems and Membranes Biology, 

University of Leeds (1999-) 

Contact: A.Utley@leeds.ac.uk 

Motor and 

Behavioural Science 

This group addresses the mechanisms 

of control and disorders of co-ordination 

in conditions such as hemiplegic 

cerebral palsy and Developmental 

Coordination Disorder. A particular 

research interest is how children and 

adults with a range of movement 

difficulties are able to control their 

movements in a variety of contexts. 

Detailed analysis of reaching/ grasping 

and catching in children has revealed 

how these children attempt to control 

multiple degrees of freedom. It also 

addresses the assessment of movement 

and how manipulating the movement 

context can be used as a rehabilitative 

strategy. Explanations of motor 

development have taken a step forward 

through the application of ideas from 

proponents of dynamic systems, here 

movement involves the final product 

or whole being the active cooperation 

of many parts, and contains multiple 

subsystems all contributing in a unique 

manner (Thelen and Spencer 1998). 

The potential for some of these ideas 

has been initially explored in the context 

of reaching and grasping in children 

with hemiplegic cerebral palsy (Utley 

and Sugden 1998) and catching in 

children with DCD (Utley and Astill 

2006). Such children have to overcome 

intrinsic constraints where the neural 

properties provide a direct link to the 

type of movement observed. External 

constraints such as task demands 

and context also influence the nature 

and extent of interlimb coupling. We 

are especially interested in the nature 

and extent of interlimb coupling and 

have provided evidence on the nature 

of bimanual co-ordination in children 

with cerebral palsy. This work has 

indicated that one solution to the 

degrees of freedom problem during 

upper limb movements is to couple the 

limbs therefore reducing the number of 

degrees of freedom to be controlled. 

Collaboration with Leeds University 

Motor Impairment Group (LUMIG) and 

external collaborators at the University 

of Nijmegen (The Netherlands) 

and University of Minnesota (USA). 

Techniques employed include 

kinematic analysis, electromyography, 

eye-tracking and modelling. 



php?tag=utley 

Funding: British Council, ESRC, 

Nuffield Institute 


Utley A, Steenbergen B, Astill SL (2007) 

Ball catching in children with developmental 

coordination disorder: control of degrees of 

freedom Developmental Medicine and Child 

Neurology 49 (1): 34-38 

Utley A, Sugden DA, Lawrence G, and Astill 

S. L (2007). The influence of perturbing the 

working surface during reaching and grasping 

in children with hemiplegic cerebral palsy. 

Disability and Rehabilitation 29 (1): 79-89 

Astill S.L.; Utley, A. (2006) Two-Handed 

Catching in Children with Developmental 

Coordination Disorder. Motor Control, 10(2), 

pp.109-124. 

Utley, A. & B. Steenbergen (2006). Discrete 

bimanual co-ordination in children and young 

adolescents with hemiparetic cerebral palsy: 

Recent findings, implications and future 

research directions. Pediatric Rehabilitation, 

9(2), 127-136. 

Steenbergen, B. & Utley A. (2005). Cerebral 

palsy: Recent insights into movement 

deviations. Motor Control, 9(4), 353-356. 

Utley A.; Steenbergen B.; Sugden D.A. 

(2004) The influence of object size on 

discrete bimanual co-ordination in children 

with hemiplegic cerebral palsy. Disability and 

Rehabilitation, 26(10), pp.603-613 .

Ed White 

University of Wales, Aberystwyth, B.Sc., Zoology 

University of Reading: Ph.D., Zoology 

University of Exeter, Dept. of Education: PGCE, Biology and Outdoor Education 

Post. doc: Oxford University 

Lectureship: Universite de Tours, France 

Lloyds of London and Wellcome Trust Fellowships, Professor of Cardiac Physiology (2007-): University of Leeds. 

Contact: e.white@leeds.ac.uk 

Mechanical stimulation 

of the heart 

Acute mechanical stimulation (e.g. 

stretch) affects the contractility of 

cardiac muscle in situations such as 

exercise, when diastolic ventricular 

volume is increased. But stretch has 

also been implicated in the triggering 

of cardiac arrhythmias. Chronic stretch 

provokes cardiac hypertrophy. Thus 

stretch may be involved in the beneficial 

effects of regular exercise and the 

cause of heart attacks, depending upon 

the circumstances. My research group 

is interested in the cellular mechanisms 

that cause these varied effects. We 

have research collaborators in France 

and the UAE and the laboratory has 

welcomed researchers from Brazil, 

Canada, France, Japan, Poland and 

the UAE. 

We can study the effects of acute 

stretch on single cardiac myocytes 

by attaching carbon fibres to the cell 

(Figure 1A) and recording the change 

in force (Figure 1B) or intracellular 

calcium (see Calaghan & White, 

2004 J.Physiol. 559, 205-214) or 

electrophysiology (Belus & White, 

2003). 

The triggers for hypertrophy in response 

e.g. to hypertension or to voluntary 

exercise are studied using functional 

approaches in conjunction with 

molecular biological techniques such 

as mRNA arrays and Western blotting. 

We are also interested in the role 

components of the cytoskeleton such 

as microtubules (Figure 2, Calaghan 

et al, 2001) may play as transducers 

of mechanical stimuli. A recent 

interest is the role that caveloae, small 

invaginations on the surface of the 

myocytes might play in the signalling 

of stretch (Calaghan & White, 2006). 

Overseas collaborators: J-Y LeGuennec 

Tours, France. FC Howarth Al Ain, UAE 


Foundation; MRC, The British Council 



php?staff=EW 

(A) 

Figure 2: Microtubule cytoskeleton in a cardiac myocyte 

imaged with confocal microscopy. 


Calaghan, S.C. & White, E. (2006) Caveolae 

modulate excitation-contraction coupling and 

β2-adrenergic signalling in adult rat ventricular 

myocytes Cardiovasc. Res. 69, 816-824 . 

White, E. (2005) Temporal modulation of 

mechano-electric feedback in cardiac muscle. 

In, Cardiac mechano-electric feedback and 

arrhythmias: from pipette to patient. Elsevier, 

eds KOHL, P., SACHS, F and FRANZ, M. 

83-91. 

McCrossan, Z.A., Billeter, R. & White, E. 

(2004) Transmural changes in size, contractile 

and electrical properties of SHR left ventricular 

myocytes during compensated hypertrophy . 

Cardiovasc. Res. 63, 283-292. 

Belus, A. & White, E. (2003) Streptomycin and 

intracellular calcium modulate the response of 

single guinea pig ventricular myocytes to axial 

stretch. J. Physiol. 546, 501-509 

Natali, A.J., Wilson, L.A., Peckham, M. Turner, 

D. L., Harison, S. M. & White, E. (2002) 

Different regional effects of voluntary exercise 

on mechanical and electrical properties of 

rat ventricular myocytes. J. Physiol. 541, 

863-875. 

(B) 

Figure 1: (A) Cardiac myocyte attached to carbon fibres 

(B) stretch of the myocte (up arrow) increase contractile 

force, release of the stretch (down arrow) reverses 

this effect.

Stanley White 

BSc (Manchester) 

PhD (Manchester) 

Beit Memorial Fellow, Yale University, CT, USA; MRC Senior Fellow, Leeds 

Lecturer and Senior Lecturer, Sheffield 


Reviewing and Associate Editor, Nephron (2000-) 

Contact: s.j.white@leeds.ac.uk 

lon-channel and transporter 

function in renal epithelia 

I investigate mechanisms of regulation 

and function of membrane proteins 

in epithelial cells, with emphasis on 

the kidney. Epithelia are comprised 

of polarized cells and to function 

properly membrane proteins such as 

transporters, receptors and channels 

must be targeted to the appropriate 

part of the cell. This is especially 

important in the kidney, because salt 

transport across kidney epithelial cells 

is an important determinant of 

blood pressure. 

Recently we have focused on the 

cellular targeting of ROMK potassium 

channels, which secrete potassium into 

the renal tubule. To do this we fuse the 

channel protein to green fluorescent 

protein. These fluorescent proteins are 

then visible in cultured epithelial cells. 

Some inherited mutations of ROMK 

that occur in Bartter’s syndrome lead 

to mistargeting of the channel. We are 

extending these approaches to study 

the targeting of other proteins, such as 

the P2X receptor, in the kidney 

(Figure 1). 

The function of ion channels is 

often regulated by interactions with 

other proteins. One protein known 

to interact with potassium channels, 

the sulphonylurea receptor, was 

discovered in my laboratory to be 

strongly expressed in kidney. However, 

its function is unknown. Kidney-specific 

gene-knockout studies may yield clues 

to its function. 

The zebrafish (Danio rerio) embryo 

has great potential as a model for 

human diseases because of its rapid 

development, optical transparency and 

the ease of genetic manipulation by 

antisense approaches. We have isolated 

the gene encoding the zebrafish version 

of ROMK, and have found that it is 

expressed in the embryonic renal tubule 

and skin (Figure 2). We are developing 

preparations of these tubules, allowing 

us to study the function of membrane 

proteins in these cells and to determine 

the role of potential partner proteins in 

membrane targeting and function. 

Overseas collaborators: 

Chou Long-Huang (USA) 

Funding: MRC, NKRF, Wellcome Trust 



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Figure 1: Cultured kidney cells expressing a P2X receptor 

(green). Endogenous markers for apical membranes 

(red) and basolateral membranes (blue). 


Stewart, GS, Fenton, RA, Wang, W et al. 

(2004) The basolateral expression of mUT-A3 

in the mouse kidney. American Journal of 

Physiology Renal Physiology 286: F979–F987. 

Hill, C, Giesberts, AN & White, SJ (2002) 

Expression of isoforms of the Na+/H+ 

exchanger in M1 collecting duct cells. 

American Journal of Physiology Renal 

Physiology 282: F649–F654. 

Zeng, W-Z, Babich, V, Ortega, B et al. (2002) 

Evidence for endocytosis of ROMK potassium 

channels via clathrin-coated vesicles. American 

Journal of Physiology Renal Physiology 283: 

F630–F639. 

Kibble, J, Neal, A, White, SJ, Green, R, 

Evans, MJ & Taylor, C (2001) Renal effects of 

glibenclamide in cystic fibrosis mice. Journal 

of the American Society of Nephrology 12: 

Figure 2: 24-h zebrafish embryo expressing ROMK mRNA 

in the pronephric duct and surface epithelial cells.

Andrew Wilson 

BSc (Hons) University of Otago, NZ 

PhD Indiana University, Bloomington IN, USA 

Post-Doctoral Research: University of Aberdeen, University of Warwick 

Lecturer in Motor Control (2009- ) 

Contact: A.D.Wilson@leeds.ac.uk 

Perception, Action and Learning 

Perceptual information plays a key 

role in the coordination and control of 

skilled action. The perception-action 

approach to studying human movement 

and motor control seeks to identify this 

perceptual information and establish 

the structure of the perception-action 

dynamic that leads to skilled behaviour. 

The main focus of my work is learning 

- how do we acquire new skills? What 

changes to allow these skills to develop? 

How does this change with age? How 

can we influence the process of learning, 

in both typical and clinical populations? 

Coordinated Rhythmic Movement 

A classic model system for studying 

skilled movement and learning is 

coordinated rhythmic movement. 

Human movement only exhibits two 

stable coordinations; in-phase (doing 

the same thing at the same time) and 

anti-phase (doing the opposite thing 

at the same time). Other coordinations 

(e.g. a syncopated rhythm) must be 

learned. This structure emerges from 

a perception-action task dynamic 

that includes very specific perceptual 

information (the relative direction of 

motion). I have developed a full set of 

experimental tools to assess and train 

both the perception and performance 

of coordinated rhythmic movements, 

and research in my lab is interested in 

identifying the nature of the changes 

Figure 1: Perceptual judgment displays 

that occur with learning. These tools 

include perceptual judgments (Figure 1), 

coordinated movements (Figure 2) and 

eye-tracking (Figure 3), and recent work 

has been investigating how learning 

changes with healthy age. 

Figure 2: Unimanual action training showing feedback 

Action Selection and Execution 

Skilled movement entails selecting 

a task appropriate movement and 

then executing it correctly. There 

are numerous factors that influence 

which action you select and how you 

perform it, including the affordances 

of the task environment, immediate 

movement history, and your ongoing 

perceptual monitoring of the world. 

I have a collaboration to investigate 

these processes in a more complex task, 

namely targeted and distance throwing. 

These are behaviours unique to humans 

that are considered to have played 

an essential role in our evolutionary 

success. Throwing entails perception 

of object affordances (suitability for 

throwing) as well as the coordination 

and control of the dynamics of throwing 

and projectile motion to actually 

execute the throw. 

Overseas Collaborators 

Geoffrey P. Bingham, Winona Snapp- 

Childs – Indiana University 

Qin Zhu – University of Wyoming 

Figure 3: Typical eye kinematics for an observer viewing 

two dots moving at 180° mean relative phase. 

Developmental Coordination 

Disorder (DCD) 

As many as 5% of young children have 

serious difficulties in producing skilled 

movements. Using many of the standard 

techniques mentioned above, I am 

interested in understanding the source 

of their difficulties and in developing 

interventions that allow them to learn 

skilled movements. 

More information: http://www.fbs.leeds. 

ac.uk/staff/profile.php?tag=Wilson_A 


Wilson AD, Snapp-Childs W & Bingham GP (in 

press) Improved perception leads immediately 

to improved movement stability. Journal of 

Experimental Psychology: Human Perception and 

Performance 

Elders V, Sheehan S, Wilson AD, Levesley M, 

Bhakta B & Mon-Williams M (2010) Head-torsohand 

coordination in children with and without 

coordination difficulties. Developmental 

Medicine and Child Neurology 52(3): 238-243 

van Swieten LM, van Bergen E, Williams JGH, 

Wilson AD, Plumb MS, Kent SW & Mon-Williams M 

(2010) A test of motor (not executive) planning in 

developmental coordination disorder and autism. 

Journal of Experimental Psychology: Human 

Perception and Performance 36(2): 493-499 

Kent SW, Wilson AD, Plumb MS, Williams JHG & 

Mon-Williams M (2009) Immediate movement 

history influences reach-to-grasp action selection 

in children and adults. Journal of Motor Behavior 

41(1): 10-15 

Wilson AD & Bingham GP (2008) Identifying the 

information for the visual perception of relative 

phase. Perception & Psychophysics 70(3): 465-476

Ian Wood 

BSc, Imperial College, University of London 

PhD, University College London, University of London 

Postdoc Scripps Research Institute, La Jolla, USA 

Postdoc, University College London; Research Fellowship University of Leeds 

Lecturer, University of Leeds (2000-2007) 

Senior Lecturer University of Leeds (2007-) 

Contact: i.c.wood@leeds.ac.uk 

Uncovering the molecular mechanisms that control 

the gene expression in human disease 

We are interested in identifying 

the molecular mechanisms that 

are important in regulating gene 

transcription in human disease. Our 

work uses many molecular biological 

techniques, in vitro and in vivo model 

systems as well as clinical samples to 

provide a complete understanding of 

disease mechanisms. 

Cardiovascular disease: Smooth 

muscle cells within blood vessels are 

important for controlling blood flow 

and pressure. In response to damage 

these cells proliferate to produce 

new smooth muscle cells which are 

important for vascular repair, but 

excessive proliferation is a major factor 

in cardiovascular diseases such as 

atherosclerosis, in-stent restenosis and 

a contributing factor to cardiovascular 

disease associated with diabetes. 

We have recently identified that the 

transcription factor REST plays an 

important role in normal blood vessels 

by repressing genes important for 

Figure 1: REST recruits several corepressor complexes to 

DNA to regulate gene expression. Adapted from Ooi L and 

Wood IC. Nature Reviews Genetics 8, 544-554. Copyright 

(2007) 

smooth muscle cell proliferation, 

including a specific potassium 

channel (IKCa) that is important for 

vascular smooth muscle proliferation. 

We are currently interested in the 

other molecular mechanisms that 

are responsible for increasing IKCa 

expression levels in disease as well 

as identifying the contributions of 

environmental factors in promoting 

changes in gene expression. 

Neuronal disease: Correct functioning 

of the nervous system requires that 

neurones are able to communicate 

with each other effectively. Neurones 

transmit signals via propagation of 

action potentials, the regulation of 

which is of utmost importance. One ion 

channel important in determining the 

excitability of neurones is the M-channel 

which is composed of subunits of 

the KCNQ potassium channel gene 

family. Mutations in KCNQ genes have 

been linked to heart disease, epilepsy, 

deafness and most recently pain. 

Despite their obvious importance, very 

little is known about how expression 

of these potassium channel genes 

is regulated. We are interested in 

determining how expression of these 

genes is regulated in normal physiology 

and in neuronal disorders such as 

epilepsy and chronic pain. 

Cancer: The transcription factor REST 

is associated with neuronal and nonneuronal 

cancers. REST is normally 

expressed at very low levels in neurones 

though increased REST expression is 

associated with a type of childhood 

brain cancer – medulloblastoma. In 

non-neuronal cells REST is normally 

expressed at quite high levels and 

reduced REST expression has recently 

been associated with colon cancer and 

may also be important in other cancers 

such as breast cancer. We are currently 

investigating a potential role for REST 

in bladder cancer and determining 

the cell specific effects of altered 

REST expression to understand the 

mechanisms by which REST can act as a 

tumour suppressor or an oncogene. 

Funding: British Heart Foundation 



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Johnson R, Samuel J, Ng CKL, Jauch R, Stanton 

LW, Wood IC (2009) Evolution of the Vertebrate 

Gene Regulatory Network Controlled by the 

Transcriptional Repressor REST. Mol Biol Evol 

26(7): 1491-1507 

Ooi L, Wood IC (2008) Regulation of gene 

expression in the nervous system. Biochem J 414: 

327-341 

Ooi L, Wood IC (2007) Chromatin crosstalk in 

development and disease: lessons from REST. Nat 

Rev Genet 8(7): 544-54 

Bingham AJ, Ooi L, Kozera L, White E, Wood 

IC (2007) The repressor element 1-silencing 

transcription factor regulates heart-specific gene 

expression using multiple chromatinmodifying 

complexes. Mol Cell Biol 27(11): 4082-92 

Ooi L, Belyaev ND, Miyake K, Wood IC, Buckley 

NJ (2006) BRG1 chromatin remodelling activity 

is required for efficient chromatin binding by 

repressor element 1-silencing transcription factor 

(REST) and facilitates REST-mediated repression. J 

Biol Chem 281(51): 38974-80 

Bruce AW, Krejci A, Ooi L, Deuchars J, Wood IC, 

Dolezal V, Buckley NJ (2006) The transcriptional 

repressor REST is a critical regulator of the 

neurosecretory phenotype. J Neurochem 98(6): 

1828-40 

Johnson R, Gamblin RJ, Ooi L, Bruce AW, 

Donaldson IJ, Westhead DR, Wood IC, Jackson 

RM, Buckley NJ (2006) Identification of the REST 

regulon reveals extensive transposable elementmediated 

binding site duplication. Nucleic Acids 

Res 34(14): 3862-77

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