Research Report 2010 - MDC

Structure of the GroupInes Ibañez-TallonGroup LeaderDr. Ines Ibañez-TallonScientistsDr. Silke FrahmDr. Julio Santos-TorresGraduate StudentsAnnika StürzebecherMartin LaquaSebastian AuerMarta SlimakLeiron FerrareseTechnical AssistantsBranka KampfrathDaniela KurzhalsSecretariatDr. Timkehet TefferaMolecular Neurobiology ofCell-surface Channels and ReceptorsIon channels and neurotransmitter receptors control cellular communication betweennerve cells influencing neuronal excitability and synaptic transmission. Our group isinterested in dissecting the contribution of individual channels and receptors on neuronalfunction in the mammalian nervous system. We use a combination of molecular, behavioral,electrophysiological, and genetic tools for the functional analysis of ion channels in thedevelopment of the nervous system and in disease, using mice as a model organism.Genetic control of neural circuitsContemporary genetic methods allow cell-selective targetingwithin complex neural circuits. We have recentlydeveloped a novel genetic method to manipulate ioniccurrents in vivo using genetically encoded cell-surfaceanchored toxins and neuropeptides, based on the discoveryof endogenous prototoxins. The ongoing projectsin our group are aimed at silencing or manipulatingspecific ion channels in defined neuronal circuits.The questions we are addressing are: how a particularclass of ion channels in one cell population contributesto the function of a given neuronal circuit, and whethersilencing one cell population has an impact in only thatcircuit and/or also affects the next circuit. Anotherquestion of interest is whether these functions can berestored upon reversibly inhibiting the expression ofthe cell-surface toxin or peptide. To approach thesequestions, we are focusing on specific neuronal circuitsin which manipulation of certain ion channels couldhelp dissecting the cascade of events that leads tochronic pain, hearing impairment, and nicotine mediatedeffects. To target these circuits, we are using geneticapproaches such as BAC and knock-in transgenesis andlentiviral vectors to achieve cell-specific and stableexpression in specific neuronal populations in vivo.Endogenous protoxin modulators of nicotinicacetylcholine receptorsThe cholinergic modulators lynx1 and lynx2 are aunique class of cell-surface regulatory molecules. Thesemolecules are members of the Ly6 superfamily thatalso includes the three-finger fold snake venom toxins,α- and κ-bungarotoxin. Both lynx1 and lynx2 form stableassociations with nicotinic acetylcholine receptors(nAChRs) and alter their function in vivo. Lynx1-like moleculesare well conserved across species, both in structureand function, suggesting the importance of cellsurfacemodulators of nicotinic receptors in nature.Cell-surface tethered toxin and peptidemodulatorsWe have developed a novel strategy, termed “tetheredtoxins and peptides” to characterize neuronal circuitsusing the evolutionary derived selectivity of venompeptide toxins and endogenous peptide ligands, suchas lynx1 prototoxins. Peptide toxins from predatory animalsthat have been routinely employed for neuroscienceresearch do not normally exist as cell-surfaceanchored molecules. Using the scaffold of the lynx1-likegene family, i.e. secretory signal and consensussequences for GPI processing and recognition, it is possibleto produce a series of tethered toxins (t-toxins)that are highly effective modifiers of neuronal activity.166 Function and Dysfunction of the Nervous System