Research Report 2010 - MDC

Martin FalckeStructure of the GroupGroup LeaderPD Dr. Martin FalckeScientistsDr. Mihaela EnculescuStart of group: March 2009Graduate StudentsKevin ThurleyR. Bianca SprincenatuThomas SchendelJuliane ZimmermannDiploma StudentMichael FaberMathematical Cell PhysiologyThe core facility group „Mathematical Cell Physiology“ develops mathematical models ofcellular processes. Current projects comprise second messenger signaling systems (cAMP,Ca 2+ ), membrane potential dynamics, pH-regulation, cardiac myocyte cell models, actin dynamicsand cell motility. The group’s service to experimental groups is to develop quantitativeformulations of their hypotheses in form of mathematical models. We provide that service on avariety of levels from assistance in usage of modeling tools to complete model formulation andtesting. The group works currently with the labs of T. Jentsch’s, I. Morano’s and H. Kettenmann’s.We also conduct independent research. Projects on IP3-induced Ca 2+ -signaling, cAMP-signalingand actin dynamics were the focus in 2008/2009. All studies reported here were closecollaborations with experimental groups.In many cell types, the inositol trisphosphate receptorIP 3 R is one of the important components controllingintracellular calcium dynamics, and an understandingof this receptor is necessary for an understanding of thecontrol of gene expression, secretion, muscle contractionand many other processes controlled by calcium.IP 3 -induced Ca 2+ -signaling comprises the structural levelschannel molecule IP 3 R, channel cluster and clusterarray on cell level. We investigated behavior on all 3 levels.Based on single-channel data from the type-1 inositoltrisphosphate receptor, we showed that the mostcomplex time-dependent model that can be unambiguouslydetermined from steady-state data is onewith three closed states and one open state (1). Becausethe transitions between these states are complex functionsof calcium concentration, each model state mustcorrespond to a group of physical states. We found thatthe main effect of [Ca 2+ ] is to modulate the probabilitythat the receptor is in a state that is able to open, ratherthan to modulate the transition rate to the open state.Another study to which we provided the simulationsdeals with the cluster level (2). It showed that low concentrationsof IP 3 cause IP 3 Rs to aggregate rapidly andreversibly into small clusters of about four closely associatedIP 3 Rs. At resting cytosolic [Ca 2+ ], clustered IP 3 Rsopen independently, but with lower open probability,shorter open time, and less IP 3 sensitivity than loneIP 3 Rs. Increasing cytosolic [Ca 2+ ] reverses the inhibitioncaused by clustering, IP 3 R gating becomes coupled, andthe duration of multiple openings is prolonged.Clustering both exposes IP 3 Rs to local Ca 2+ rises andincreases the effects of Ca 2+ . Dynamic regulation of clusteringby IP 3 retunes IP 3 R sensitivity to IP 3 and Ca 2+ , facilitatinghierarchical recruitment of the elementaryevents that underlie all IP 3 -evoked Ca 2+ signals.Two studies deal with the cellular level. Our group hadpredicted in 2003/2004 on theoretical grounds, thatCa 2+ spiking exhibits a random sequence of interspikeintervals instead of a regular oscillation and that theaverage length of interspike intervals and their standarddeviation will sensitively depend on the cytosolicCa 2+ buffering capacity. That was verified experimentallyfor spontaneous spiking in astrocytes, microglia andPLA cells and also for stimulated spiking in HEK cells (5).The effect of Ca 2+ buffers on individual spikes was investigatedin a pure simulation study in collaboration withI.Parker’s experimental group (4). It provided new explanationsfor previously measured time courses of fluorescencesignals upon photo-uncaging of IP 3 . There is alow cluster density regime and a high cluster density220 Technology Platforms