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Identification of the dynamic mechanisms regulating the targeting and clustering of sodium and potassium channels in neurons (Channel Targeting)
Start date: 01 Jul 2009, End date: 30 Jun 2013 PROJECT  FINISHED 

The electrical excitability is a fundamental property of neurons. Diversity in intrinsic neuronal excitability is generated by the variable expression, subcellular localization, and function of a complex repertoire of ion channels. Dynamic regulation of intrinsic excitability can further alter the behavior of neurons and confer plasticity to neuronal signaling. Aberrant expression, localization, and function of ion channels can result in channel-based pathophysiologies. One of the challenging questions is to understand how neurons regulate the expression and localization of ion channels. The Axon Inital Segment (AIS) and the nodes of Ranvier are key sub-compartments that generate and conduct the action potentials along the axon. The voltage-dependent sodium (Nav) and potassium (Kv) channels are critically concentrated at the AIS and nodes of Ranvier to ensure proper axon potential propagation. Despite the central role of these channels in excitability, the molecular and cellular determinants governing their appropriate targeting and membrane organization are just beginning to emerge. An intricate assembly of adhesion molecules and cytoskeletal scaffold proteins hold Nav and Kv channels in place. However, how such a complex is dynamically regulated is still largely unknown. We recently identified two new processes based on phosphorylation of Nav and Kv complexes by two kinases, casein kinase 2 (CK2) and cyclin-dependant kinase (Cdks). The phosphorylation/dephosphorylation modifications of these channels modify indeed their localization at the AIS. Here, I propose to analyze, using a multidisciplinary approach, the respective role of CK2 and Cdks signaling pathways on dynamic targeting/assembly of Nav1 and Kv1 channels at the AIS and in the node of Ranvier. The end-results of this proposal should provide new insights into the mechanisms involved in the dynamic regulation of excitability and opens new paths to better understand defects leading to neuronal dysfunction.
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