The role of NaV2.4 in mediation of resurgent sodium current

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DESCRIPTION (provided by applicant): Resurgent current is an unusual component of voltage gated sodium (Na) current that flows upon repolarization. This current may play an important role in the firing patterns, intrinsic excitability, and modulation of sodium currents and it has been recorded in many brain regions. These brain regions have well-established links to ataxias, Parkinson's Disease, Huntington's Disease, autism, and other movement disorders. Studying this current has relevance for these disease states in that any complete models of pathophysiology would need to take this current into account. Prior work has suggested that resurgent current is due to the actions a proteinaceous open-channel blocking particle that is separate but associated with the Na channel alpha subunit. However, the protein machinery responsible still remains a mystery and its identification would aid detailed study of the mechanism and facilitate its manipulation in situ. There is evidence for and against the hypothesis that the beta4 Na channel subunit (NaV2.4) is the endogenous blocking particle. Here we intend to first test the necessity of the subunit directly by knocking down the expression in culture using an RNAi approach and recording resurgent current. Secondly we will examine the effect of this knockdown on firing patterns. Lastly, based on prior work we propose experiments to test if the blocking machinery is a competitive endogenous ligand for the local anesthetic receptor site within the sodium channel pore. This data will be important to new therapeutic manipulations and fully understanding the effects of current local anesthetic, anti-arrhythmic, and anticonvulsant drugs. Together these data will help characterize a molecular mechanism for a critical component of sodium currents found in a number of brain regions.