Interaction of Subunits Regulating Resurgent Current Through Voltage Gated Na Channels

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Project Summary/Abstract Resurgent Na current is current through voltage-gated Na channels that flows upon repolarization of the cell, leading to increased availability of channels between spikes, and enabling high frequency firing of neurons. This high frequency firing behavior can be useful physiologically, as in the case of cerebellar Purkinje neurons and dorsal root ganglion neurons, but can also lead to several pathophysiological states, including ataxia, epilepsy, paroxysmal extreme pain disorder, and long QT syndrome. While many studies have described the biophysical characteristics of resurgent current in detail, the molecular mechanism of resurgent current production remains unknown. We are investigating the roles of several auxiliary subunits to the Na channel which may play a role in resurgent current. We will do this by performing whole-cell voltage clamp recordings of Na current through both expressed and native channels, in the context of their interaction with auxiliary subunits, as well as examining these proteins’ roles in contributing to behavior in vivo. By elucidating what factors are important for producing and modulating resurgent current, we will define a molecular mechanism by which many neuron types produce high frequency firing, which will help shape our understanding of neural communication in both physiological and pathophysiological states.