Rapid firing of cerebellar Purkinje neurons is facilitated in part by a voltage-gated Na + (Na V ) 'resurgent' current, which allows renewed Na + influx during membrane repolarization. Resurgent current results from unbinding of a blocking particle that competes with normal channel inactivation. The underlying molecular components contributing to resurgent current have not been fully identified. In this study, we show that the Na V channel auxiliary subunit FGF14 'b' isoform, a locus for inherited spinocerebellar ataxias, controls resurgent current and repetitive firing in Purkinje neurons. FGF14 knockdown biased Na V channels towards the inactivated state by decreasing channel availability, diminishing the 'late' Na V current, and accelerating channel inactivation rate, thereby reducing resurgent current and repetitive spiking. Critical for these effects was both the alternatively spliced FGF14b N-terminus and direct interaction between FGF14b and the Na V C-terminus. Together, these data suggest that the FGF14b N-terminus is a potent regulator of resurgent Na V current in cerebellar Purkinje neurons.
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