Subunit dependence of Na channel open-channel block and slow inactivation in cerebellar neurons

¹ Northwestern University

^* To whom correspondence should be addressed. E-mail: i-raman{at}northwestern.edu.

Submitted on July 18, 2006
Revised on August 17, 2006
Accepted on 1 December 2006

	Abstract

Purkinje and cerebellar nuclear neurons both have Na currents with resurgent kinetics. Previous observations, however, suggest that their Na channels differ in their susceptibility to entering long-lived inactivated states. To compare fast inactivation, slow inactivation, and open-channel block, we recorded voltage-clamped, tetrodotoxin-sensitive Na currents in Purkinje and nuclear neurons acutely isolated from mouse cerebellum. In nuclear neurons, recovery from all inactivated states was slower and open-channel unblock was less voltage-dependent than in Purkinje cells. To test whether specific subunits contributed to this differential stability of inactivation, experiments were repeated in NaV1.6-null (med) mice. In med Purkinje cells, recovery times were prolonged and the voltage-dependence of open-channel block was reduced relative to control cells, suggesting that availability of NaV1.6 is quickly restored at negative potentials. In med nuclear cells, however, currents were unchanged, suggesting that NaV1.6 contributes little to wild-type nuclear cells. Extracellular Na+ prevented slow inactivation more effectively in Purkinje than in nuclear neurons, consistent with a resilience of NaV1.6 to slow inactivation. The tendency of nuclear Na channels to inactivate produced a low availability during trains of spike-like depolarizations. Hyperpolarizations that approximated synaptic inhibition effectively recovered channels, suggesting that increases in Na channel availability promote rebound firing following inhibition.

Key Words: NaV1.6, Purkinje, cerebellar nuclei, med, rebound burst, resurgent

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