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Use-Dependent Potentiation of the Na_v1.6 Sodium Channel

Department of Microbiology & Molecular Genetics, University of California, Irvine, California 92697-4025

Correspondence: Address reprint requests to A. L. Goldin, Tel.: 949-824-5334; Fax: 949-824-8504; E-mail: agoldin{at}uci.edu.

Na_v1.2 and Na_v1.6 are two voltage-gated sodium channel isoforms that are abundant in the adult central nervous system. These channels are expressed in different cells and localized in different neuronal regions, which may reflect functional specialization. To examine this possibility, we compared the properties of Na_v1.2 and Na_v1.6 in response to a rapid series of repetitive depolarizations. Currents through Na_v1.6 coexpressed with ß1 demonstrated use-dependent potentiation during a rapid train of depolarizations. This potentiation was in contrast to the use-dependent decrease in current for Na_v1.2 with ß1. The voltage dependence of potentiation correlated with the voltage dependence of activation, and it still occurred when fast inactivation was removed by mutation. Rapid stimulation accelerated a slow phase of activation in the Na_v1.6 channel that had fast inactivation removed, resulting in faster channel activation. Although the Na_v1.2 channel with fast inactivation removed also demonstrated slightly faster activation, that channel showed very pronounced slow inactivation compared to Na_v1.6. These results indicate that potentiation of Na_v1.6 sodium currents results from faster channel activation, and that this effect is masked by slow inactivation in Na_v1.2. The data suggest that Na_v1.6 might be more resistant to inactivation, which might be helpful for high-frequency firing at nodes of Ranvier compared to Na_v1.2.

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