Use-dependent potentiation of the Nav1.6 sodium channel

Na(v)1.2 and Na(v)1.6 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(v)1.2 and Na(v)1.6 in response to a rapid series of repetitive depolarizations. Currents through Na(v)1.6 coexpressed with beta1 demonstrated use-dependent potentiation during a rapid train of depolarizations. This potentiation was in contrast to the use-dependent decrease in current for Na(v)1.2 with beta1. 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(v)1.6 channel that had fast inactivation removed, resulting in faster channel activation. Although the Na(v)1.2 channel with fast inactivation removed also demonstrated slightly faster activation, that channel showed very pronounced slow inactivation compared to Na(v)1.6. These results indicate that potentiation of Na(v)1.6 sodium currents results from faster channel activation, and that this effect is masked by slow inactivation in Na(v)1.2. The data suggest that Na(v)1.6 might be more resistant to inactivation, which might be helpful for high-frequency. ring at nodes of Ranvier compared to Na(v)1.2.