Structural mechanism of voltage-gated sodium channel slow inactivation.

Abstract

Voltage-gated sodium (Na_V) channels mediate a plethora of electrical activities. Na_V channels govern cellular excitability in response to depolarizing stimuli. Inactivation is an intrinsic property of Na_V channels that regulates cellular excitability by controlling the channel availability. The fast inactivation, mediated by the Ile-Phe-Met (IFM) motif and the N-terminal helix (N-helix), has been well-characterized. However, the molecular mechanism underlying Na_V channel slow inactivation remains elusive. Here, we demonstrate that the removal of the N-helix of Na_VEh (Na_VEh^ΔN) results in a slow-inactivated channel, and present cryo-EM structure of Na_VEh^ΔN in a potential slow-inactivated state. The structure features a closed activation gate and a dilated selectivity filter (SF), indicating that the upper SF and the inner gate could serve as a gate for slow inactivation. In comparison to the Na_VEh structure, Na_VEh^ΔN undergoes marked conformational shifts on the intracellular side. Together, our results provide important mechanistic insights into Na_V channel slow inactivation.