Structure-function analysis of lithium-ion selectivity of voltage-gated sodium channel

Voltage-gated sodium channels (Navs) selectively conduct Na⁺to generate action potentials. Na⁺permeates Navs with significantly higher efficiency than many other cations, but Li⁺can also permeate Navs to a comparable extent as Na⁺. It had been known that Li⁺in blood enters cell via Navs and effects beneficially on various neuropathies. However, the molecular basis of the high Li⁺selectivity of Navs had been unclear. In this study, using a prokaryotic Nav, we successfully created the first Nav mutant that is more selective for Li⁺than for Na⁺. Electrophysiological and crystallographic analyses revealed the critical determinants of high Li⁺selectivity: the strong electrostatic interaction between the ion pathway and hydrated ions, and the smaller number of hydration water exchanges within the ion pathway. Additionally, the extensive interactions around the ion pathway were shown to support monovalent cation selectivity. New drug directions based on the molecular basis for Li⁺permeation may target various neurological disorders and clarify the broader biological effects of lithium.