Elementary mechanisms underlying activation of leak sodium channels.

Abstract

The sodium-leak channel (NALCN) are weakly voltage-dependent ion channels responsible for background Na+ permeability that controls resting membrane potential in neurons and other excitable cells. Although homologous to voltage-gated Na+ and Ca2+ channels, NALCN is distinct in associating with auxiliary subunits FAM155A, UNC-79, and UNC-80 which augment its function. Precise regulation of this channel's activity is physiologically crucial, as gain of function mutations in humans lead to severe congenital neurodevelopmental disorders in humans, including infantile hypotonia with psychomotor retardation and characteristic facies 1 (IHPRF1) and congenital contractures of limbs and face, hypotonia and developmental delay (CLIFAHDD). Here we performed cell-attached low noise single-channel recordings to dissect elementary properties of NALCN gating. Expression of NALCN with its canonical subunits revealed a largely non-selective channel with ∼27 pS conductance and a reversal potential of ∼5.7 mV. Scrutiny of single channel recordings showed distinct gating modes and low open probabilities. As extracellular Ca2+ block of NALCN is fundamental to its physiological function, we further probed underlying single channel mechanisms. In all, these results provide a framework to establish regulatory mechanisms in physiology and to contextualize altered channel function in pathophysiology.