Sodium Channels

Abstract

Abstract Excitable cells, such as neurons or cardiomyocytes, communicate with each other via action potentials. This fast change in membrane voltage is initiated by the rapid opening of voltage‐gated sodium selective channels, of which to date nine subtypes are known (Nav1.1–Nav1.9). These large membrane spanning proteins undergo gating changes on a timescale ranging from milliseconds to minutes. Depolarization past threshold leads to activation and sodium ions flow into the cell. Within milliseconds the inactivation particle blocks the pore, current flow is interrupted and the channel is fast inactivated. Channels need to recover from fast inactivation at negative potentials to be able to reopen anew. Recent data on crystal structures shape our 3D picture of sodium channels and mutagenesis studies help understanding their structure–function relation. Sodium channels are major regulators of membrane excitability and play an important role in pain, arrhythmias and muscle diseases, and subtype‐specific blockers have been currently developed. Key Concepts The fast upstroke of the action potential (AP) is initiated by the opening of voltage‐gated sodium channels (Navs). Navs are large transmembrane proteins consisting of four homologous domains (DI–DIV). Each domain consists of six transmembrane segments S1–S6, which form a voltage sensor (S1–S4) and parts of the pore module (S5–S6). The domains are connected by intracellular linkers. The DIII–DIV linker contains the inactivation particle. Upon depolarization, Navs open quickly, sodium ions flow into the cell, and within milliseconds, fast inactivation occurs. Slow inactivation happens on a much slower timescale (seconds to minutes) and involves other parts of the channel protein. Recently, crystal structures of bacterial sodium channels have helped explicate the changes in 3D structure that accompany gating. Navs are involved in the generation of pain, arrhythmias and myopathies (among others).