Voltage-gated sodium channel Nav1.4 (Nav1.4)

Voltage-gated sodium channel Nav1.4 (Nav1.4) is a transmembrane glycoprotein complex predominantly expressed in skeletal muscle, where it serves as the primary mediator of the rapid depolarizing phase of action potentials essential for muscle contraction and excitation-contraction coupling. Composed of a large alpha subunit (SCN4A) with four homologous domains each containing voltage-sensing (S1-S4) and pore-forming (S5-S6) segments, Nav1.4 responds to membrane depolarization by undergoing conformational changes that open a selective Na+ pore, allowing influx that triggers Ca2+ release from the sarcoplasmic reticulum. Gain-of-function mutations in SCN4A, such as those causing persistent Na+ currents or impaired inactivation, lead to channelopathies including myotonia congenita, hyperkalemic periodic paralysis, and paramyotonia congenita, characterized by muscle stiffness, weakness, or paralysis. Loss-of-function mutations can result in hypokalemic periodic paralysis or congenital myasthenia. Therapeutically, Nav1.4 is targeted by local anesthetics like lidocaine and antiarrhythmics like flecainide, which exhibit state- and use-dependent blockade to suppress hyperexcitability, though selectivity challenges arise from homology with cardiac (Nav1.5) and neuronal isoforms. High-resolution cryo-EM structures of the human Nav1.4-β1 complex reveal asymmetric voltage sensor activation and allosteric fast inactivation mechanisms, guiding structure-based drug design for muscle disorders.

Other names

SCN4Asodium channel protein type 4 subunit alpha

state-dependent blockade (preferential binding to open/inactivated states), use-dependent blockade (increased potency at high firing frequencies), pore blockade, voltage sensor domain inhibition, gating modification