ABSTRACT
Voltage-gated sodium (Na+) channels initiate action potentials in neurons, muscle, and other excitable cells. They are complexes of a large α subunit with one or two smaller β subunits. The α subunits contain four homologous domains with six transmembrane segments (S1–S6) that form a voltage-sensing module (S1–S4) and a pore-forming module (S5 and S6). Na+ channels are activated when membrane depolarization induces outward movement and rotation of the S4 segment in each voltage-sensing module, which is physically coupled to opening of the pore by the S4–S5 linker. The fast inactivation gate formed by the intracellular loop connecting domains III and IV folds into a receptor site next to the inner mouth of the pore and blocks it rapidly during sustained depolarization. Many classes of potent neurotoxins bind to distinct receptor sites and alter Na+ channel function. Local anesthetic, antiepileptic, and antiarrhythmic drugs bind to a receptor site within the pore of the sodium channel and block it to reduce channel function in local anesthesia and in diseases of hyperexcitability. Mutations in Na+ channels cause rare inherited forms of epilepsy, chronic pain, periodic paralysis, cardiac arrhythmia and other syndromes, which provide important experimental models for more widespread forms of these diseases.
