Molecular Mechanisms of Gating and Drug Block of Sodium Channels

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Abstract
Voltage-gated Na+ channels are composed of an subunit of 260 kDa associated with β subunits of 33–36 kDa. α subunits have four homologous domains (I to IV) containing six transmembrane α helices (S1, S6). The S4 segments serve as voltage sensors and move outward to initiate activation. The S5 and S6 segments and the short membrane-associated loops between them form the pore. Fast inactivation is mediated by closure of an inactivation gate formed by the intracellular loop between domains III and IV. The 340 structure of the inactivation gate has been determined by NMR spectroscopy, revealing the conformation of the pore-blocking IFM motif. Peptide scorpion toxins that alter gating of Na+ channels bind to the extracellular ends of the HS4 and IVS4 segments, trap them in either an activated or non-activated position and thereby selectively alter channel activation or inactivation. Voltage sensor-trapping may be a general mechanism of toxin action on voltage-gated ion channels. Local anaesthetics block the pore of Na+ channels by binding to a receptor site in segment S6 in domains III and IV. Anticonvulsants and antiarrhythmic drugs also interact with this site. A high affinity Na+ channel blocker has recently been developed with this site as its target. The emerging knowledge of the molecular mechanisms of Na+ channel gating and drug block may allow development of novel therapeutics for epilepsy, cardiac arrhythmia and persistent pain syndromes.

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