Molecular mechanisms of gating and drug block of sodium channels.
Voltage-gated Na+ channels are composed of an alpha subunit of 260 kDa associated with beta subunits of 33-36 kDa. Alpha subunits have four homologous domains (I to IV) containing six transmembrane alpha 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 3-D structure of the inactivation gate has been determined bv 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 IIS4 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.
Catterall
William A
WA
Department of Pharmacology, University of Washington, Seattle 98195-7280, USA.
D000818:Animals; D001921:Brain / Q000502:physiology; D015640:Ion Channel Gating / Q000187:drug effects* / Q000235:genetics; D008958:Models, Molecular; D011487:Protein Conformation; D021122:Protein Subunits; D012604:Scorpion Venoms / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects / Q000235:genetics / Q000502:physiology*
D021122:Protein Subunits; D012604:Scorpion Venoms; D015222:Sodium Channels