Molecular mechanisms of gating and drug block of sodium channels.
Molecular mechanisms of gating and drug block of sodium channels.
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DOI：
10.1002/0470846682.ch14
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发表时间：
2002
影响因子：
--
通讯作者：
W. Catterall
中科院分区：
文献类型：
--
作者：
W. Catterall
电压门控Na+通道由260 kDa的α亚基和33-36 kDa的β亚基组成。α亚基有4个同源结构域（I至IV），包含6个跨膜α螺旋（S1-S6）。S4段作为电压传感器，向外移动以启动激活。S5和S6节段以及它们之间的短膜相关环形成孔。快速失活是由细胞内环在III和IV结构域之间形成的失活门的关闭介导的。失活门的三维结构已通过核磁共振波谱确定，揭示了孔隙阻断IFM基序的构象。改变Na+通道门控的肽蝎毒素与IIS4和IVS4片段的细胞外末端结合，将它们困在激活或非激活的位置，从而选择性地改变通道的激活或失活。电压传感器捕获可能是毒素作用于电压门控离子通道的一般机制。局部麻醉剂通过与S6节段III和IV结构域的受体位点结合来阻断Na+通道的孔。抗惊厥药和抗心律失常药物也与该位点相互作用。一种高亲和力的Na+通道阻滞剂最近以该位点为靶点被开发出来。对Na+通道门控和药物阻滞的分子机制的新认识可能有助于开发治疗癫痫、心律失常和持续性疼痛综合征的新疗法。
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.