Differential interactions of lamotrigine and related drugs with transmembrane segment IVS6 of voltage-gated sodium channels
Differential interactions of lamotrigine and related drugs with transmembrane segment IVS6 of voltage-gated sodium channels
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DOI：
10.1016/s0028-3908(02)00400-8
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发表时间：
2003-03-01
影响因子：
4.7
通讯作者：
Catterall, WA
中科院分区：
文献类型：
--
作者：
Liu, G;Yarov-Yarovoy, V;Catterall, WA
电压门控钠通道被局部麻醉药和抗惊厥药阻断。局部麻醉剂的受体位点已被确定在α亚基的结构域IV（IVS6）的跨膜片段S6中，但抗惊厥药拉莫三嗪和相关化合物具有比局部麻醉剂更复杂的结构，并可能与其他氨基酸残基相互作用。拉莫三嗪和化合物227 c89、4030 w92和619 c89在非洲爪蟾卵母细胞中表达的大鼠脑IIA型钠通道失活状态阻滞的表观KD值分别为31.9 μ M、17.3 μ M、3.7 μ M和10.3 μ M。化合物619c89是最强的频率依赖性阻滞剂，与拉莫三嗪相比，其与更高的亲和力和从药物阻滞中恢复慢5倍相关。拉莫三嗪阻断突变型钠通道α的实验研究。亚基，其中丙氨酸已取代IVS6中的每个单独的氨基酸，鉴定出突变11760A、F1764A和Y1771A导致亲和力的最大降低（分别为6倍、7倍和12倍）。对于化合物227c89、4030w92和619c89，这三种突变的效应比率不同。与这些孔阻断药物相互作用的氨基酸残基限定了暴露于孔的IVS6表面，并且可以在门控期间旋转。(C)2003爱思唯尔科技有限公司版权所有。
Voltage-gated sodium channels are blocked by local anesthetic and anticonvulsant drugs. A receptor site for local anesthetics has been defined in transmembrane segment S6 in domain IV (IVS6) of the alpha subunit, but the anticonvulsant lamotrigine and related compounds have more complex structures than local anesthetics and may interact with additional amino acid residues. Apparent K-D values for inactivated-state block of rat brain type IIA sodium channels expressed in Xenopus oocytes were 31.9 muM, 17.3 muM, 3.7 muM and 10.3 muM for lamotrigine and compounds 227c89, 4030w92 and 619c89, respectively. Compound 619c89 was the strongest frequency-dependent blocker, which correlated with higher affinity and a five-fold slower recovery from drug block compared to lamotrigine. Examination of lamotrigine block of mutant sodium channel alpha. subunits, in which alanine had been substituted for each individual amino acid in IVS6, identified mutations 11760A, F1764A and Y1771A as causing the largest reductions in affinity (six-, seven- and 12-fold, respectively). The ratios of effects of these three mutations differed for compounds 227c89, 4030w92, and 619c89. The amino acid residues interacting with these pore-blocking drugs define a surface of IVS6 that is exposed to the pore and may rotate during gating. (C) 2003 Elsevier Science Ltd. All rights reserved.