Interaction of local anesthetics with a peptide encompassing the IV/S4-S5 linker of the Na+ channel
Interaction of local anesthetics with a peptide encompassing the IV/S4-S5 linker of the Na+ channel
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DOI：
10.1016/j.bpc.2006.03.010
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发表时间：
2006-08-20
影响因子：
3.8
通讯作者：
Pertinhez, Thelma A.
中科院分区：
文献类型：
--
作者：
Fraceto, Leonardo F.;Oyama, Sergio, Jr.;Pertinhez, Thelma A.
肽pIV/S4-S5包含电压门控Na+通道结构域IV中螺旋S4-S5之间的胞质接头，残基1644-1664。（2）用DOSY、H_1-N-15-HSQC谱和计算方法研究了两种局麻药利多卡因和苯扎替尼与pIV/S_4-S_5的相互作用。DOSY表示。中性酯苯并咪唑与pIV/S4-S5的相互作用强于带电荷的胺-酰胺利多卡因。加权平均化学位移Δ Δ（H-1-N-15）表明，苯并咪唑影响残基L-1653、M-1655和S-1656，而利多卡因分别轻微干扰N-和C-末端附近的残基I-1646、L-1649和A（1659）、L-1660。计算方法证实了苯并咪唑结合的稳定性和利多卡因两个结合位点的存在。即使考虑到在共溶剂（TFE/H2O，30%/70%v/v）存在下研究肽的方法具有固有的有限含义，我们的数据也强烈支持IV/S4-S5接头中存在多个LA结合位点，如文献中所建议的。此外，我们认为LA可以以不同的结合模式和强度与S4-S5接头结合，因为该接头是“失活门颗粒”的受体的一部分。在这项工作中提出了设计新的功能研究，旨在更好地了解Na+通道功能以及LA药理活性的各个方面的条件。(c)2006 Elsevier B. V.保留所有权利。
The peptide pIV/S4-S5 encompasses the cytoplasmic linker between helices S4-S5 in domain IV of the voltage-gated Na+ channel, residues 1644-1664. (2)The interaction of two local anesthetics (LA), lidocaine and benzocaine, with pIV/S4-S5 has been studied by DOSY, heteronuclear NMR H-1-N-15-HSQC spectroscopy and computational methods. DOSY indicates that. benzocaine, a neutral ester, exhibits stronger interaction with pIV/S4-S5 than lidocaine, a charged amine-amide. Weighted average chemical shifts, Delta delta(H-1-N-15), show that benzocaine affects residues L-1653, M-1655 and S-1656 while lidocame slightly perturbs residues I-1646, L-1649 and A(1659), L-1660, near the N-and C-terminus, respectively. Computational methods confirmed the stability of the benzocaine binding and the existence of two binding sites for lidocaine. Even considering that the approach of studying the peptide in the presence of a co-solvent (TFE/H2O, 30%/70% v/v) has an inherently limited implication, our data strongly support the existence of multiple LA binding sites in the IV/S4-S5 linker, as suggested in the literature. In addition, we consider that LA can bind to the S4-S5 linker with diverse binding modes and strength since this linker is part of the receptor for the "inactivation gate particle". Conditions for devising new functional studies, aiming to better understand Na+ channel functionality as well as the various facets of LA pharmacological activity are proposed in this work. (c) 2006 Elsevier B.V. All rights reserved.