Interactions between 3-(Trifluoromethyl)-3-(m-[(125)I]iodophenyl)diazirine and tetracaine, phencyclidine, or histrionicotoxin in the Torpedo series nicotinic acetylcholine receptor ion channel.
Interactions between 3-(Trifluoromethyl)-3-(m-[(125)I]iodophenyl)diazirine and tetracaine, phencyclidine, or histrionicotoxin in the Torpedo series nicotinic acetylcholine receptor ion channel.
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鱼雷系列烟碱乙酰胆碱受体离子通道中 3-(三氟甲基)-3-(间-[(125)I]碘苯基)二氮丙啶与丁卡因、苯环利定或组烟毒素之间的相互作用。
DOI：
10.1124/mol.59.6.1514
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发表时间：
2001
影响因子：
3.6
通讯作者：
Cohen,JB
中科院分区：
文献类型：
--
作者：
Gallagher,MJ;Chiara,DC;Cohen,JB
3-（三氟甲基）-3-（m-[125I]碘苯基）重氮嘧啶（[125I]TID）和[3H]丁卡因是一种芳香胺，它们是烟碱类乙酰胆碱受体（nAChR）的非竞争性拮抗剂（NCAs），通过光亲和标记表明它们在封闭状态下结合在离子通道的共同位点上。虽然丁卡因和TID结合在同一位点，但胺类NCAs苯环利啶（PCP）和组氨酸毒素（HTX）也被认为在离子通道内结合，它们与丁卡因竞争性相互作用，但与TID发生变构性相互作用。为了更好地表征封闭状态下nAChR离子通道内的药物相互作用，我们鉴定了由[125I]TID标记的氨基酸在丁卡因、PCP或HTX存在下的光亲和性。在没有其他药物的情况下，[125I]TID与α leu -251 （αM2-9）和α val -255 （αM2-13）以及其他亚基中的同源残基发生反应。没有一种NCAs将[125I]TID标记位点转移到离子通道内的其他残基上。丁卡因抑制了[125I]TID在M2-9和M2-13的标记，但没有改变这些位置的相对125I掺入，而PCP和HTX分别改变了[125I]TID在M2-9和M2-13的掺入模式。这些结果表明，丁卡因和TID以互排斥的方式结合在封闭通道中的一个共同位点上，该位点与PCP和HTX的结合位点在空间上分离。
3-(Trifluoromethyl)-3-(m-[125I]iodophenyl)diazirine ([125I]TID) and [3H]tetracaine, an aromatic amine, are noncompetitive antagonists (NCAs) of theTorpedospecies nicotinic acetylcholine receptor (nAChR), which have been shown by photoaffinity labeling to bind to a common site in the ion channel in the closed state. Although tetracaine and TID bind to the same site, the amine NCAs phencyclidine (PCP) and histrionicotoxin (HTX), which are also believed to bind within the ion channel, interact competitively with tetracaine but allosterically with TID. To better characterize drug interactions within the nAChR ion channel in the closed state, we identified the amino acids photoaffinity labeled by [125I]TID in the presence of tetracaine, PCP, or HTX. In the absence of other drugs, [125I]TID reacts withαLeu-251 (αM2-9) andαVal-255 (αM2-13) and the homologous residues in each of the other subunits. None of the NCAs shifted the sites of [125I]TID labeling to other residues within the ion channel. Tetracaine inhibited [125I]TID labeling of M2-9 and M2-13 without changing the relative125I incorporation at these positions, whereas PCP and HTX each altered the pattern of [125I]TID incorporation at M2-9 and M2-13. These results indicate that tetracaine and TID bind in a mutually exclusive manner to a common site in the closed channel that is spatially separated from the binding sites for PCP and HTX.