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首页> 外文期刊>Journal of receptor and signal transduction research >Localization by site-directed mutagenesis of a galantamine binding site on α7 nicotinic acetylcholine receptor extracellular domain
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Localization by site-directed mutagenesis of a galantamine binding site on α7 nicotinic acetylcholine receptor extracellular domain

机译：通过定点诱变在α7烟碱型乙酰胆碱受体胞外域上的加兰他敏结合位点进行定位诱变

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摘要

Galantamine is an approved drug treatment for Alzheimer's disease. Initially identified as a weak cholinesterase inhibitor, we have established that galantamine mainly acts as an 'allosterically potentiating ligand (APL)' of nicotinic acetylcholine receptors (nAChR). Meanwhile other 'positive allosteric modulators (PAM)' of nAChR channel activity have been discovered, and for one of them a binding site within the transmembrane domain has been proposed. Here we show, by performing site-directed mutagenesis studies of ectopically expressed chimeric chicken α7/mouse 5-hydroxytryptamine 3 receptor-channel complex, in combination with whole-cell current measurements, in the presence and absence of galantamine, that the APL binding site is different from the proposed PAM binding site. We demonstrate that residues T197, I196, and F198 of ?-strand 10 represent major elements of the galantamine binding site. Residue K123, earlier suggested as being 'close to' the APL binding site, is not part of this site but rather appears to play a role in coupling of agonist binding to channel opening and closing. Our data confirm our earlier results that the galantamine binding site is different from the ACh binding site. Both sites are in close proximity and hence may influence each other in a synergistic fashion. Other interesting areas identified in the present study are a 'hinge' region around and containing residues F122, K123, and K143 possibly being involved in relaying the signal of agonist binding to gating of the transmembrane channel, and a 'folding centre', with P119 as the dominating residue, that crucially positions the agonist binding site with respect to the hinge region.
机译：加兰他敏是一种被批准用于治疗阿尔茨海默氏病的药物。最初被确定为弱胆碱酯酶抑制剂，我们已经确定加兰他敏主要充当烟碱乙酰胆碱受体（nAChR）的“变构增强配体（APL）”。同时，还发现了nAChR通道活性的其他“正变构调节剂（PAM）”，并提出了其中一个跨膜结构域内的结合位点。在这里，我们通过对异位表达的嵌合鸡α7/小鼠5-羟基色胺3受体通道复合物进行定点诱变研究，结合全细胞电流测量，在有和没有加兰他敏的情况下，发现了APL结合位点与建议的PAM绑定位点不同。我们证明了α链10的残基T197，I196和F198代表加兰他敏结合位点的主要元素。先前提出的残基K123“靠近” APL结合位点，不是该位点的一部分，而是似乎在激动剂结合与通道打开和关闭之间起着作用。我们的数据证实了我们较早的结果，即加兰他敏结合位点与ACh结合位点不同。两个站点非常靠近，因此可能会以协同方式相互影响。在本研究中发现的其他有趣的区域是一个残基F122，K123和K143周围并包含残基F122，K123和K143的“铰链”区域，该残基可能与通过P119传递激动剂结合到跨膜通道门控的信号以及一个“折叠中心”有关。作为主要残基，其相对于铰链区至关重要地定位激动剂结合位点。

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