Molecular basis for the differential sensitivity of rat and human α9α10 nAChRs to α-conotoxin RgIA.
Molecular basis for the differential sensitivity of rat and human α9α10 nAChRs to α-conotoxin RgIA.
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DOI：
10.1111/j.1471-4159.2012.07867.x
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发表时间：
2012-09
影响因子：
4.7
通讯作者：
McIntosh JM
中科院分区：
文献类型：
--
作者：
Azam L;McIntosh JM
α9α10烟碱型乙酰胆碱受体（nAChR）可能是听觉系统、慢性疼痛、乳腺癌和肺癌病理生理学的潜在靶点。α-芋螺毒素是一种强效的烟碱拮抗剂，其中一些对α9α10 nAChR具有选择性。在这里，我们报告了α-芋螺毒素RgIA对大鼠与人α9α10 nAChR的效力的两个数量级的物种差异。我们研究了这种差异的分子机制。在非洲爪蟾卵母细胞中，大鼠α9与人α10亚基的异源表达产生了一种受体，该受体被RgIA阻断，其效力与大鼠α9α10 nAChR相似。相反，人α9与大鼠α10亚基的表达产生被RgIA阻断的受体，其效力接近人α9α10受体。将人α9亚基中发现的残基系统性替换为大鼠α9亚基中的同源位置，发现单一点突变（Thr 56至Ile 56）主要是造成这种种属差异的原因。值得注意的是，虽然先前已报道α9 nAChR亚基提供RgIA结合的主要（+）结合面，但Thr 56位于（-）互补结合面。
The α9α10 nicotinic acetylcholine receptor (nAChR) may be a potential target in pathophysiology of the auditory system, chronic pain and breast and lung cancers. Alpha-conotoxins, from the predatory marine snail Conus, are potent nicotinic antagonists, some of which are selective for the α9α10 nAChR. Here we report a two-order of magnitude species difference in the potency of α-conotoxin RgIA for the rat vs. human α9α10 nAChR. We investigated the molecular mechanism of this difference. Heterologous expression of the rat α9 with the human α10 subunit in Xenopus oocytes resulted in a receptor that was blocked by RgIA with potency similar to that of the rat α9α10 nAChR. Conversely, expression of the human α9 with that of the rat α10 subunit resulted in a receptor that was blocked by RgIA with potency approaching that of the human α9α10 receptor. Systematic substitution of residues found in the human α9 subunit into the homologous position in the rat α9 subunit revealed that a single point mutation, Thr56 to Ile56, primarily accounts for this species difference. Remarkably, although the α9 nAChR subunit has previously been reported to provide the principal (+) binding face for binding of RgIA, Thr56 is located in the (−) complementary binding face.
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