Molecular distinction between muscarinic acetylcholine receptor subtypes
Molecular distinction between muscarinic acetylcholine receptor subtypes
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毒蕈碱乙酰胆碱受体亚型之间的分子区别
作者：
K. Fukuda;T. Kubo;I. Akiba;A. Maeda;M. Mishina;S. Numa
毒蕈碱乙酰胆碱受体 (mAChR) 通过鸟嘌呤核苷酸结合调节蛋白的作用介导各种细胞反应，包括腺苷酸环化酶的抑制、磷酸肌醇的分解和钾通道的调节1-3。 mAChR 的药理学上可区分的形式存在于不同的组织中，根据其与拮抗剂的表观亲和力的差异，暂时分为 M1 (I)、M2 心脏 (II) 和 M2 腺体 (III) 亚型4-8。为了阐明 mAChR 功能异质性的分子基础，我们克隆并测序了与编码 mAChR 的猪脑和心脏信使 RNA 互补的 DNA，从而推导出受体蛋白的一级结构9,10。我们在此报道，心脏互补DNA转录产生的信使RNA指导非洲爪蟾卵母细胞中功能性mAChR的形成，并且该mAChR在乙酰胆碱（ACh）诱导的反应和拮抗剂结合特性方面均不同于由大脑cDNA9表达形成的mAChR。我们的结果提供证据表明，由大脑 cDNA 编码的 mAChR（称为 mAChR I）和由心脏 cDNA 编码的 mAChR（mAChR II）分别属于 M1 (I) 和 M2 心脏 (II) 亚型。
The muscarinic acetylcholine receptor (mAChR) mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels, through the action of guanine nucleotide-binding regulatory proteins1–3. Pharmacologically distinguishable forms of the mAChR occur in different tissues and have provisionally been classified into M1 (I), M2 cardiac (II) and M2 glandular (III) subtypes on the basis of their difference in apparent affinity for antagonists4–8. In an attempt to elucidate the molecular basis of the functional heterogeneity of the mAChR, we have cloned and sequenced DNAs complementary to porcine cerebral and cardiac messenger RNAs encoding mAChRs and have thereby deduced the primary structures of the receptor proteins9,10. We report here that the messenger RNA generated by transcription of the cardiac complementary DNA directs the formation of a functional mAChR in Xenopus oocytes and that this mAChR differs from the mAChR formed by expression of the cerebral cDNA9 both in acetylcholine (ACh)-induced response and in antagonist binding properties. Our results provide evidence indicating that the mAChR encoded by the cerebral cDNA (designated as mAChR I) and the mAChR encoded by the cardiac cDNA (mAChR II) are of the M1 (I) and the M2 cardiac (II) subtype, respectively.