Peralta E G, Ashkenazi A, Winslow J W, Ramachandran J, Capon D J
Department of Molecular Biology, Genentech, Inc., South San Francisco, CA 94080.
Nature. 1988 Aug 4;334(6181):434-7. doi: 10.1038/334434a0.
Muscarinic acetylcholine receptors (mAChRs), like many other neurotransmitter and hormone receptors, transduce agonist signals by activating G proteins to regulate ion channel activity and the generation of second messengers via the phosphoinositide (PI) and adenylyl cyclase systems. Human mAChRs are a family of at least four gene products which have distinct primary structures, ligand-binding properties and patterns of tissue-specific expression. To examine the question of whether functional differences exist between multiple receptor subtypes, we have investigated the ability of each subtype to regulate PI hydrolysis and adenylyl cyclase when expressed individually in a cell lacking endogenous mAChRs. We show that the HM2 and HM3 mAChRs efficiently inhibit adenylyl cyclase activity but poorly activate PI hydrolysis. In contrast, the HM1 and HM4 mAChRs strongly activate PI hydrolysis, but do not inhibit adenylyl cyclase, and in fact can substantially elevate cAMP levels. Interestingly, the subtypes that we find to be functionally similar are also more similar in sequence. Our results indicate that the different receptor subtypes are functionally specialized.
毒蕈碱型乙酰胆碱受体（mAChRs）与许多其他神经递质和激素受体一样，通过激活G蛋白来转导激动剂信号，从而调节离子通道活性，并通过磷酸肌醇（PI）和腺苷酸环化酶系统生成第二信使。人类mAChRs是一个至少由四种基因产物组成的家族，它们具有不同的一级结构、配体结合特性和组织特异性表达模式。为了研究多种受体亚型之间是否存在功能差异的问题，我们研究了在缺乏内源性mAChRs的细胞中单独表达时，每种亚型调节PI水解和腺苷酸环化酶的能力。我们发现，HM2和HM3 mAChRs能有效抑制腺苷酸环化酶活性，但激活PI水解的能力较弱。相反，HM1和HM4 mAChRs强烈激活PI水解，但不抑制腺苷酸环化酶，实际上还能大幅提高cAMP水平。有趣的是，我们发现功能相似的亚型在序列上也更相似。我们的结果表明，不同的受体亚型在功能上是专门化的。
