对M3毒蕈碱型乙酰胆碱受体生理学和结构的新见解。
Novel insights into M3 muscarinic acetylcholine receptor physiology and structure.
作者信息
Kruse Andrew C, Li Jianhua, Hu Jianxin, Kobilka Brian K, Wess Jürgen
机构信息
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.
出版信息
J Mol Neurosci. 2014 Jul;53(3):316-23. doi: 10.1007/s12031-013-0127-0. Epub 2013 Sep 26.
Abstract
Recent studies with M3 muscarinic acetylcholine receptor (M3R) mutant mice suggest that drugs selectively targeting this receptor subtype may prove useful for the treatment of various pathophysiological conditions. Moreover, the use of M3R-based designer G protein-coupled receptors (GPCRs) has provided novel insights into how Gq-coupled GPCRs can modulate whole-body glucose homeostasis by acting on specific peripheral cell types. More recently, we succeeded in using X-ray crystallography to determine the structure of the M3R bound to the bronchodilating drug tiotropium, a muscarinic antagonist (inverse agonist). This new structural information should facilitate the development of orthosteric or allosteric M3R-selective drugs that are predicted to have considerable therapeutic potential.
摘要
最近对M3毒蕈碱型乙酰胆碱受体（M3R）突变小鼠的研究表明，选择性靶向该受体亚型的药物可能被证明对治疗各种病理生理状况有用。此外，基于M3R的设计型G蛋白偶联受体（GPCR）的应用，为Gq偶联GPCR如何通过作用于特定外周细胞类型来调节全身葡萄糖稳态提供了新的见解。最近，我们成功利用X射线晶体学确定了与支气管扩张药物噻托溴铵（一种毒蕈碱拮抗剂，即反向激动剂）结合的M3R的结构。这一新的结构信息应有助于开发预计具有相当治疗潜力的正构或变构M3R选择性药物。
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