Eglen R M
DiscoveRx Corp, 42501, Albrae St., Suite 100, Fremont, CA 94538, USA.
Auton Autacoid Pharmacol. 2006 Jul;26(3):219-33. doi: 10.1111/j.1474-8673.2006.00368.x.
1 Muscarinic M1-M5 receptors mediate the metabotropic actions of acetylcholine in the nervous system. A growing body of data indicate they also mediate autocrine functions of the molecule. The availability of novel and selective muscarinic agonists and antagonists, as well as in vivo gene disruption techniques, has clarified the roles of muscarinic receptors in mediating both functions of acetylcholine. 2 Selective M1 agonists or mixed M1 agonists/M2 antagonists may provide an approach to the treatment of cognitive disorders, while M3 antagonism, or mixed M2/M3 antagonists, are approved for the treatment of contractility disorders including overactive bladder and chronic obstructive pulmonary disease. Preclinical data suggest that selective agonism of the M4 receptor will provide novel anti-nociceptive agents, while therapeutics-based upon agonism or antagonism of the muscarinic M5 receptor have yet to be reported. 3 The autocrine functions of muscarinic receptors broadly fall into two areas - control of cell growth or proliferation and mediation of the release of chemical mediators from epithelial cells, ultimately causing muscle relaxation. The former particularly are involved in embryological development, oncogenesis, keratinocyte function and immune responsiveness. The latter regulate contractility of smooth muscle in the vasculature, airways and urinary bladder. 4 Most attention has focused on muscarinic M1 or M3 receptors which mediate lymphocyte immunoresponsiveness, cell migration and release of smooth muscle relaxant factors. Muscarinic M4 receptors are implicated in the regulation of keratinocyte adhesion and M2 receptors in stem cell proliferation and development. Little data are available concerning the M5 receptor, partly due to the difficulties in defining the subtype pharmacologically. 5 The autocrine functions of acetylcholine, like those in the nervous system, involve activation of several muscarinic receptor subtypes. Consequently, the role of these subtypes in autocrine, as well neuronal cholinergic systems, significantly expands their importance in physiology and pathophysiology.
毒蕈碱型M1 - M5受体介导乙酰胆碱在神经系统中的代谢型作用。越来越多的数据表明，它们还介导该分子的自分泌功能。新型选择性毒蕈碱激动剂和拮抗剂的出现，以及体内基因破坏技术，已经阐明了毒蕈碱受体在介导乙酰胆碱这两种功能中的作用。
选择性M1激动剂或M1激动剂/M2拮抗剂混合物可能为认知障碍的治疗提供一种方法，而M3拮抗剂或M2/M3拮抗剂混合物已被批准用于治疗包括膀胱过度活动症和慢性阻塞性肺疾病在内的收缩性疾病。临床前数据表明，M4受体的选择性激动将提供新型抗伤害感受药物，而基于毒蕈碱型M5受体激动或拮抗的治疗方法尚未见报道。
毒蕈碱受体的自分泌功能大致可分为两个领域——细胞生长或增殖的控制以及上皮细胞化学介质释放的介导，最终导致肌肉松弛。前者尤其涉及胚胎发育、肿瘤发生、角质形成细胞功能和免疫反应性。后者调节血管、气道和膀胱中平滑肌的收缩性。
大多数关注集中在介导淋巴细胞免疫反应性、细胞迁移和平滑肌舒张因子释放的毒蕈碱型M1或M3受体上。毒蕈碱型M4受体与角质形成细胞黏附的调节有关，M2受体与干细胞增殖和发育有关。关于M5受体的数据很少，部分原因是在药理学上定义该亚型存在困难。
乙酰胆碱的自分泌功能，与神经系统中的功能一样，涉及几种毒蕈碱受体亚型的激活。因此，这些亚型在自分泌以及神经元胆碱能系统中的作用，显著扩大了它们在生理学和病理生理学中的重要性。
