Muscarinic acetylcholine receptors mediate diverse physiological functions. At present, five receptor subtypes (M1 - M5) have been identified. The odd-numbered receptors (M1, M3, and M5) are preferentially coupled to Gq/11 and activate phospholipase C, which initiates the phosphatidylinositol trisphosphate cascade leading to intracellular Ca2+ mobilization and activation of protein kinase C. On the other hand, the even-numbered receptors (M2 and M4) are coupled to Gi/o, and inhibit adenylyl cyclase activity. They also activate G protein-gated potassium channels, which leads to hyperpolarization of the plasma membrane in different excitable cells. Individual members of the family are expressed in an overlapping fashion in various tissues and cell types. Recent gene targeting approaches have unraveled the specific function of these muscarinic receptor subtypes, which were not able to be fully elucidated with pharmacological approaches because of the non-selective effects of the available ligands. Based on these findings, muscarinic receptors have been emerging as an important therapeutic target for various diseases, including dry mouth, incontinence and chronic obstructive pulmonary disease. Here we review the latest advances in the structural and functional characterization of muscarinic acetylcholine receptors and the pharmaceutical development of muscarinic receptor ligands.
Muscarinic acetylcholine receptor, G protein, phospholipase C, adenylyl cyclase, G protein-gated potassium channel, pharmacology, gene targeting
Department of Pharmacology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita,Osaka 565-0871, Japan.