Muscarinic receptor subtypes in neuronal and non‐neuronal cholinergic function

Summary1 Muscarinic M1–M5receptors 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 asin vivogene disruption techniques, has clarified the roles of muscarinic receptors in mediating both functions of acetylcholine.2 Selective M1agonists or mixed M1agonists/M2antagonists may provide an approach to the treatment of cognitive disorders, while M3antagonism, or mixed M2/M3antagonists, are approved for the treatment of contractility disorders including overactive bladder and chronic obstructive pulmonary disease. Preclinical data suggest that selective agonism of the M4receptor will provide novel anti‐nociceptive agents, while therapeutics‐based upon agonism or antagonism of the muscarinic M5receptor 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 M1or M3receptors which mediate lymphocyte immunoresponsiveness, cell migration and release of smooth muscle relaxant factors. Muscarinic M4receptors are implicated in the regulation of keratinocyte adhesion and M2receptors in stem cell proliferation and development. Little data are available concerning the M5receptor, 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.