MUSCARINIC STIMULATION OF AIRWAY SMOOTH-MUSCLE CELLS

1. Acetylcholine, the principal neurotransmitter of the parasympatheti c nervous system, is released at both ganglionic synapses and postgang lionic neuroeffector junctions and acts by activation of nicotinic and muscarinic cholinoceptors. This review focuses on the effects of post junctional muscarinic stimulation of airway smooth muscle. 2. On pharm acological criteria, four distinct subtypes of muscarinic cholinocepto r, denoted M-1, M-2, M-3 and M-4 receptors, have been identified by us e of selective antagonists. Cloned muscarinic cholinoceptors are membe rs of the family of GTP-binding protein-coupled receptors, which are c haracterized by seven transmembrane (TM) regions connected by intra- a nd extracellular loops. Between the fifth and the-sixth TM regions, mu scarinic receptors possess a large intracytoplasmic loop that is consi dered to be responsible for G-protein-coupling selectivity and exhibit s high divergence between the different subtypes. 3. At the site of th e smooth muscle itself, both binding and Northern blot studies have de monstrated, in a variety of species, that muscarinic receptor subtypes present are M-2 and M-3. M-2 receptors are coupled to G(1) proteins a nd adenylyl cyclase inhibition and thus to cAMP signaling. M-3 recepto rs are coupled to G(q/11) protein and phosphoinositide hydrolysis and thus to calcium signaling. 4. Muscarinic-induced contraction of airway smooth muscle is mediated by M-3 receptors. M-2-mediated inhibition o f adenylyl cyclase contributes to the prevention of bronchodilation. C ross-talk between muscarinic and beta(2) adrenoceptors is likely to be present in airway smooth muscle. The pathophysiological role of this cross-talk requires further investigation. GEN PHARMAC 31;3:349-356, 1 998. (C) 1998 Elsevier Science Inc.