REVIEW
Muscarinic Stimulation of Airway Smooth Muscle Cells

https://doi.org/10.1016/S0306-3623(98)00007-XGet rights and content

Abstract

  • 1.

    Acetylcholine, the principal neurotransmitter of the parasympathetic nervous system, is released at both ganglionic synapses and postganglionic neuroeffector junctions and acts by activation of nicotinic and muscarinic cholinoceptors. This review focuses on the effects of postjunctional muscarinic stimulation of airway smooth muscle.

  • 2.

    On pharmacological criteria, four distinct subtypes of muscarinic cholinoceptor, denoted M1, M2, M3 and M4 receptors, have been identified by use of selective antagonists. Cloned muscarinic cholinoceptors are members of the family of GTP-binding protein-coupled receptors, which are characterized by seven transmembrane (TM) regions connected by intra- and extracellular loops. Between the fifth and the sixth TM regions, muscarinic receptors possess a large intracytoplasmic loop that is considered to be responsible for G-protein-coupling selectivity and exhibits high divergence between the different subtypes.

  • 3.

    At the site of the smooth muscle itself, both binding and Northern blot studies have demonstrated, in a variety of species, that muscarinic receptor subtypes present are M2 and M3. M2 receptors are coupled to Gi proteins and adenylyl cyclase inhibition and thus to cAMP signaling. M3 receptors are coupled to Gq/11 protein and phosphoinositide hydrolysis and thus to calcium signaling.

  • 4.

    Muscarinic-induced contraction of airway smooth muscle is mediated by M3 receptors. M2-mediated inhibition of adenylyl cyclase contributes to the prevention of bronchodilation. Cross-talk between muscarinic and β2 adrenoceptors is likely to be present in airway smooth muscle. The pathophysiological role of this cross-talk requires further investigation.

Introduction

The parasympathetic nervous system is the major bronchoconstrictor neural pathway in the airways. Cholinergic fibers travel down the vagus nerve into the parasympathetic ganglia within the airway wall. From these ganglia, short postsynaptic fibers reach the smooth muscle and glands. Acetylcholine (ACh), the principal neurotransmitter of the parasympathetic nervous system, is released at both ganglionic synapses and postganglionic neuroeffector junctions and acts by activation of nicotinic and muscarinic cholinoceptors (Fig. 1). Nicotinic receptors belong to the family of receptor-channel proteins. They are located at the parasympathetic ganglia and mediate ganglionic transmission. Muscarinic receptors belong to the family of G-protein-coupled receptors and are present on the postganglionic nerve fibers and on target cells such as epithelial, submucosal gland and smooth muscle cells (Barnes, 1993). The action of ACh on these receptors leads to airway smooth muscle contraction, mucus secretion and permeabilization of blood vessel walls. ACh is one of the most efficacious contractile agents of airway smooth muscle. This review will focus on the effect of postjunctional muscarinic stimulation of airway smooth muscle.

Section snippets

Pharmacology and structure

Although muscarinic cholinoceptors have long been thought to constitute one homogenous population defined by selective activation by muscarine and blockade by atropine, functional and binding studies brought pharmacological evidence that several classes of muscarinic cholinoceptor exist. More recently, the molecular basis of the different subtypes has been unravelled. For example, early in vitro studies in guinea pig trachea suggested that the acetylcholine receptors mediating contraction of

Coupling of cholinoceptor subtypes

As already indicated, muscarinic receptors are members of the G-protein-coupled receptor family. Mutational analyses revealed that the second and third intracellular loops (i2 and i3) and the membrane-proximal part of the intracellular tail of the receptor are implicated in G-protein coupling. Although amino acid residues of i2 may contribute to G-protein-coupling selectivity, the critical determinants of this selectivity reside in the third intracellular loop (i3) (Hulme et al., 1990). This

M3-mediated airway contraction

Owing to the mixed muscarinic receptor population in airway smooth muscle, identification of the muscarinic cholinoceptor subtype(s) that mediate(s) airway contraction has been investigated in various mammalian species by comparing the sensitivity of the ACh-induced contraction with M1- (pirenzepine), M2- (AF-DX 116, gallamine, methoctramine) and M3-selective (4-DAMP, hexahydrosiladifenidol) muscarinic antagonists in tracheal or bronchial smooth muscle preparations or both in vitro (Eglen et al.

Acknowledgements

Work from the authors’ laboratory was supported by grants from Conseil Regional d’Aquitaine (No. 960301117) and ADEME (No. 9593017).

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