General Pharmacology: The Vascular System
REVIEWMuscarinic Stimulation of Airway Smooth Muscle Cells
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).
References (58)
Muscarinic receptor subtypes in airways
Life Sci.
(1993)- et al.
Muscarinic acetylcholine receptor subtypeslocalization and structure/function
Prog. Brain Res.
(1993) - et al.
Muscarinic acetylcholine receptor subtypes in smooth muscle
Trends Pharmac. Sci.
(1994) - et al.
G proteins
Trends Biochem. Sci.
(1992) - et al.
Prejunctional muscarinic receptors regulating neurotransmitter release in airways
Life Sci.
(1995) - et al.
Visualization of muscarinic m4 mRNA and M4 receptor subtype in rabbit lung
Life Sci.
(1993) - et al.
Muscarinic M3 receptors mediate contraction of human central and peripheral airway smooth muscle
Pulm. Pharmac.
(1990) - et al.
The G protein beta-gamma subunit transduces the muscarinic receptor signal for Ca2+ release in Xenopus oocytes
J. Biol. Chem.
(1995) - et al.
The inhibition of adenylyl cyclase activity in isolated lung membranes by muscarinic and alpha-adrenoceptor agonistsrole of G-protein alpha and beta gamma sub-units
Cell. Signal.
(1995) Beta-adrenoceptors, cAMP and airway smooth muscle relaxationchallenges to the dogma
Trends Pharmac. Sci.
(1994)
Getting it togethersignal transduction in G-protein coupled receptors by association of receptor domains
Chem. Biol.
Role of muscarinic M2 and M3 receptors in guinea-pig tracheaeffects of receptor alkylation
Eur. J. Pharmac.
Muscarinic acetylcholine receptorsstructural basis of ligand binding and G protein coupling
Life Sci.
Effect of cAMP elevating agents on carbachol-induced phosphoinositide hydrolysis and calcium mobilization in cultured canine tracheal smooth muscle cells
Cell Calcium
Differences in Ca2+ mobilization by muscarinic agonists in tracheal smooth muscle
Am. J. Physiol.
Ca2+ increase and Ca2+-influx in human tracheal smooth muscle cellsrole of Ca2+ pools controlled by sarco-endoplasmic reticulum Ca2+-ATPase 2 isoform
Br. J. Pharmac.
A comparison of the affinities of antagonists for acetylcholine receptors in the ileum, bronchial muscle and iris of the guinea-pig
Br. J. Pharmac.
Modulation of neurotransmission in airways
Phys. Rev.
Inositol triphosphate and calcium signalling
Nature
Muscarinic receptor subtypes and smooth muscle function
Pharmac. Rev.
M2 muscarinic receptors inhibit isoproterenol-induced relaxation of canine airway smooth muscle
J. Pharmac. Exp. Ther.
Effects of beta 2-adrenoceptor agonists on anti-IgE-induced contraction and smooth muscle reactivity in human airways
Br. J. Pharmac.
Angiotensin II-induced Ca2+ oscillations in vascular myocytes from the rat pulmonary artery
Am. J. Physiol.
Muscarinic receptor reserve and beta-adrenergic sensitivity in tracheal smooth muscle
J. Appl. Physiol.
Muscarinic receptor subtypes in guinea pig airways
Am. J. Physiol.
Mechanism of cytokine-induced modulation of beta-adrenoceptor responsiveness in airway smooth muscle
J. Clin. Invest.
Functional antagonism by salbutamol suggests differences in the relative efficacies and dissociation constants of the peptidoleukotrienes in guinea pig trachea
J. Pharmac. Exp. Ther.
Muscarinic receptor subtypes
Annu. Rev. Pharmac. Toxicol.
Acetylcholine and caffeine activate Cl− and suppress K+ conductances in human bronchial smooth muscle
Am. J. Physiol.
Cited by (63)
Role of dual bronchodilators in COPD: A review of the current evidence for indacaterol/glycopyrronium
2017, Pulmonary Pharmacology and TherapeuticsCitation Excerpt :Bronchoconstriction is mediated by the activation of muscarinic type 1 (M1) and type 3 (M3) receptors; the activation of inhibitory type 2 (M2) receptors triggers feedback inhibition of ACh release [9]. The binding of ACh to M3 receptors results in the formation of diacylglycerol, which activates protein kinase C (PK-C) [10]. ACh binding also leads to an increase in intracellular calcium; both activated PK-C and increased intracellular calcium lead to airway smooth muscle contraction [10].
R- and S-terbutaline activate large conductance and Ca<sup>2 +</sup> dependent K<sup>+</sup> (BK<inf>Ca</inf>) channel through interacting with β<inf>2</inf> and M receptor respectively
2016, Biochimica et Biophysica Acta - BiomembranesCitation Excerpt :We speculate that M3 receptor may be involved in the channel activating effect of S-terbutaline. M3 receptor is coupled to Gq protein, which leads to phospholipase C activation and an increase in cytoplasmic Ca2 + and finally increase the activity of BKCa channel [34,35]. Considering that the gating of BKCa channel can also be regulated by intracellular Ca2 +, it is not surprising that S-terbutaline could indirectly activated BKCa channel by muscarinic receptor-mediated pathway.
Salmeterol Xinafoate
2015, Profiles of Drug Substances, Excipients and Related MethodologyCitation Excerpt :Thus, activation of the β2-adrenergic receptor results directly in bronchodilation. Muscarinic antagonists also facilitate bronchodilation but work by competing with acetylcholine for muscarinic receptors [9]. Salmeterol xinafoate as LABA with a 12-h duration of action showed positive experience in asthma [10], providing improvements in bronchodilator efficacy and patient outcomes compared with short-acting β-agonist (SABA), which have duration of action of only 4–6 h [11].
Recent advances in the treatment of childhood asthma: a clinical pharmacology perspective
2022, Expert Review of Clinical PharmacologyEffects of indacaterol on the LPS-evoked changes in fluid secretion rate and pH in swine tracheal membrane
2021, Pflugers Archiv European Journal of Physiology