Contractile role of M2 and M3 muscarinic receptors in gastrointestinal smooth muscle

Ehlert, Frederick J.; Sawyer, Gregory W.; Esqueda, Evette E.

doi:10.1016/s0024-3205(98)00584-0

Cited by 97 publications

(72 citation statements)

References 29 publications

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“…consistent with an M 3 mechanism (Lambrecht et al, 1989;Eglen et al, 1996;Ehlert et al, 1997b). Such behavior is consistent with the coupling of M 3 muscarinic receptors to phosphoinositide hydrolysis and the mobilization of Ca 2ϩ in smooth muscle (Lazareno and Roberts, 1989;Candell et al, 1990).…”

supporting

confidence: 76%

Muscarinic Agonist-Mediated Heterologous Desensitization in Isolated Ileum Requires Activation of Both Muscarinic M₂ and M₃ Receptors

Griffin

Matsui

Shehnaz

et al. 2003

J Pharmacol Exp Ther

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We investigated the subtypes of the muscarinic receptor mediating short-term heterologous desensitization in the isolated ileum. Treatment of the ileum from C57BL/6 mice with acetylcholine (30 M) for 20 min caused a subsequent decrease in contractile sensitivity to both prostaglandin F 2␣ (PGF 2␣ ) and the muscarinic agonist, oxotremorine-M. This subsensitivity was characterized by 7-and 3-fold increases in the EC 50 values of the agonists, respectively, with no significant effect on the maximal response. The subsensitivity to PGF 2␣ was prevented in both M 2 and M 3 muscarinic receptor knockout mice. Similarly, the subsensitivity to oxotremorine-M was prevented in M 2 knockout mice. Acetylcholine-mediated desensitization of histamine-induced contractions in the guinea pig ileum was inhibited by both M 2 -and M 3 -selective muscarinic antagonists with high potency, although careful analysis of the data suggested behavior more consistent with an M 2 antagonistic profile. Modeling studies showed that the competitive antagonism of response contingent upon activation of two receptor subtypes should exhibit a pharmacological profile similar to that of the least sensitive signaling pathway. Our results demonstrate that muscarinic agonist-mediated short-term heterologous desensitization of intestinal smooth muscle is contingent upon activation of both M 2 and M 3 muscarinic receptors and that activation of either receptor by itself is insufficient to cause desensitization.It has long been known that the sensitivity of gastrointestinal smooth muscle to the contractile effects of muscarinic agonists decreases after incubation of the tissue with moderate to high concentrations of agonist for relatively short periods (i.e., 5-30 min) (Cantoni and Eastman, 1946;Dale, 1958;Paton, 1961). The mechanism for this short-term desensitization seems to be at a locus downstream from the muscarinic receptor because muscarinic agonist-mediated desensitization is characterized by a decrease in sensitivity to other spasmogens as well. Such a generalized subsensitivity is not surprising considering the metabolic costs required to maintain tonic muscle contraction for several minutes. Thus, prolonged contraction caused by continuous exposure to a muscarinic agonist causes a decreased responsiveness of the contractile machinery to subsequent activation by muscarinic as well as other heterologous agents. It seems likely, therefore, that the muscarinic receptor subtypes mediating heterologous desensitization may be the same as those eliciting contraction.In isolated ileum, subtype-selective muscarinic antagonists inhibit the contractile response to agonists in a manner

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supporting

confidence: 76%

Muscarinic Agonist-Mediated Heterologous Desensitization in Isolated Ileum Requires Activation of Both Muscarinic M₂ and M₃ Receptors

Griffin

Matsui

Shehnaz

et al. 2003

J Pharmacol Exp Ther

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“…Whereas multiple subtypes of mAChRs coexist in the same tissue, it has been suggested through in vitro studies that the most abundant subtype is not necessarily predominant in exerting biological effects. In many smooth muscle tissues, for example, the M 3 receptors have been demonstrated to play dominant roles in eliciting cholinergic contraction in vitro, despite the fact that the major acetylcholine-binding site shows the M 2 type of affinity (4). However, further characterization of physiological roles of each mAChR subtype in vivo has been hampered by lack of subtype-specific ligands.…”

mentioning

confidence: 99%

Multiple functional defects in peripheral autonomic organs in mice lacking muscarinic acetylcholine receptor gene for the M ₃ subtype

Matsui

Motomura

Karasawa

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

409

325

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Muscarinic acetylcholine receptors consist of five distinct subtypes and have been important targets for drug development. In the periphery, muscarinic acetylcholine receptors mediate cholinergic signals to autonomic organs, but specific physiological functions of each subtype remain poorly elucidated. Here, we have constructed and analyzed mutant mice lacking the M3 receptor and have demonstrated that this subtype plays key roles in salivary secretion, pupillary constriction, and bladder detrusor contractions. However, M 3-mediated signals in digestive and reproductive organs are dispensable, likely because of redundant mechanisms through other muscarinic acetylcholine receptor subtypes or other mediators. In addition, we have found prominent urinary retention only in the male, which indicates a considerable sex difference in the micturition mechanism. Accordingly, this mutant mouse should provide a useful animal model for investigation of human diseases that are affected in the peripheral cholinergic functions.

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“…Studies 11,44,[53][54][55] have revealed that > 1 mAChR subtype may be responsible for mediation of cholinergic contraction in tissues. Analysis of results of the study reported here indicated that the effect of bethanechol in the intestinal segments of interest was mediated by both M 2 and M 3 mAChRs, with activation of M 3 mAChRs causing stronger increases in contractility traits than for activation of M 2 mAChRs, as indicated by use of both sets of receptor antagonists.…”

Section: Discussionmentioning

confidence: 99%

“…1,10 However, the M 3 receptor subtype is considered to be of predominant importance in eliciting muscle contractions, and the exact role of the more abundant M 2 subtype remains unclear. 10,11 A study 12 in M 3 receptor knockout mice has emphasized the role of M 3 mAChRs for smooth muscle contraction because ileal contractile response to carbachol in vitro was reduced by 75% as compared to control animals. In comparison, ileal responses to carbachol were only slightly depressed in smooth muscle tissues from M 2 knock-out mice.…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

“…Thus, the affinity pattern for pirenzepine 47 15,45,50 Affinity data for tropicamide are sparse, but this receptor antagonist appears to bind primarily to M 4 . 51,52 We are not aware of any receptor antagonists with high affinity for M 5 receptors.Studies 11,44,[53][54][55] have revealed that > 1 mAChR subtype may be responsible for mediation of cholinergic contraction in tissues. Analysis of results of the study reported here indicated that the effect of bethanechol in the intestinal segments of interest was mediated by both M 2 and M 3 mAChRs, with activation of M 3 mAChRs causing stronger increases in contractility traits than for activation of M 2 mAChRs, as indicated by use of both sets of receptor antagonists.…”

mentioning

confidence: 99%

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In vitro effects of bethanechol on specimens of intestinal smooth muscle obtained from the duodenum and jejunum of healthy dairy cows

Pfeiffer

Mevissen²,

Steiner³

et al. 2007

ajvr

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Objective-To describe the in vitro effects of bethanechol on contractility of smooth muscle preparations from the small intestines of healthy cows and define the muscarinic receptor subtypes involved in mediating contraction.Sample Population-Tissue samples from the duodenum and jejunum collected immediately after slaughter of 40 healthy cows.Procedures-Cumulative concentration-response curves were determined for the muscarinic receptor agonist bethanechol with or without prior incubation with subtype-specific receptor antagonists in an organ bath. Effects of bethanechol and antagonists and the influence of intestinal location on basal tone, maximal amplitude (A max ), and area under the curve (AUC) were evaluated.Results-Bethanechol induced a significant, concentration-dependent increase in all preparations and variables. The effect of bethanechol was more pronounced in jejunal than in duodenal samples and in circular than in longitudinal preparations. Significant inhibition of the effects of bethanechol was observed after prior incubation with muscarinic receptor subtype M 3 antagonists (more commonly for basal tone than for A max and AUC). The M 2 receptor antagonists partly inhibited the response to bethanechol, especially for basal tone. The M 3 receptor antagonists were generally more potent than the M 2 receptor antagonists. In a protection experiment, an M 3 receptor antagonist was less potent than when used in combination with an M 2 receptor antagonist. Receptor antagonists for M 1 and M 4 did not affect contractility variables. Conclusions and ClinicalRelevance-Bethanechol acting on muscarinic receptor subtypes M 2 and M 3 may be of clinical use as a prokinetic drug for motility disorders of the duodenum and jejunum in dairy cows.The important role of the parasympathetic nervous system in physiologic processes of GI tract motility and in the pathophysiology of motility disorders has been described for various species. [1][2][3][4][5][6][7] In the cholinergic system, acetylcholine activates G-protein-coupled muscarinic receptors to cause smooth muscle contraction in several organs. 1,2 Five mAChR subtypes (M 1 to M 5 , respectively) have been cloned 8 and defined pharmacologically. 3,9 Address correspondence to Dr. Meylan.. NIH Public Access Author ManuscriptAm J Vet Res. Author manuscript; available in PMC 2009 September 7.Published in final edited form as: Am J Vet Res. 2007 March ; 68(3): 313-322. doi:10.2460/ajvr.68.3.313. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptThe M 2 and M 3 mAChR subtypes are the predominant receptors in the GI tract of several species, with a ratio for M 2 :M 3 of approximately 4:1. 1,10 However, the M 3 receptor subtype is considered to be of predominant importance in eliciting muscle contractions, and the exact role of the more abundant M 2 subtype remains unclear. 10,11 A study 12 in M 3 receptor knockout mice has emphasized the role of M 3 mAChRs for smooth muscle contraction because ileal contractile response to carbachol in vi...

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Contractile role of M2 and M3 muscarinic receptors in gastrointestinal smooth muscle

Cited by 97 publications

References 29 publications

Muscarinic Agonist-Mediated Heterologous Desensitization in Isolated Ileum Requires Activation of Both Muscarinic M₂ and M₃ Receptors

Muscarinic Agonist-Mediated Heterologous Desensitization in Isolated Ileum Requires Activation of Both Muscarinic M₂ and M₃ Receptors

Multiple functional defects in peripheral autonomic organs in mice lacking muscarinic acetylcholine receptor gene for the M ₃ subtype

In vitro effects of bethanechol on specimens of intestinal smooth muscle obtained from the duodenum and jejunum of healthy dairy cows

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Contractile role of M2 and M3 muscarinic receptors in gastrointestinal smooth muscle

Cited by 97 publications

References 29 publications

Muscarinic Agonist-Mediated Heterologous Desensitization in Isolated Ileum Requires Activation of Both Muscarinic M2 and M3 Receptors

Muscarinic Agonist-Mediated Heterologous Desensitization in Isolated Ileum Requires Activation of Both Muscarinic M2 and M3 Receptors

Multiple functional defects in peripheral autonomic organs in mice lacking muscarinic acetylcholine receptor gene for the M 3 subtype

In vitro effects of bethanechol on specimens of intestinal smooth muscle obtained from the duodenum and jejunum of healthy dairy cows

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Muscarinic Agonist-Mediated Heterologous Desensitization in Isolated Ileum Requires Activation of Both Muscarinic M₂ and M₃ Receptors

Muscarinic Agonist-Mediated Heterologous Desensitization in Isolated Ileum Requires Activation of Both Muscarinic M₂ and M₃ Receptors

Multiple functional defects in peripheral autonomic organs in mice lacking muscarinic acetylcholine receptor gene for the M ₃ subtype