Determination of Region-Specific Roles of the M3 Muscarinic Acetylcholine Receptor in Gastrointestinal Motility

• Published in: Digestive diseases and sciences Vol. 68; no. 2; pp. 439 - 450
• Main Authors: Igarashi-Hisayoshi, Yoko, Ihara, Eikichi, Bai, Xiaopeng, Higashi, Chika, Ikeda, Hiroko, Tanaka, Yoshimasa, Hirano, Mayumi, Ogino, Haruei, Chinen, Takatoshi, Taguchi, Yasushi, Ogawa, Yoshihiro
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-02-2023; Springer Nature B.V
• Subjects: Biochemistry; Colon; Esophagus; Gastroenterology; Hepatology; Medicine; Medicine & Public Health; Motility; Oncology; Original Article; Physiology; Small intestine; Smooth muscle; Transplant Surgery; Physiological condition; muscarinic acetylcholine receptor; Positive allosteric modulator; Smooth muscle; Acetylcholine; Gastrointestinal motility function; M
• ISSN: 0163-2116; 1573-2568
• DOI: 10.1007/s10620-022-07637-y

Background
The specific role of the M
3
muscarinic acetylcholine receptor in gastrointestinal motility under physiological conditions is unclear, due to a lack of subtype-selective compounds.
Aims
The objective of this study was to determine the region-specific role of the M
3
receptor in gastrointestinal motility.
Methods
We developed a novel positive allosteric modulator (PAM) for the M
3
receptor, PAM-369. The effects of PAM-369 on the carbachol-induced contractile response of porcine esophageal smooth muscle and mouse colonic smooth muscle (ex vivo) and on the transit in mouse small intestine and rat colon (in vivo) were examined.
Results
PAM-369 selectively potentiated the M
3
receptor under the stimulation of its orthosteric ligands without agonistic or antagonistic activity. Half-maximal effective concentrations of PAM activity for human, mouse, and rat M
3
receptors were 0.253, 0.345, and 0.127 μM, respectively. PAM-369 enhanced carbachol-induced contraction in porcine esophageal smooth muscle and mouse colonic smooth muscle without causing any contractile responses by itself. The oral administration of 30 mg/kg PAM-369 increased the small intestinal transit in both normal motility and loperamide-induced intestinal dysmotility mice but had no effects on the colonic transit, although the M
3
receptor mRNA expression is higher in the colon than in the small intestine.
Conclusions
This study provided the first direct evidence that the M
3
receptor has different region-specific roles in the motility function between the small intestine and colon in physiological and pathophysiological contexts. Selective PAMs designed for targeted subtypes of muscarinic receptors are useful for elucidating the subtype-specific function.