Submitted on November 15, 2004
Accepted on January 24, 2005
Cholinergically stimulated gastric acid secretion is mediated by M3 and M5, but not M1, muscarinic acetylcholine receptors in mice
Takeshi Aihara1, Yusuke Nakamura1, Makoto M. Taketo2, Minoru Matsui3, and Susumu Okabe1*
1 Department of Applied Pharmacology, Kyoto Pharmaceutical University, Kyoto, Japan
2 Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Laboratory of Biomedical Genetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan
3 Division of Neuronal Network, Department of Basic Medical Sciences, The Institute of Medical Science, University of Tokyo, Tokyo, Japan; Laboratory of Biomedical Genetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan
* To whom correspondence should be addressed. E-mail: okabe{at}mb.kyoto-phu.ac.jp.
Muscarinic acetylcholine receptors play an important role in the regulation of gastric
acid secretion stimulated by acetylcholine; nonetheless, the precise role of each receptor
subtype (M1-M5) remains unclear. This study examined the involvement of M1, M3, and M5
receptors in cholinergic regulation of acid secretion using muscarinic receptor knockout (KO)
mice. Gastric acid secretion was measured in both mice subjected to acute gastric fistula
production under urethane anesthesia and conscious mice that had previously undergone
pylorus ligation. M3KO mice exhibited impaired gastric acid secretion in response to
carbachol. Unexpectedly, M1KO mice exhibited normal intragastric pH, serum gastrin and
mucosal histamine levels, and gastric acid secretion stimulatied by carbachol, histamine, and
gastrin. Pirenzepine, known as an M1-receptor antagonist, inhibited carbachol-stimulated
gastric acid secretion in a dose-dependent manner in M1KO mice, as well as in wild-type
(WT) mice, suggesting that the inhibitory effect of pirenzepine on gastric acid secretion is
independent of M1-receptor antagonism. Notably, M5KO mice exhibited both significantly
lower carbachol-stimulated gastric acid secretion and histamine-secretory responses to
carbachol compared with WT mice. RT-PCR analysis revealed M5-mRNA expression in the
stomach, but not in either the fundic or antral mucosa. Consequently, cholinergic stimulation
of gastric acid secretion is clearly mediated by M3 (on parietal cells) and M5 receptors
(conceivably in the submucosal plexus), but not M1 receptors.
