Pancreas-specific CHRM3 activation causes pancreatitis in mice

Hyperstimulation of the cholecystokinin 1 receptor (CCK1R), a G protein-coupled receptor (GPCR), in pancreatic acinar cells is commonly used to induce pancreatitis in rodents. Human pancreatic acinar cells lack CCK1R but express cholinergic receptor muscarinic 3 (M3R), another GPCR. To test whether...

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Bibliographic Details
Published in:JCI insight 2021-09, Vol.6 (17)
Main Authors: Wan, Jianhua, Wang, Jiale, Wagner, 2nd, Larry E, Wang, Oliver H, Gui, Fu, Chen, Jiaxiang, Zhu, Xiaohui, Haddock, Ashley N, Edenfield, Brandy H, Haight, Brian, Mukhopadhyay, Debabrata, Wang, Ying, Yule, David I, Bi, Yan, Ji, Baoan
Format: Article
Language:English
Subjects:
Acinar Cells - metabolism
Acinar Cells - pathology
Animals
Cells, Cultured
Disease Models, Animal
Gastroenterology
Gene Expression Regulation
Inflammation
Mice
Mice, Mutant Strains
Mice, Transgenic
Pancreatitis - genetics
Pancreatitis - metabolism
Pancreatitis - pathology
Receptor, Muscarinic M3 - biosynthesis
Receptor, Muscarinic M3 - genetics
RNA - genetics
Signal Transduction
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Summary:Hyperstimulation of the cholecystokinin 1 receptor (CCK1R), a G protein-coupled receptor (GPCR), in pancreatic acinar cells is commonly used to induce pancreatitis in rodents. Human pancreatic acinar cells lack CCK1R but express cholinergic receptor muscarinic 3 (M3R), another GPCR. To test whether M3R activation is involved in pancreatitis, a mutant M3R was conditionally expressed in pancreatic acinar cells in mice. This mutant receptor loses responsiveness to its native ligand, acetylcholine, but can be activated by an inert small molecule, clozapine-N-oxide (CNO). Intracellular calcium and amylase were elicited by CNO in pancreatic acinar cells isolated from mutant M3R mice but not WT mice. Similarly, acute pancreatitis (AP) could be induced by a single injection of CNO in the transgenic mice but not WT mice. Compared with the cerulein-induced AP, CNO caused more widespread acinar cell death and inflammation. Furthermore, chronic pancreatitis developed at 4 weeks after 3 episodes of CNO-induced AP. In contrast, in mice with 3 recurrent episodes of cerulein-included AP, pancreas histology was restored in 4 weeks. Furthermore, the M3R antagonist ameliorated the severity of cerulein-induced AP in WT mice. We conclude that M3R activation can cause the pathogenesis of pancreatitis. This model may provide an alternative approach for pancreatitis research.
ISSN:2379-3708
2379-3708
DOI:10.1172/jci.insight.132585