Abstract
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.
Highlights
Pancreatitis, in both acute and chronic forms, is an inflammatory disease of the pancreas, which is painful and often lethal in severe cases [1]
Alternative clinically relevant animal models need to be established for the investigation into the mechanisms of pancreatitis pathogenesis and the development of effective preventive and therapeutic interventions
A clozapine-N-oxide–responsive DREADD mutant M3R mimics the functions of WT M3R. Both CCK receptor and M3R belong to the G protein–coupled receptor (GPCR) family and elicit similar calcium signaling and amylase secretion patterns [15]
Summary
Pancreatitis, in both acute and chronic forms, is an inflammatory disease of the pancreas, which is painful and often lethal in severe cases [1]. Most of our knowledge on pancreatitis is based on research conducted using experimental animal models. Various experimental pancreatitis models have been developed in mice, rats, dogs, cats, guinea pigs, pigs, and zebrafish [2, 3]. No effective, targeted drug for pancreatitis therapy has been approved by the US Food and Drug Administration (FDA), suggesting that there are difficulties in translating animal research into clinical practice. Alternative clinically relevant animal models need to be established for the investigation into the mechanisms of pancreatitis pathogenesis and the development of effective preventive and therapeutic interventions
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