Related Experiment Video
Updated: Oct 26, 2025
Sodium Taurocholate Induced Severe Acute Pancreatitis in C57BL/6 Mice
Published on: June 28, 2021
Pancreas-specific CHRM3 activation causes pancreatitis in mice
Jianhua Wan1,2, Jiale Wang1, Larry E Wagner3
1Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, USA.
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.
Insights
Activation of the muscarinic M3 receptor (M3R) in pancreatic acinar cells can induce pancreatitis. This finding suggests M3R activation plays a role in pancreatitis pathogenesis and offers a new research model.
Area of Science:
- G protein-coupled receptor (GPCR) signaling in pancreatic physiology.
- Pathogenesis of pancreatitis and pancreatic diseases.
Background:
- Rodent models of pancreatitis commonly utilize cholecystokinin 1 receptor (CCK1R) stimulation.
- Human pancreatic acinar cells express muscarinic M3 receptor (M3R), not CCK1R, suggesting a different mechanism for pancreatitis induction.
Purpose of the Study:
- To investigate the role of M3R activation in the pathogenesis of pancreatitis.
- To develop a novel mouse model for studying pancreatitis.
Main Methods:
- Conditional expression of a clozapine-N-oxide (CNO)-activatable mutant M3R in mouse pancreatic acinar cells.
- Induction of pancreatitis using CNO in transgenic mice and comparison with cerulein-induced pancreatitis in wild-type (WT) mice.
- Assessment of M3R antagonist effects on cerulein-induced pancreatitis.
Main Results:
- CNO administration induced intracellular calcium release and amylase secretion in isolated M3R-expressing cells.
- CNO injection triggered acute pancreatitis (AP) in transgenic mice, characterized by widespread acinar cell death and inflammation, exceeding cerulein effects.
- Recurrent CNO-induced AP led to chronic pancreatitis, whereas cerulein-induced AP showed histological recovery.
- M3R antagonist treatment ameliorated cerulein-induced AP severity in WT mice.
Conclusions:
- Muscarinic M3 receptor activation is implicated in the pathogenesis of pancreatitis.
- The developed M3R-activation model provides a new avenue for pancreatitis research.
More Related Videos
07:38Preparing a Mice Model of Severe Acute Pancreatitis via a Combination of Caerulein and Lipopolysaccharide Intraperitoneal Injection
Published on: May 10, 2024
07:10Establishment of a Mouse Severe Acute Pancreatitis Model using Retrograde Injection of Sodium Taurocholate into the Biliopancreatic Duct
Published on: April 1, 2022
Related Concept Videos
01:24Chronic Pancreatitis I: Introduction
Pancreatitis is the inflammation of the pancreas, which occurs when the immune system becomes active and causes swelling, pain, and disruptions in organ function. Pancreatitis can manifest as either an acute or chronic condition.
Acute pancreatitis arises suddenly and lasts for a brief duration, while chronic pancreatitis is a long-term affliction...
01:27Acute Pancreatitis I: Introduction
Acute pancreatitis is characterized by rapid inflammation of the pancreas, often caused by factors like gallstone blockage or excessive alcohol consumption. Chronic pancreatitis, on the other hand, is a slow, progressive inflammation that may result from long-term alcohol abuse, obstructions in the pancreatic duct, or genetic factors.
The causes of acute pancreatitis include: