Pancreas-specific CHRM3 activation causes pancreatitis in mice

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.

Trophoblasts Modulate the Ca2+ Oscillation and Contraction of Myometrial Smooth Muscle Cells by Small Extracellular Vesicle‐ (sEV‐) Mediated Exporting of miR‐25‐3p during Premature Labor

“…More importantly, the increased miR-25-3p level injured the contractile function of the heart muscle cells via the suppression of SERCA2a [ 24 ]. The expression of the T-type calcium channel protein Cav3.2 was increased in the uterine smooth muscle of pregnant rats [ 21 ]; we further found that the Cav3.2 was overexpressed in the myometrial smooth muscle of infected preterm mice [ 53 ] and the disturbance of the Cav3.2 pathway attenuated absolute contraction of cells [ 54 ]. Thus, we aimed to define whether miR-25-3p participates in PTL by regulating HMSM contraction in vitro.…”

Multiple roles for cholinergic signaling in pancreatic diseases

“…The M3 receptor is highly expressed in human pancreatic acinar cells[ 31 ]. Wan et al [ 55 ] used chemical genetic technology, in which designer receptors are exclusively activated by designer drugs, to express mutant M3 receptors in mouse acinar cells, causing them to lose their response to acetylcholine but can be activated by the specific drug clozapine-N-oxide (CNO). CNO can induce AP in mutant M3 receptor mice and cause more extensive acinar cell necrosis and inflammation.…”

“…CNO can induce AP in mutant M3 receptor mice and cause more extensive acinar cell necrosis and inflammation. In addition, the use of M3 receptor antagonists can improve the severity of AP induced by cerulein in wild-type mice (Figure 1 )[ 55 ].…”

“…Compared with AP, few CP models use injury mechanisms that may be related to the pathogenesis of human diseases, and the clinical relevance of the pathogenesis of most CP models is unclear[ 48 ]. However, Wan et al [ 55 ] used a mutant M3 receptor mouse-induced CP model and observed typical CP features, such as extensive chronic inflammation, fibrosis, adipose tissue infiltration, and pancreatic atrophy (Figure 1 )[ 55 ]. The use of this M3 receptor model may increase our understanding of the pathophysiological process of human CP and identify specific treatments.…”

Differential Actions of Muscarinic Receptor Subtypes in Gastric, Pancreatic, and Colon Cancer

“…M 3 R plays an important role in endocrine and exocrine pancreatic secretion, with many potential clinical applications [ 79 , 91 ]. Hyperactivation of M 3 Rs induces pancreatitis in mice, and allosteric modulation of M 3 R activity can normalize glucose homeostasis in obese mice [ 92 , 93 ]. The contribution of M 3 Rs to exocrine gland secretion, and, in particular, to salivary gland secretion, helps explain the common side effect of dry mouth (xerostomia) associated with the use of muscarinic receptor antagonists [ 94 ] and the finding of anti-M 3 R antibodies in Sjogren’s syndrome [ 95 , 96 ].…”