Berberine inhibits intracellular Ca²⁺ signals in mouse pancreatic acinar cells through M₃ muscarinic receptors: Novel target, mechanism, and implication

Berberine, a natural isoquinoline alkaloid, exhibits a variety of pharmacological effects, but the pharmacological targets and mechanisms remain elusive. Here, we report a novel finding that berberine inhibits acetylcholine (ACh)-induced intracellular Ca²⁺ oscillations, mediated through an inhibition of the muscarinic subtype 3 (M₃) receptor. Patch-clamp recordings and confocal Ca²⁺ imaging were applied to acute dissociated pancreatic acinar cells prepared from CD1 mice to examine the effects of berberine on ACh-induced Ca²⁺ oscillations. Whole-cell patch-clamp recordings showed that berberine (from 0.1 to 10 µM) reduced ACh-induced Ca²⁺ oscillations in a concentration-dependent manner, and this inhibition also depended on ACh concentrations. The inhibitory effect of berberine neither occurred in intracellular targets nor extracellular cholecystokinin (CCK) receptors, chloride (Cl^-) channels, and store-operated Ca²⁺ channels. Together, the results demonstrate that berberine directly inhibits the muscarinic M₃ receptors, further confirmed by evidence of the interaction between berberine and M₃ receptors in pancreatic acinar cells.