PACAP stimulates insulin secretion by PAC1 receptor and ion channels in β-cells

Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) plays a crucial role in the endocrine system. The present study aimed to investigate the effect of PACAP38 on insulin secretion and the underlying mechanism in rat pancreatic beta-cells. The insulin secretion results showed that PACAP38 stimulated insulin secretion in a glucose- and dose-dependent manner. The insulinotropic effect was mediated by PAC(1) receptor, but not by VPAC(1) and VPAC(2) receptors. Inhibition of adenylyl cyclase and protein kinase A suppressed PACAP38-augmented insulin secretion. Glucose-regulated insulin secretion is dependent on a series of electrophysiological activities. Current-clamp technology suggested that PACAP38 prolonged action potential duration. Voltage-clamp recordings revealed that PACAP38 blocked voltage-dependent potassium currents, and this effect was reversed by inhibition of PAC(1) receptor, adenylyl cyclase, or protein kinase A. Activation of Ca2+ channels by PACAP38 was also observed, which could be antagonized by the PAC(1) receptor antagonist. In addition, calcium imaging analysis indicated that PACAP38 increased intracellular Ca2+ concentration, which was decreased by PAC(1) receptor antagonist. These findings demonstrate that PACAP38 stimulates glucose-induced insulin secretion mainly by acting on PAC(1) receptor, inhibiting voltage-dependent potassium channels, activating Ca2+ channels and increasing intracellular Ca2+ concentration. Further, PACAP blocks voltage-dependent potassium currents via the adenylyl cyclase/protein kinase A signaling pathway.