VPAC2 receptor mediates VIP-potentiated insulin secretion via ion channels in rat pancreatic β cells

Vasoactive intestinal peptide (VIP), a small neuropeptide composing of 28 Amino acids, functions as a neuromodulator with insulinotropic effect on pancreatic β cells, in which it is of vital importance in regulating the levels of blood glucose. VIP potently agonizes VPAC2 receptor (VPAC2-R). Agonists of VPAC2-R stimulate glucose-dependent Insulin secretion. The purpose of this study was to further investigate the possible ion channel mechanisms in VPAC2-R-mediated VIP-potentiated Insulin secretion. The results of Insulin secretion experiments showed that VIP augmented Insulin secretion in a glucose-dependent manner. The insulinotropic effect was mediated by VPAC2-R rather than VPAC1 receptor (VPAC1-R), through the adenylyl cyclase (AC)/protein kinase A (PKA) signalling pathway. The calcium imaging analysis demonstrated that VIP increased intracellular CA²⁺ concentration ([CA²⁺]_i). In addition, in the whole-cell voltage-clamp mode, we found that VIP blocked the voltage-dependent potassium (Kv) channel currents, while this effect was reversed by inhibiting the VPAC2-R, AC or PKA respectively. Taken together, these findings suggest that VIP stimulates Insulin secretion by inhibiting the Kv channels, activating the CA²⁺ channels, and increasing [CA²⁺]_i through the VPAC2-R and AC/PKA signalling pathway. These findings provide theoretical basis for the research of VPAC2-R as a novel therapeutic target.

Insulin secretion; Ion channels; VPAC2 receptor; Vasoactive intestinal peptide; β cell.