Promiscuous multi-agonists that simultaneously activate two or three key receptors (incretin- and/or glucagon receptor) were recently shown to improve glycemic control in mice. Here we investigated the underlying mechanisms of multi-agonists to enhance insulin secretion in murine islets and human pancreatic β-cells. These mixed agonists display a greater potency in cAMP signaling as compared to the native incretins. However, pharmacological blockade of cAMP signaling only partially inhibited the increases in insulin secretion. Therefore, additional mechanisms independent from Gs signaling-coupled Ca2+ influx appear to mediate insulin secretion. Here, we showed multi-agonists evoked significant increases in Ca2+ influx through activation of both voltage-dependent Ca2+ channels (VDCCs) and transient receptor potential channels (TRPs). These responses were more rapid and larger after multi-agonist stimulation than those after mono-agonists. Pharmacological blockade of TRP channels suppressed Ca2+ transients induced by multi-agonists to a greater degree than exposure to VDCC blocker. TRP blockers also blunted cAMP accumulation and abolished increases in whole-cell currents that are evoked with multi-agonists. These observations argue for a direct TRP channel activation by ligand-engaged incretin receptors. Collectively, direct activation of adenylyl cyclase through GPCR/channel constellations and concomitant rapid Ca2+ influx likely contribute to the increases in insulin secretion induced by multi-agonists.
20 May 2017 - 23 May 2017