CK2 acts as a potent negative regulator of receptor-mediated insulin release in vitro and in vivo.

ABSTRACT: G protein-coupled receptors (GPCRs) regulate virtually all physiological functions including the release of insulin from pancreatic ?-cells. ?-Cell M3 muscarinic receptors (M3Rs) are known to play an essential role in facilitating insulin release and maintaining proper whole-body glucose homeostasis. As is the case with other GPCRs, M3R activity is regulated by phosphorylation by various kinases, including GPCR kinases and casein kinase 2 (CK2). At present, it remains unknown which of these various kinases are physiologically relevant for the regulation of ?-cell activity. In the present study, we demonstrate that inhibition of CK2 in pancreatic ?-cells, knockdown of CK2? expression, or genetic deletion of CK2? in ?-cells of mutant mice selectively augmented M3R-stimulated insulin release in vitro and in vivo. In vitro studies showed that this effect was associated with an M3R-mediated increase in intracellular calcium levels. Treatment of mouse pancreatic islets with CX4945, a highly selective CK2 inhibitor, greatly reduced agonist-induced phosphorylation of ?-cell M3Rs, indicative of CK2-mediated M3R phosphorylation. We also showed that inhibition of CK2 greatly enhanced M3R-stimulated insulin secretion in human islets. Finally, CX4945 treatment protected mice against diet-induced hyperglycemia and glucose intolerance in an M3R-dependent fashion. Our data demonstrate, for the first time to our knowledge, the physiological relevance of CK2 phosphorylation of a GPCR and suggest the novel concept that kinases acting on ?-cell GPCRs may represent novel therapeutic targets.

SUBMITTER: Rossi M 

PROVIDER: S-EPMC4679045 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature