期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 112, 期 49, 页码 E6818-E6824出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1519430112
关键词
G protein-coupled receptors; beta-cell function; mouse models; glucose homeostasis; GPCR regulation
资金
- NIDDK, NIH, Department of Health and Human Services
- Medical Research Council Toxicology Unit
- American Diabetes Association [7-11-BS-34]
- Diabetes Center [NIH DK-19525]
- Rapid Response Grant by the Michael J. Fox Foundation
- NIH-Japan Society for Promotion of Science Research Fellowship Program
- NIH-Brazilian National Council for Scientific and Technological Development Visiting Fellows Program
- Biotechnology and Biological Sciences Research Council [BB/L02781X/1] Funding Source: researchfish
- Medical Research Council [MC_UP_A600_1110] Funding Source: researchfish
- BBSRC [BB/L02781X/1] Funding Source: UKRI
- MRC [MC_UP_A600_1110] Funding Source: UKRI
G protein-coupled receptors (GPCRs) regulate virtually all physiological functions including the release of insulin from pancreatic beta-cells. beta-Cell M-3 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 beta-cell activity. In the present study, we demonstrate that inhibition of CK2 in pancreatic beta-cells, knockdown of CK2 alpha expression, or genetic deletion of CK2 alpha in beta-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 beta-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 beta-cell GPCRs may represent novel therapeutic targets.
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