期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 289, 期 18, 页码 12435-12445出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M114.562587
关键词
Calcium Channels; Calcium Imaging; CaMKII; Diabetes; Insulin; Insulin Secretion; Islet; Pancreatic Islets
资金
- National Institutes of Health [DK096122, DK081666, DK20593]
- Pilot and Feasibility Grant through the Vanderbilt University Diabetes Research Training Center [P60 DK20593]
Background: Glucose activates CaMKII in -cells, how this influences glucose homeostasis has not been determined. Results: Inhibiting CaMKII in mouse -cells causes glucose intolerance by reducing Ca2+ entry and insulin secretion. Conclusion: CaMKII is a -cell Ca2+ sensor that amplifies secretagogue-induced Ca2+ entry and insulin secretion to maintain glucose homeostasis. Significance: This provides the first evidence that -cell CaMKII modulates glucose homeostasis under physiological and insulin resistant states. Glucose-stimulated insulin secretion (GSIS) from pancreatic -cells is caused by Ca2+ entry via voltage-dependent Ca2+ channels. CaMKII is a key mediator and feedback regulator of Ca2+ signaling in many tissues, but its role in -cells is poorly understood, especially in vivo. Here, we report that mice with conditional inhibition of CaMKII in -cells show significantly impaired glucose tolerance due to decreased GSIS. Moreover, -cell CaMKII inhibition dramatically exacerbates glucose intolerance following exposure to a high fat diet. The impairment of islet GSIS by -cell CaMKII inhibition is not accompanied by changes in either glucose metabolism or the activities of K-ATP and voltage-gated potassium channels. However, glucose-stimulated Ca2+ entry via voltage-dependent Ca2+ channels is reduced in islet -cells with CaMKII inhibition, as well as in primary wild-type -cells treated with a peptide inhibitor of CaMKII. The levels of basal -cell cytoplasmic Ca2+ and of endoplasmic reticulum Ca2+ stores are also decreased by CaMKII inhibition. In addition, CaMKII inhibition suppresses glucose-stimulated action potential firing frequency. These results reveal that CaMKII is a Ca2+ sensor with a key role as a feed-forward stimulator of -cell Ca2+ signals that enhance GSIS under physiological and pathological conditions.
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