Inhibition of pancreatic beta-cell CaMKII reduces glucose-stimulated calcium influx and insulin secretion, impairing glucose tolerance [Cell Biology]

March 13th, 2014 by Dadi, P. K., Vierra, N. C., Ustione, A., Piston, D. W., Colbran, R. J., Jacobson, D. A.

Glucose stimulated insulin secretion (GSIS) from pancreatic β-cells is caused by Ca2+ entry via voltage-dependent Ca2+ channels (VDCCs). CaMKII is a key mediator and feedback regulator of Ca2+ signaling in many tissues, but its role in β-cells is poorly understood, especially in vivo. Here we report that mice with conditional inhibition of CaMKII in β-cells show significantly impaired glucose tolerance due to decreased GSIS. Moreover, β-cell CaMKII inhibition dramatically exacerbates glucose intolerance following exposure to a high fat diet (HFD). The impairment of islet GSIS by β-cell CaMKII inhibition is not accompanied by changes in either glucose metabolism or the activities of KATP and voltage-gated potassium channels. However, glucose-stimulated Ca2+ entry via VDCCs is reduced in islet β-cells with CaMKII inhibition, as well as in primary wild-type β-cells treated with a peptide inhibitor of CaMKII. The levels of basal β-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 β-cell Ca2+ signals that enhance GSIS under physiological and pathological conditions.
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