Inhibition of pancreatic β-cell Ca2+/calmodulin-dependent protein kinase II reduces glucose-stimulated calcium influx and insulin secretion, impairing glucose tolerance.

Dadi PK, Vierra NC, Ustione A, Piston DW, Colbran RJ, Jacobson DA
J Biol Chem. 2014 289 (18): 12435-45

PMID: 24627477 · PMCID: PMC4007438 · DOI:10.1074/jbc.M114.562587

Glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells is caused by Ca(2+) entry via voltage-dependent Ca(2+) channels. CaMKII is a key mediator and feedback regulator of Ca(2+) 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. 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 Ca(2+) entry via voltage-dependent Ca(2+) channels 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 Ca(2+) and of endoplasmic reticulum Ca(2+) 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 Ca(2+) sensor with a key role as a feed-forward stimulator of β-cell Ca(2+) signals that enhance GSIS under physiological and pathological conditions.

MeSH Terms (25)

Action Potentials Animals Biological Transport Blotting, Western Calcium Calcium-Calmodulin-Dependent Protein Kinase Type 2 Calcium Channels Cells, Cultured Cytoplasm Doxycycline Endoplasmic Reticulum Glucose Glucose Intolerance Green Fluorescent Proteins Homeostasis Insulin Insulin-Secreting Cells Insulin Secretion Mice Mice, Inbred C57BL Mice, Transgenic Microscopy, Confocal Patch-Clamp Techniques Peptides Potassium Channels

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