title: Inhibition of pancreatic β-cell Ca2+/calmodulin-dependent protein kinase II reduces glucose-stimulated calcium influx and insulin secretion, impairing glucose tolerance.
abstract: 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.
authors.affiliation: From the Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee 37232.
authors.forename: Prasanna K
authors.initials: PK
authors.lastname: Dadi
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Vierra
authors.forename: Alessandro
authors.initials: A
authors.lastname: Ustione
authors.forename: David W
authors.initials: DW
authors.lastname: Piston
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Colbran
authors.forename: David A
authors.initials: DA
authors.lastname: Jacobson
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D004318:Doxycycline / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D018149:Glucose Intolerance / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000201:enzymology / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism
chemical_list: D015220:Calcium Channels; D007328:Insulin; D010455:Peptides; D015221:Potassium Channels; C514527:autocamptide-2-related inhibitory peptide II; D049452:Green Fluorescent Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D005947:Glucose; D004318:Doxycycline; D002118:Calcium
keywords: CaMKII; Calcium Channels; Calcium Imaging; Diabetes; Insulin; Insulin Secretion; Islet; Pancreatic Islets