题名：Effects of CaMKII-mediated phosphorylation of ryanodine receptor type 2 on islet calcium handling, insulin secretion, and glucose tolerance.
作者：DIXIT SS; WANG T; MANZANO EJ; YOO S; LEE J; CHIANG DY; RYAN N; RESPRESS JL; YECHOOR VK; WEHRENS XH;
来源：PLoS One. 2013;8(3):e58655. doi: 10.1371/journal.pone.0058655. Epub 2013 Mar 13. [ IF= 4.09 ] ]
摘要：Altered insulin secretion contributes to the pathogenesis of type 2 diabetes.
This alteration is correlated with altered intracellular Ca(2+)-handling in
pancreatic beta cells. Insulin secretion is triggered by elevation in cytoplasmic
Ca(2+) concentration ([Ca(2+)]cyt) of beta cells. This elevation in [Ca(2+)]cyt
leads to activation of Ca(2+)/calmodulin-dependent protein kinase II (CAMKII),
which, in turn, controls multiple aspects of insulin secretion. CaMKII is known
to phosphorylate ryanodine receptor 2 (RyR2), an intracellular Ca(2+)-release
channel implicated in Ca(2+)-dependent steps of insulin secretion. Our data show
that RyR2 is CaMKII phosphorylated in a pancreatic beta-cell line in a
glucose-sensitive manner. However, it is not clear whether any change in
CaMKII-mediated phosphorylation underlies abnormal RyR2 function in beta cells
and whether such a change contributes to alterations in insulin secretion.
Therefore, knock-in mice with a mutation in RyR2 that mimics its constitutive
CaMKII phosphorylation, RyR2-S2814D, were studied. This mutation led to a
gain-of-function defect in RyR2 indicated by increased basal RyR2-mediated Ca(2+)
leak in islets of these mice. This chronic in vivo defect in RyR2 resulted in
basal hyperinsulinemia. In addition, S2814D mice also developed glucose
intolerance, impaired glucose-stimulated insulin secretion and lowered
[Ca(2+)]cyt transients, which are hallmarks of pre-diabetes. The
glucose-sensitive Ca(2+) pool in islets from S2814D mice was also reduced. These
observations were supported by immunohistochemical analyses of islets in diabetic
human and mouse pancreata that revealed significantly enhanced CaMKII
phosphorylation of RyR2 in type 2 diabetes. Together, these studies implicate
that the chronic gain-of-function defect in RyR2 due to CaMKII
hyperphosphorylation is a novel mechanism that contributes to pathogenesis of
type 2 diabetes.