title: Effects of CaMKII-mediated phosphorylation of ryanodine receptor type 2 on islet calcium handling, insulin secretion, and glucose tolerance.
abstract: Altered insulin secretion contributes to the pathogenesis of type 2 diabetes. This alteration is correlated with altered intracellular Ca(2+)-handling in pancreatic β cells. Insulin secretion is triggered by elevation in cytoplasmic Ca(2+) concentration ([Ca(2+)]cyt) of β 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 β-cell line in a glucose-sensitive manner. However, it is not clear whether any change in CaMKII-mediated phosphorylation underlies abnormal RyR2 function in β 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.
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Sayali S
authors.initials: SS
authors.lastname: Dixit
authors.forename: Tiannan
authors.initials: T
authors.lastname: Wang
authors.forename: Eiffel John Q
authors.initials: EJ
authors.lastname: Manzano
authors.forename: Shin
authors.initials: S
authors.lastname: Yoo
authors.forename: Jeongkyung
authors.initials: J
authors.lastname: Lee
authors.forename: David Y
authors.initials: DY
authors.lastname: Chiang
authors.forename: Nicole
authors.initials: N
authors.lastname: Ryan
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Respress
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Yechoor
authors.forename: Xander H T
authors.initials: XH
authors.lastname: Wehrens
mesh_terms: D000328:Adult; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D055879:Gene Knock-In Techniques; D005947:Glucose / Q000494:pharmacology; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*
chemical_list: D007328:Insulin; D019837:Ryanodine Receptor Calcium Release Channel; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D005947:Glucose; D002118:Calcium