βiV-Spectrin and CaMKII facilitate Kir6.2 regulation in pancreatic beta cells

Kline C.F.; Wright P.J.; Koval O.M.Zmuda E.J.Johnson B.L.Anderson M.E.Hai T.Hund T.J.Mohler P.J.

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βiV-Spectrin and CaMKII facilitate Kir6.2 regulation in pancreatic beta cells

机译：βiV-Spectrin and CaMKII facilitate Kir6.2 regulation in pancreatic beta cells

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Identified over a dozen years ago in the brain and pancreatic islet, β_(IV)-spectrin is critical for the local organization of protein complexes throughout the nervous system. β_(IV)-Spectrin targets ion channels and adapter proteins to axon initial segments and nodes of Ranvier in neurons, and β_(IV)-spectrin dysfunction underlies ataxia and early death in mice. Despite advances in β_(IV)-spectrin research in the nervous system, its role in pancreatic islet biology is unknown. Here, we report that β_(IV)-spectrin serves as a multifunctional structural and signaling platform in the pancreatic islet. We report that β_(IV)-spectrin directly associates with and targets the calcium/calmodulin-dependent protein kinase II (CaMKII) in pancreatic islets. In parallel, β_(IV)-spectrin targets ankyrin-B and the ATP-sensitive potassium channel. Consistent with these findings, β_(IV)IV- spectrin mutant mice lacking CaMKII- or ankyrin-binding motifs display selective loss of expression and targeting of key protein components, including CaMKIIδ. β_(IV)IV-Spectrin-targeted CaMKII directly phosphorylates the inwardly-rectifying potassium channel, Kir6.2 (alpha subunit of K_(ATP) channel complex), and we identify the specific residue, Kir6.2 T224, responsible for CaMKII-dependent regulation of K_(ATP) channel function. CaMKII-dependent phosphorylation alters channel regulation resulting in K_(ATP) channel inhibition, a cellular phenotype consistent with aberrant insulin regulation. Finally, we demonstrate aberrant K ATP channel phosphorylation in β_(IV)-spectrin mutant mice. In summary, our findings establish a broader role for β_(IV)- spectrin in regulation of cell membrane excitability in the pancreatic islet, define the pathway for CaMKII local control in pancreatic beta cells, and identify the mechanism for CaMKII-dependent regulation of K_(ATP) channels.

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《Proceedings of the National Academy of Sciences of the United States of America》 |2013年第43期|17576-17581|共6页
作者
Kline C.F.; Wright P.J.; Koval O.M.Zmuda E.J.Johnson B.L.Anderson M.E.Hai T.Hund T.J.Mohler P.J.;
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作者单位

Dorothy M. Davis Heart and Lung Research Institute, Ohio State University Wexner Medical Center, Columbus, OH 43210, United States;

Department of Biomedical Engineering, College of Engineering, Ohio State University, Columbus, OH 43210, United States;

Department of Molecular and Cellular Biochemistry, Ohio State University Wexner Medical Center, Columbus, OH 43210, United StatesDivision of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242, United States;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
Local regulation; Trafficking;

βiV-Spectrin and CaMKII facilitate Kir6.2 regulation in pancreatic beta cells

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