Journal article
beta(IV)-Spectrin and CaMKII facilitate Kir6.2 regulation in pancreatic beta cells
Proceedings of the National Academy of Sciences - PNAS, Vol.110(43), pp.17576-17581
10/22/2013
DOI: 10.1073/pnas.1314195110
PMCID: PMC3808601
PMID: 24101510
Abstract
Identified over a dozen years ago in the brain and pancreatic islet, beta(IV)-spectrin is critical for the local organization of protein complexes throughout the nervous system. beta(IV)-Spectrin targets ion channels and adapter proteins to axon initial segments and nodes of Ranvier in neurons, and beta(IV)-spectrin dysfunction underlies ataxia and early death in mice. Despite advances in beta(IV)-spectrin research in the nervous system, its role in pancreatic islet biology is unknown. Here, we report that beta(IV)-spectrin serves as a multifunctional structural and signaling platform in the pancreatic islet. We report that beta(IV)-spectrin directly associates with and targets the calcium/calmodulin-dependent protein kinase II (CaMKII) in pancreatic islets. In parallel, beta(IV)-spectrin targets ankyrin-B and the ATP-sensitive potassium channel. Consistent with these findings, beta(IV)-spectrin mutant mice lacking CaMKII-or ankyrin-binding motifs display selective loss of expression and targeting of key protein components, including CaMKIId. beta(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 beta(IV)-spectrin mutant mice. In summary, our findings establish a broader role for beta(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.
Details
- Title: Subtitle
- beta(IV)-Spectrin and CaMKII facilitate Kir6.2 regulation in pancreatic beta cells
- Creators
- Crystal F. Kline - The Ohio State University Wexner Medical CenterPatrick J. Wright - The Ohio State UniversityOlha M. Koval - The Ohio State UniversityErik J. Zmuda - Cellular ResearchBenjamin L. Johnson - The Ohio State UniversityMark E. Anderson - Roy J. and Lucille A. Carver College of MedicineTsonwin Hai - Cellular ResearchThomas J. Hund - The Ohio State UniversityPeter J. Mohler - The Ohio State University Wexner Medical Center
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.110(43), pp.17576-17581
- Publisher
- Natl Acad Sciences
- DOI
- 10.1073/pnas.1314195110
- PMID
- 24101510
- PMCID
- PMC3808601
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Number of pages
- 6
- Grant note
- Saving Tiny Hearts Society 08CVD01 / Fondation Leducq; Leducq Foundation K99HL096805 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) American Heart Association HL096805; HL114893; HL084583; HL083422; HL079031; HL096652; HL070250 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Gilead Scholars Program
- Language
- English
- Date published
- 10/22/2013
- Academic Unit
- Cardiovascular Medicine; Internal Medicine
- Record Identifier
- 9984359787302771
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