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

Crystal F. Kline, Patrick J. Wright, Olha M. Koval, Erik J. Zmuda, Benjamin L. Johnson, Mark Anderson, Tsonwin Hai, Thomas J. Hund, Peter J. Mohler

Research output: Contribution to journalArticle

Abstract

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

Original languageEnglish (US)
Pages (from-to)17576-17581
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number43
DOIs
StatePublished - Oct 22 2013
Externally publishedYes

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Calcium-Calmodulin-Dependent Protein Kinase Type 2
Spectrin
Insulin-Secreting Cells
KATP Channels
Islets of Langerhans
Ankyrins
Nervous System
Phosphorylation
Ranvier's Nodes
Inwardly Rectifying Potassium Channel
Calcium-Calmodulin-Dependent Protein Kinases
Protein Transport
Ataxia
Ion Channels
Proteins
Adenosine Triphosphate
Cell Membrane

Keywords

  • Local regulation
  • Trafficking

ASJC Scopus subject areas

  • General

Cite this

βiV-Spectrin and CaMKII facilitate Kir6.2 regulation in pancreatic beta cells. / Kline, Crystal F.; Wright, Patrick J.; Koval, Olha M.; Zmuda, Erik J.; Johnson, Benjamin L.; Anderson, Mark; Hai, Tsonwin; Hund, Thomas J.; Mohler, Peter J.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, No. 43, 22.10.2013, p. 17576-17581.

Research output: Contribution to journalArticle

Kline, Crystal F. ; Wright, Patrick J. ; Koval, Olha M. ; Zmuda, Erik J. ; Johnson, Benjamin L. ; Anderson, Mark ; Hai, Tsonwin ; Hund, Thomas J. ; Mohler, Peter J. / βiV-Spectrin and CaMKII facilitate Kir6.2 regulation in pancreatic beta cells. In: Proceedings of the National Academy of Sciences of the United States of America. 2013 ; Vol. 110, No. 43. pp. 17576-17581.
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T1 - βiV-Spectrin and CaMKII facilitate Kir6.2 regulation in pancreatic beta cells

AU - Kline, Crystal F.

AU - Wright, Patrick J.

AU - Koval, Olha M.

AU - Zmuda, Erik J.

AU - Johnson, Benjamin L.

AU - Anderson, Mark

AU - Hai, Tsonwin

AU - Hund, Thomas J.

AU - Mohler, Peter J.

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

KW - Local regulation

KW - Trafficking

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