Regulation of Cardiac ATP-sensitive Potassium Channel Surface Expression by Calcium/Calmodulin-dependent Protein Kinase II

Ana Sierra; Zhiyong Zhu; Nicolas Sapay; Vikas Sharotri; Crystal F Kline; Elizabeth D Luczak; Ekaterina Subbotina; Asipu Sivaprasadarao; Peter M Snyder; Peter J Mohler; Mark E Anderson; Michel Vivaudou; Leonid V Zingman; Denice M Hodgson-Zingman

doi:10.1074/jbc.M112.429548

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Regulation of Cardiac ATP-sensitive Potassium Channel Surface Expression by Calcium/Calmodulin-dependent Protein Kinase II

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Regulation of Cardiac ATP-sensitive Potassium Channel Surface Expression by Calcium/Calmodulin-dependent Protein Kinase II

Ana Sierra, Zhiyong Zhu, Nicolas Sapay, Vikas Sharotri, Crystal F Kline, Elizabeth D Luczak, Ekaterina Subbotina, Asipu Sivaprasadarao, Peter M Snyder, Peter J Mohler, …

The Journal of biological chemistry, Vol.288(3), pp.1568-1581

01/18/2013

DOI: 10.1074/jbc.M112.429548

PMCID: PMC3548467

PMID: 23223335

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Abstract

Background: Surface expression of cardiac ATP-sensitive potassium ( K ATP ) channels impacts cellular energy homeostasis. Results: Activation of calcium/calmodulin-dependent protein kinase II (CaMKII) results in K ATP channel internalization, requiring specific motifs on the Kir6.2 channel subunit. Conclusion: CaMKII phosphorylation of Kir6.2 promotes endocytosis of cardiac K ATP channels. Significance: This mechanism reveals new targets to improve cardiac energy efficiency and stress resistance. Cardiac ATP-sensitive potassium ( K ATP ) channels are key sensors and effectors of the metabolic status of cardiomyocytes. Alteration in their expression impacts their effectiveness in maintaining cellular energy homeostasis and resistance to injury. We sought to determine how activation of calcium/calmodulin-dependent protein kinase II (CaMKII), a central regulator of calcium signaling, translates into reduced membrane expression and current capacity of cardiac K ATP channels. We used real-time monitoring of K ATP channel current density, immunohistochemistry, and biotinylation studies in isolated hearts and cardiomyocytes from wild-type and transgenic mice as well as HEK cells expressing wild-type and mutant K ATP channel subunits to track the dynamics of K ATP channel surface expression. Results showed that activation of CaMKII triggered dynamin-dependent internalization of K ATP channels. This process required phosphorylation of threonine at 180 and 224 and an intact 330 YSKF 333 endocytosis motif of the K ATP channel Kir6.2 pore-forming subunit. A molecular model of the μ2 subunit of the endocytosis adaptor protein, AP2, complexed with Kir6.2 predicted that μ2 docks by interaction with 330 YSKF 333 and Thr-180 on one and Thr-224 on the adjacent Kir6.2 subunit. Phosphorylation of Thr-180 and Thr-224 would favor interactions with the corresponding arginine- and lysine-rich loops on μ2. We concluded that calcium-dependent activation of CaMKII results in phosphorylation of Kir6.2, which promotes endocytosis of cardiac K ATP channel subunits. This mechanism couples the surface expression of cardiac K ATP channels with calcium signaling and reveals new targets to improve cardiac energy efficiency and stress resistance.

Heart

Bioenergetics

Ion Channels

Immunofluorescence

Cell Biology

Endocytosis

ABC Transporter

Internalization

Homology Modeling

K-ATP Channel

Details

Title: Subtitle: Regulation of Cardiac ATP-sensitive Potassium Channel Surface Expression by Calcium/Calmodulin-dependent Protein Kinase II
Creators: Ana Sierra
Zhiyong Zhu - From the
Nicolas Sapay - Laboratoire de Chimie et Biologie des Métaux (Commissariat à l'Energie Atomique/Université Grenoble 1/CNRS), 38054 Grenoble, France
Vikas Sharotri - From the
Crystal F Kline - Dorothy M. Davis Heart and Lung Research Institute and Department of Internal Medicine, Ohio State University Wexner Medical Center, Columbus, Ohio 43210
Elizabeth D Luczak - From the
Ekaterina Subbotina - From the
Asipu Sivaprasadarao - Multidisciplinary Cardiovascular Research Centre, Institute of Membrane and Systems Biology, University of Leeds, LS2 9JT Leeds, United Kingdom
Peter M Snyder - From the
Peter J Mohler - Dorothy M. Davis Heart and Lung Research Institute and Department of Internal Medicine, Ohio State University Wexner Medical Center, Columbus, Ohio 43210
Mark E Anderson - From the
Michel Vivaudou - CNRS, Commissariat à l'Energie Atomique, Université Grenoble I, Institut de Biologie Structurale, 75794 Grenoble, France, and
Leonid V Zingman - From the
Denice M Hodgson-Zingman - From the
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.288(3), pp.1568-1581
DOI: 10.1074/jbc.M112.429548
PMID: 23223335
PMCID: PMC3548467
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: American Society for Biochemistry and Molecular Biology; 9650 Rockville Pike, Bethesda, MD 20814, U.S.A
Grant note: HL092286; R01HL113089; HL093368; R01DK092412; R01HL079031; R01HL62494; R01HL70250; R01HL113001; HL084583; HL083422; HL058812 / National Institutes of Health
Alternative title: Cardiac KATP Channel Endocytosis by CaMKII
Language: English
Date published: 01/18/2013
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Cardiovascular Medicine; Medicine Administration; Internal Medicine
Record Identifier: 9984025356802771

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