Journal article
CaV1.2 β-subunit coordinates CaMKII-triggered cardiomyocyte death and afterdepolarizations
Proceedings of the National Academy of Sciences - PNAS, Vol.107(11), pp.4996-5000
03/16/2010
DOI: 10.1073/pnas.0913760107
PMCID: PMC2841943
PMID: 20194790
Abstract
Excessive activation of calmodulin kinase II (CaMKII) causes arrhythmias and heart failure, but the cellular mechanisms for CaMKII-targeted proteins causing disordered cell membrane excitability and myocardial dysfunction remain uncertain. Failing human cardiomyocytes exhibit increased CaMKII and voltage-gated Ca
2+
channel (Ca
V
1.2) activity, and enhanced expression of a specific Ca
V
1.2 β-subunit protein isoform (
β
2a
). We recently identified Ca
V
1.2
β
2a
residues critical for CaMKII phosphorylation (Thr 498) and binding (Leu 493), suggesting the hypothesis that these amino acids are crucial for cardiomyopathic consequences of CaMKII signaling. Here we show WT
β
2a
expression causes cellular Ca
2+
overload, arrhythmia-triggering cell membrane potential oscillations called early afterdepolarizations (EADs), and premature death in paced adult rabbit ventricular myocytes. Prevention of intracellular Ca
2+
release by ryanodine or global cellular CaMKII inhibition reduced EADs and improved cell survival to control levels in WT
β
2a
-expressing ventricular myocytes. In contrast, expression of
β
2a
T498A or L493A mutants mimicked the protective effects of ryanodine or global cellular CaMKII inhibition by reducing Ca
2+
entry through Ca
V
1.2 and inhibiting EADs. Furthermore, Ca
V
1.2 currents recorded from cells overexpressing CaMKII phosphorylation- or binding-incompetent
β
2a
subunits were incapable of entering a CaMKII-dependent high-activity gating mode (mode 2), indicating that
β
2a
Thr 498 and Leu 493 are required for Ca
V
1.2 activation by CaMKII in native cells. These data show that CaMKII binding and phosphorylation sites on
β
2a
are concise but pivotal components of a molecular and biophysical and mechanism for EADs and impaired survival in adult cardiomyocytes.
Details
- Title: Subtitle
- CaV1.2 β-subunit coordinates CaMKII-triggered cardiomyocyte death and afterdepolarizations
- Creators
- Olha M Koval - Department of Internal Medicine, University of Iowa, 2256 Carver Biomedical Research Building, Iowa City, IA 52242Xiaoquan Guan - Department of Internal Medicine, University of Iowa, 2256 Carver Biomedical Research Building, Iowa City, IA 52242Yuejin Wu - Department of Internal Medicine, University of Iowa, 2256 Carver Biomedical Research Building, Iowa City, IA 52242Mei-ling Joiner - Department of Internal Medicine, University of Iowa, 2256 Carver Biomedical Research Building, Iowa City, IA 52242Zhan Gao - Department of Internal Medicine, University of Iowa, 2256 Carver Biomedical Research Building, Iowa City, IA 52242Biyi Chen - Department of Internal Medicine, University of Iowa, 2256 Carver Biomedical Research Building, Iowa City, IA 52242Isabella M Grumbach - Department of Internal Medicine, University of Iowa, 2256 Carver Biomedical Research Building, Iowa City, IA 52242Elizabeth D Luczak - Department of Internal Medicine, University of Iowa, 2256 Carver Biomedical Research Building, Iowa City, IA 52242Roger J Colbran - Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232; andLong-Sheng Song - Department of Internal Medicine, University of Iowa, 2256 Carver Biomedical Research Building, Iowa City, IA 52242Thomas J Hund - Department of Internal Medicine, University of Iowa, 2256 Carver Biomedical Research Building, Iowa City, IA 52242Peter J Mohler - Department of Internal Medicine, University of Iowa, 2256 Carver Biomedical Research Building, Iowa City, IA 52242Mark E Anderson - Department of Internal Medicine, University of Iowa, 2256 Carver Biomedical Research Building, Iowa City, IA 52242
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.107(11), pp.4996-5000
- DOI
- 10.1073/pnas.0913760107
- PMID
- 20194790
- PMCID
- PMC2841943
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Publisher
- National Academy of Sciences
- Language
- English
- Date published
- 03/16/2010
- Academic Unit
- Cardiovascular Medicine; Biology; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Internal Medicine
- Record Identifier
- 9984094212502771
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