Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 107, Issue 11, Pages 4996-5000Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0913760107
Keywords
arrhythmias; calcium; calcium channel; calmodulin kinase; cardiac myocytes
Categories
Funding
- University of Iowa Gene Transfer Vector Core
- National Institutes of Health (NIH) [R01 HL079031, R01 HL070250, R01 HL096652, R01 HL084583, R01 HL083422]
- Pew Scholars Trust
- Fondation Leducq Award
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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 Ca2+ channel (Ca-V 1.2) activity, and enhanced expression of a specific Ca-V 1.2 beta-subunit protein isoform (beta(2a)). We recently identified Ca-V 1.2 beta(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 beta(2a) expression causes cellular Ca2+ overload, arrhythmia-triggering cell membrane potential oscillations called early afterdepolarizations (EADs), and premature death in paced adult rabbit ventricular myocytes. Prevention of intracellular Ca2+ release by ryanodine or global cellular CaMKII inhibition reduced EADs and improved cell survival to control levels in WT beta(2a)-expressing ventricular myocytes. In contrast, expression of beta(2a) T498A or L493A mutants mimicked the protective effects of ryanodine or global cellular CaMKII inhibition by reducing Ca2+ entry through Ca-V 1.2 and inhibiting EADs. Furthermore, Ca-V 1.2 currents recorded from cells overexpressing CaMKII phosphorylation-or binding-incompetent beta(2a) subunits were incapable of entering a CaMKII-dependent high-activity gating mode (mode 2), indicating that beta(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 beta(2a) are concise but pivotal components of a molecular and biophysical and mechanism for EADs and impaired survival in adult cardiomyocytes.
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