CaV1.2 β-subunit coordinates CaMKII-triggered cardiomyocyte death and afterdepolarizations

Olha M. Koval, Xiaoquan Guan, Yuejin Wu, Mei Ling Joiner, Zhan Gao, Biyi Chen, Isabella M. Grumbach, Elizabeth D. Luczak, Roger J. Colbran, Long Sheng Song, Thomas J. Hund, Peter J. Mohler, Mark E. Anderson

Research output: Contribution to journalArticlepeer-review

98 Scopus citations

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 voltagegated Ca2+ channel (CaV1.2) activity, and enhanced expression of a specific CaV1.2 β-subunit protein isoform (β2a). We recently identified CaV1.2 β2a 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 β2a 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 β2a-expressing ventricular myocytes. In contrast, expression of β2a T498A or L493A mutants mimicked the protective effects of ryanodine or global cellular CaMKII inhibition by reducing Ca2+ entry through CaV1.2 and inhibiting EADs. Furthermore, CaV1.2 currents recorded from cells overexpressing CaMKII phosphorylation-or binding-incompetent β2a subunits were incapable of entering a CaMKII-dependent high-activity gating mode (mode 2), indicating that β2a Thr 498 and Leu 493 are required for CaV1.2 activation by CaMKII in native cells. These data show that CaMKII binding and phosphorylation sites on β2a are concise but pivotal components of a molecular and biophysical and mechanism for EADs and impaired survival in adult cardiomyocytes.

Original languageEnglish (US)
Pages (from-to)4996-5000
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number11
DOIs
StatePublished - Mar 16 2010
Externally publishedYes

Keywords

  • Arrhythmias
  • Calcium
  • Calcium channel
  • Calmodulin kinase
  • Cardiac myocytes

ASJC Scopus subject areas

  • General

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