CaV1.2 β-subunit coordinates CaMKII-triggered cardiomyocyte death and afterdepolarizations
2010
Koval, Olha M. | Guan, Xiaoquan | Wu, Yuejin | Joiner, Mei-ling | Gao, Zhan | Chen, Biyi | Grumbach, Isabella M. | Luczak, Elizabeth D. | Colbran, Roger J. | Song, Long-Sheng | Hund, Thomas J. | Mohler, Peter J. | Anderson, Mark E.
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 (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.
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