Suppression of dynamic Ca(2+) transient responses to pacing in ventricular myocytes from mice with genetic calmodulin kinase II inhibition.
The multifunctional Ca(2+) and calmodulin-dependent protein kinase II (CaMKII) is important for regulating L-type Ca(2+) current (I(Ca)) and cytoplasmic Ca(2+) (Ca(2+)(i)) uptake and release from the sarcoplasmic reticulum (SR), key elements of the 'Ca(2+)-induced Ca(2+) release' (CICR) mechanism. However, the effects of chronic CaMKII inhibition on Ca(2+)(i) responses during CICR are unknown. We hypothesized that chronic CaMKII inhibition significantly affects CICR in ventricular myocytes. We studied CICR by simultaneously measuring Ca(2+)(i) transients and I(Ca) in voltage-clamped ventricular myocytes isolated from a recently developed genetic mouse model of cardiac CaMKII inhibition. These measurements were repeated in ventricular myocytes from novel mice with cardiac CaMKII inhibition lacking phospholamban (PLN), a known CaMKII substrate and a negative regulator of Ca(2+)(i) uptake into the SR Ca(2+) store. CaMKII inhibition eliminated a pattern of I(Ca) increases called facilitation and significantly reduced beat-to-beat and cell-to-cell variability of peak Ca(2+)(i) transients in ventricular myocytes with PLN. PLN ablation eliminated I(Ca) facilitation even in the absence of CaMKII inhibition and the effects of CaMKII inhibition to reduce SR Ca(2+) content and slow SR Ca(2+) uptake were lost in the absence of PLN. PLN ablation significantly reduced I(Ca) beat-to-beat variability in cells with CaMKII inhibition. These findings show that chronic CaMKII inhibition reduces variability of CICR responses in a manner that is partly dependent on the presence of PLN.[1]References
- Suppression of dynamic Ca(2+) transient responses to pacing in ventricular myocytes from mice with genetic calmodulin kinase II inhibition. Wu, Y., Shintani, A., Grueter, C., Zhang, R., Hou, Y., Yang, J., Kranias, E.G., Colbran, R.J., Anderson, M.E. J. Mol. Cell. Cardiol. (2006) [Pubmed]
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