Suppression of dynamic Ca2+ transient responses to pacing in ventricular myocytes from mice with genetic calmodulin kinase II inhibition

The multifunctional Ca2+ and calmodulin-dependent protein kinase II (CaMKII) is important for regulating L-type Ca2+ current (I-Ca) and cytoplasmic Ca2+ (Ca-i(2+)) uptake and release frorn the sarcoplasmic reticulum(SR), key elements of the 'Ca2+-induced Ca2+ release' (CICR) mechanism. However, the effects of chronic CaMKII inhibition on Ca-i(2+) responses during CICR are unknown. We hypothesized that chronic CaMKII inhibition significantly affects CICR in ventricular myocytes. We Studied CICR by simultaneously measuring Ca-i(2+) transients and I-Ca in voltage-clamped ventricular myocytes isolated frorn a recently developed genetic mouse model of cardiac CaMKII inhibition. These measurements were repeated in ventricular myocytes frorn novel mice with cardiac CaMKII inhibition lacking phospholamban (PLN), a known CaMKII substrate and a negative regulator of Ca-i(2+) uptake into the SR Ca2+ 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-i(2+) 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 Ca2+ content and slow SR Ca2+ 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. (c) 2006 Elsevier Ltd. All rights reserved.