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

Y Wu, A Shintani, C Grueter, R Zhang, Y Hou… - Journal of molecular and …, 2006 - Elsevier
Y Wu, A Shintani, C Grueter, R Zhang, Y Hou, J Yang, EG Kranias, RJ Colbran
Journal of molecular and cellular cardiology, 2006Elsevier
The multifunctional Ca2+ and calmodulin-dependent protein kinase II (CaMKII) is important
for regulating L-type Ca2+ current (ICa) and cytoplasmic Ca2+ (Ca2+ i) uptake and release
from the sarcoplasmic reticulum (SR), key elements of the 'Ca2+-induced Ca2+
release'(CICR) mechanism. However, the effects of chronic CaMKII inhibition on Ca2+ i
responses during CICR are unknown. We hypothesized that chronic CaMKII inhibition
significantly affects CICR in ventricular myocytes. We studied CICR by simultaneously …
The multifunctional Ca2+ and calmodulin-dependent protein kinase II (CaMKII) is important for regulating L-type Ca2+ current (ICa) and cytoplasmic Ca2+ (Ca2+i) uptake and release from the sarcoplasmic reticulum (SR), key elements of the ‘Ca2+-induced Ca2+ release’ (CICR) mechanism. However, the effects of chronic CaMKII inhibition on Ca2+i responses during CICR are unknown. We hypothesized that chronic CaMKII inhibition significantly affects CICR in ventricular myocytes. We studied CICR by simultaneously measuring Ca2+i transients and ICa 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 Ca2+i uptake into the SR Ca2+ store. CaMKII inhibition eliminated a pattern of ICa increases called facilitation and significantly reduced beat-to-beat and cell-to-cell variability of peak Ca2+i transients in ventricular myocytes with PLN. PLN ablation eliminated ICa 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 ICa 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.
Elsevier