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.
Wu
Yuejin
Y
Department of Internal Medicine, Vanderbilt University.
Shintani
Ayumi
A
Grueter
Chad
C
Zhang
Rong
R
Hou
Yue
Y
Yang
Jinying
J
Kranias
Evangelia G
EG
Colbran
Roger J
RJ
Anderson
Mark E
ME
D000818:Animals; D020013:Calcium Signaling / Q000502:physiology*; D002135:Calcium-Binding Proteins / Q000172:deficiency / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors*; D002478:Cells, Cultured; D004594:Electrophysiology; D006352:Heart Ventricles / Q000166:cytology / Q000201:enzymology; D051379:Mice; D032383:Myocytes, Cardiac / Q000201:enzymology*; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000201:enzymology; D000099211:Phospholamban
D002135:Calcium-Binding Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D019837:Ryanodine Receptor Calcium Release Channel; D000099211:Phospholamban