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

Yuejin Wu, Ayumi Shintani, Chad Grueter, Rong Zhang, Yue Hou, Jinying Yang, Evangelia G. Kranias, Roger J. Colbran, Mark E. Anderson

Research output: Contribution to journalArticlepeer-review

Abstract

The multifunctional Ca2+ and calmodulin-dependent protein kinase II (CaMKII) is important for regulating L-type Ca2+ current (I Ca) 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 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 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.

Original languageEnglish (US)
Pages (from-to)213-223
Number of pages11
JournalJournal of Molecular and Cellular Cardiology
Volume40
Issue number2
DOIs
StatePublished - Feb 2006
Externally publishedYes

Keywords

  • Calmodulin-dependent protein kinase II
  • Phospholamban
  • Ventricular myocytes

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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