Differential effects of phospholamban and Ca2+/calmodulin- dependent kinase II on [Ca2+]i transients in cardiac myocytes at physiological stimulation frequencies

Andreas A. Werdich, Eduardo A. Lima, Igor Dzhura, Madhu V. Singh, Jingdong Li, Mark E. Anderson, Franz J. Baudenbacher

Research output: Contribution to journalArticlepeer-review

Abstract

In cardiac myocytes, the activity of the Ca2+/calmodulin- dependent protein kinase II (CaMKII) is hypothesized to regulate Ca2+ release from and Ca2+ uptake into the sarcoplasmic reticulum via the phosphorylation of the ryanodine receptor 2 and phospholamban (PLN), respectively. We tested the role of CaMKII and PLN on the frequency adaptation of cytosolic Ca2+ concentration ([Ca2+]i) transients in nearly 500 isolated cardiac myocytes from transgenic mice chronically expressing a specific CaMKII inhibitor, interbred into wild-type or PLN null backgrounds under physiologically relevant pacing conditions (frequencies from 0.2 to 10 Hz and at 37°C). When compared with that of mice lacking PLN only, the combined chronic CaMKII inhibition and PLN ablation decreased the maximum Ca2+ release rate by more than 50% at 10 Hz. Although PLN ablation increased the rate of Ca2+ uptake at all frequencies, its combination with CaMKII inhibition did not prevent a frequency-dependent reduction of the amplitude and the duration of the [Ca 2+]i transient. High stimulation frequencies in the physiological range diminished the effects of PLN ablation on the decay time constant and on the maximum decay rate of the [Ca2+]i transient, indicating that the PLN-mediated feedback on [Ca2+] i removal is limited by high stimulation frequencies. Taken together, our results suggest that in isolated mouse ventricular cardiac myocytes, the combined chronic CaMKII inhibition and PLN ablation slowed Ca2+ release at physiological frequencies: the frequency-dependent decay of the amplitude and shortening of the [Ca2+]i transient occurs independent of chronic CaMKII inhibition and PLN ablation, and the PLN-mediated regulation of Ca2+ uptake is diminished at higher stimulation frequencies within the physiological range.

Original languageEnglish (US)
Pages (from-to)H2352-H2362
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume294
Issue number5
DOIs
StatePublished - May 2008
Externally publishedYes

Keywords

  • Cytosolic calcium concentration
  • Frequency adaptation
  • Frequency-dependent acceleration of relaxation

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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