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This Article Full Text Full Text (PDF) All Versions of this Article: 294/5/H2352    most recent 01398.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Werdich, A. A. Articles by Baudenbacher, F. J. Search for Related Content PubMed PubMed Citation Articles by Werdich, A. A. Articles by Baudenbacher, F. J.

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

¹Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee; and Departments of ²Medicine and ³Molecular Physiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa

Submitted 20 December 2006 ; accepted in final form 20 March 2008

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 [Ca²⁺]_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.

frequency adaptation; frequency-dependent acceleration of relaxation; cytosolic calcium concentration