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 Anderson, Franz J. Baudenbacher

Research output: Contribution to journalArticle

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)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume294
Issue number5
DOIs
StatePublished - May 2008
Externally publishedYes

Fingerprint

Calcium-Calmodulin-Dependent Protein Kinases
Cardiac Myocytes
Calcium-Calmodulin-Dependent Protein Kinase Type 2
phospholamban
Ryanodine Receptor Calcium Release Channel
Sarcoplasmic Reticulum
Protein Kinase Inhibitors
Transgenic Mice
Phosphorylation

Keywords

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

ASJC Scopus subject areas

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

Cite this

Differential effects of phospholamban and Ca2+/calmodulin- dependent kinase II on [Ca2+]i transients in cardiac myocytes at physiological stimulation frequencies. / Werdich, Andreas A.; Lima, Eduardo A.; Dzhura, Igor; Singh, Madhu V.; Li, Jingdong; Anderson, Mark; Baudenbacher, Franz J.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 294, No. 5, 05.2008.

Research output: Contribution to journalArticle

@article{a25884567e87433c9a7d76ded7c41ed8,
title = "Differential effects of phospholamban and Ca2+/calmodulin- dependent kinase II on [Ca2+]i transients in cardiac myocytes at physiological stimulation frequencies",
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.",
keywords = "Cytosolic calcium concentration, Frequency adaptation, Frequency-dependent acceleration of relaxation",
author = "Werdich, {Andreas A.} and Lima, {Eduardo A.} and Igor Dzhura and Singh, {Madhu V.} and Jingdong Li and Mark Anderson and Baudenbacher, {Franz J.}",
year = "2008",
month = "5",
doi = "10.1152/ajpheart.01398.2006",
language = "English (US)",
volume = "294",
journal = "American Journal of Physiology",
issn = "0363-6135",
publisher = "American Physiological Society",
number = "5",

}

TY - JOUR

T1 - Differential effects of phospholamban and Ca2+/calmodulin- dependent kinase II on [Ca2+]i transients in cardiac myocytes at physiological stimulation frequencies

AU - Werdich, Andreas A.

AU - Lima, Eduardo A.

AU - Dzhura, Igor

AU - Singh, Madhu V.

AU - Li, Jingdong

AU - Anderson, Mark

AU - Baudenbacher, Franz J.

PY - 2008/5

Y1 - 2008/5

N2 - 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.

AB - 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.

KW - Cytosolic calcium concentration

KW - Frequency adaptation

KW - Frequency-dependent acceleration of relaxation

UR - http://www.scopus.com/inward/record.url?scp=44949120809&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=44949120809&partnerID=8YFLogxK

U2 - 10.1152/ajpheart.01398.2006

DO - 10.1152/ajpheart.01398.2006

M3 - Article

C2 - 18359893

AN - SCOPUS:44949120809

VL - 294

JO - American Journal of Physiology

JF - American Journal of Physiology

SN - 0363-6135

IS - 5

ER -