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Role of CaMKII in RyR leak, EC coupling and action potential duration: a computational model

Yasmin L Hashambhoy1, Joseph L Greenstein, Raimond L Winslow

  • 1Institute for Computational Medicine, Center for Cardiovascular Bioinformatics and Modeling, The Johns Hopkins University, Baltimore, MD, USA.

Journal of Molecular and Cellular Cardiology
|July 27, 2010
PubMed

Insights

Heart failure impairs calcium handling. Mathematical modeling suggests CaMKII phosphorylation of L-type calcium channels, not RyRs, more effectively modulates calcium leak and cardiac function.

Area of Science:

  • Cardiovascular Physiology
  • Computational Biology
  • Molecular Cardiology

Background:

  • Heart failure involves impaired sarcoplasmic reticulum Ca(2+) storage, abnormal Ca(2+) cycling, and excitation-contraction coupling.
  • Leaky ryanodine receptors (RyRs) are implicated in reduced SR Ca(2+) levels during heart failure.
  • Ca(2+)/calmodulin-dependent kinase II (CaMKII) phosphorylation of RyRs is experimentally studied but complex due to ion and protein modulation.

Purpose of the Study:

  • To develop a mathematical model of CaMKII-RyR interaction in canine ventricular myocytes.
  • To investigate the impact of CaMKII phosphorylation on RyR function and Ca(2+) handling.
  • To compare the effects of L-type calcium channel (LCC) phosphorylation versus RyR phosphorylation on cardiac function.

Main Methods:

  • Extended a previous model of CaMKII phosphorylation of LCCs to include CaMKII-RyR interactions.
  • Modeled RyR phosphorylation as a function of dyadic CaMKII activity and local Ca(2+) levels.
  • Constrained the model using experimental data on Ca(2+) spark frequency and RyR phosphorylation.

Main Results:

  • The model replicated steady-state RyR (leak) fluxes within experimental ranges without a separate leak pathway.
  • CaMKII phosphorylation of LCCs had a greater effect on RyR flux than RyR phosphorylation under physiological conditions.
  • LCC phosphorylation significantly decreased excitation-contraction coupling gain and increased action potential duration.

Conclusions:

  • CaMKII phosphorylation of LCCs is a more significant modulator of diastolic RyR flux than RyR phosphorylation.
  • Targeting LCC phosphorylation sites may be more effective for modulating diastolic RyR flux in heart failure.
  • The model provides insights into Ca(2+) dysregulation and potential therapeutic targets in cardiac dysfunction.

Keywords:
CaMKIIEC couplingL-type Ca channelRyRcomputational model

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