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Assessment of Sarcoplasmic Reticulum Calcium Reserve and Intracellular Diastolic Calcium Removal in Isolated Ventricular Cardiomyocytes
11:00

Assessment of Sarcoplasmic Reticulum Calcium Reserve and Intracellular Diastolic Calcium Removal in Isolated Ventricular Cardiomyocytes

Published on: September 18, 2017

Ca2+/calmodulin-dependent protein kinase modulates cardiac ryanodine receptor phosphorylation and sarcoplasmic

Xun Ai1, Jerry W Curran, Thomas R Shannon

  • 1Department of Medicine, University of Illinois at Chicago, IL 60612, USA.

Circulation Research
|November 5, 2005
PubMed

Insights

Abnormal calcium release from the sarcoplasmic reticulum (SR) in heart failure (HF) is linked to CaMKII-dependent RyR2 phosphorylation. This enhances SR calcium leak, contributing to HF

Area of Science:

  • Cardiovascular Biology
  • Molecular Cardiology
  • Heart Failure Pathophysiology

Background:

  • Abnormal calcium (Ca) release from the sarcoplasmic reticulum (SR) via the cardiac ryanodine receptor (RyR2) is implicated in heart failure (HF) contractile dysfunction and arrhythmias.
  • Previous studies in a rabbit HF model showed reduced Ca transient amplitude and SR Ca load, with increased Na/Ca exchanger expression and diastolic SR Ca leak.

Purpose of the Study:

  • To investigate the expression and phosphorylation status of key Ca handling proteins in HF rabbit myocytes.
  • To measure SR Ca leak and assess the role of CaMKII and PKA in HF-associated Ca handling abnormalities.

Main Methods:

  • Western blotting to assess protein expression and phosphorylation.
  • Measurement of SR Ca leak in isolated control and HF rabbit myocytes.
  • Pharmacological inhibition of CaMKII and PKA to evaluate their effects on SR Ca handling.

Main Results:

  • HF myocytes exhibited reduced RyR2 and FKBP12.6, but increased IP3R2 and CaMKII expression.
  • RyR2 complex in HF myocytes showed increased activated CaMKII and phosphorylation, but reduced calmodulin, FKBP12.6, and phosphatases.
  • CaMKII inhibition reduced SR Ca leak and increased SR Ca content in HF myocytes, while PKA inhibition had no significant effect.

Conclusions:

  • CaMKII-dependent phosphorylation of RyR2 contributes to enhanced SR diastolic Ca leak and reduced SR Ca load in HF.
  • These Ca handling abnormalities mediated by CaMKII may play a significant role in HF-related arrhythmias and contractile dysfunction.

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