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Assessment of Sarcoplasmic Reticulum Calcium Reserve and Intracellular Diastolic Calcium Removal in Isolated Ventricular Cardiomyocytes
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Dissociation of calmodulin from cardiac ryanodine receptor causes aberrant Ca(2+) release in heart failure

Makoto Ono1, Masafumi Yano, Akihiro Hino

  • 1Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi 755-8505, Japan.

Cardiovascular Research
|April 15, 2010
PubMed
Abstract

Insights

Calmodulin binding to cardiac ryanodine receptors (RyR2) is reduced in failing hearts, leading to abnormal calcium release. Restoring this calmodulin binding may protect against heart failure.

Area of Science:

  • Cardiovascular Physiology
  • Molecular Cardiology
  • Calcium Signaling

Background:

  • Calmodulin (CaM) regulates cardiac ryanodine receptor (RyR2) function.
  • The role of CaM in aberrant calcium release in heart failure is not fully understood.

Purpose of the Study:

  • Investigate CaM binding to RyR2 in pacing-induced failing hearts.
  • Assess CaM's role in aberrant calcium release and RyR2 channel dysfunction.

Main Methods:

  • Assessed CaM binding affinity to RyR2 in normal and failing canine hearts.
  • Utilized FK506 and dantrolene to probe RyR2 inter-domain interactions.
  • Measured spontaneous calcium sparks in cardiomyocytes.

Main Results:

  • CaM binding affinity to RyR2 was lower in failing hearts.
  • Defective RyR2 inter-domain interaction, targeted by dantrolene, correlated with reduced CaM binding.
  • Increased spontaneous Ca(2+) sparks in failing cardiomyocytes were attenuated by high CaM concentrations.

Conclusions:

  • Defective RyR2 inter-domain interaction reduces CaM binding, causing spontaneous calcium release in heart failure.
  • Correcting defective CaM binding presents a potential therapeutic strategy for heart failure.

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