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Ca2+/calmodulin-dependent protein kinase II phosphorylation regulates the cardiac ryanodine receptor

Xander H T Wehrens1, Stephan E Lehnart, Steven R Reiken

  • 1Department of Physiology and Cellular Biophysics, Columbia University College of Physicians and Surgeons, 630 W 168th St, P&S 9-401, Box 65, New York, NY 10032, USA.

Circulation Research
|March 16, 2004
PubMed

Insights

Calcium/calmodulin-dependent protein kinase II (CaMKII) phosphorylation of the cardiac ryanodine receptor (RyR2) enhances calcium sensitivity. This CaMKII-RyR2 interaction is impaired in heart failure, impacting cardiac contractility.

Area of Science:

  • Cardiovascular Physiology
  • Molecular Cardiology
  • Biochemistry

Background:

  • The cardiac ryanodine receptor (RyR2) is crucial for excitation-contraction coupling in muscle.
  • Protein kinase A (PKA) phosphorylation of RyR2 mediates the stress response.
  • The role of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in RyR2 regulation is less understood.

Purpose of the Study:

  • To identify the specific CaMKII phosphorylation site on RyR2.
  • To investigate the functional consequences of CaMKII phosphorylation on RyR2.
  • To examine the role of CaMKII-RyR2 interaction in heart failure.

Main Methods:

  • Site-directed mutagenesis of recombinant RyR2.
  • Biochemical assays to assess RyR2 phosphorylation and activity.
  • Studies on RyR2 function at varying heart rates and in heart failure models.

Main Results:

  • A distinct CaMKII phosphorylation site on RyR2 was identified, separate from the PKA site.
  • CaMKII phosphorylation increased RyR2 Ca2+ sensitivity and open probability.
  • CaMKII activation at higher heart rates enhanced Ca2+-induced Ca2+ release, but this was defective in heart failure.

Conclusions:

  • CaMKII phosphorylation of RyR2 enhances its activity and may contribute to increased contractility at higher heart rates.
  • Impaired rate-dependent CaMKII phosphorylation of RyR2 in heart failure suggests a role in cardiac dysfunction.
  • Targeting CaMKII-RyR2 interaction could be a therapeutic strategy for heart failure.

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