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CaMKIIδ mediates β-adrenergic effects on RyR2 phosphorylation and SR Ca(2+) leak and the pathophysiological response

Michael Grimm1, Haiyun Ling1, Andrew Willeford1

  • 1Department of Pharmacology, University of California, San Diego, CA, USA.

Journal of Molecular and Cellular Cardiology
|June 17, 2015
PubMed

Insights

Chronic CaMKII activation worsens heart function via RyR2 Ca(2+) leak. Blocking CaMKIIδ or RyR2-S2814 prevents heart damage from prolonged beta-adrenergic receptor signaling, independent of hypertrophy.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Physiology

Background:

  • Chronic Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) activation contributes to detrimental beta-adrenergic receptor (β-AR) signaling in the heart.
  • This process is partly mediated by enhanced ryanodine receptor type 2 (RyR2)-mediated sarcoplasmic reticulum (SR) Ca(2+) leak.

Purpose of the Study:

  • To investigate the role of CaMKIIδ and RyR2 phosphorylation in β-AR signaling and cardiac remodeling.
  • To determine if CaMKIIδ-dependent RyR2 phosphorylation contributes to cardiomyopathy induced by prolonged β-AR stimulation.

Main Methods:

  • Utilized CaMKIIδ knockout (CaMKIIδ-KO) mice and knock-in mice with an inactivated CaMKII site S2814 on RyR2 (S2814A).
  • Assessed cardiac function, hypertrophy, fibrosis, and SR Ca(2+) leak in response to isoproterenol (ISO) stimulation in isolated myocytes and Langendorff-perfused hearts.

Main Results:

  • CaMKIIδ-KO mice exhibited reduced CaMKII phosphorylation of phospholamban and RyR2, with decreased SR Ca(2+) leak in response to ISO.
  • Chronic ISO stress induced comparable cardiac hypertrophy in WT and CaMKIIδ-KO mice, but prevented cardiac fibrosis in CaMKIIδ-KO animals.
  • WT mice developed reduced cardiac function and pulmonary congestion after 4 weeks of ISO, while CaMKIIδ-KO and S2814A mice did not.

Conclusions:

  • CaMKIIδ-dependent phosphorylation of RyR2-S2814 is critical in the development of cardiomyopathy caused by prolonged β-AR stimulation.
  • This RyR2-S2814 phosphorylation contributes to cardiac dysfunction independently of hypertrophy.
  • Targeting CaMKIIδ or RyR2-S2814 phosphorylation may offer therapeutic strategies for heart conditions associated with chronic β-AR activation.
Keywords:
Beta-adrenergicCaMKIIFibrosisHypertrophyPhosphorylation

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