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Early cardiac hypertrophy in mice with impaired calmodulin regulation of cardiac muscle Ca release channel.

http://www.ncbi.nlm.nih.gov/pubmed/17431507

Studies with isolated membrane fractions have shown that calmodulin (CaM) inhibits the activity of cardiac muscle cell Ca(2+) release channel ryanodine receptor 2 (RyR2). To determine the physiological importance of CaM regulation of RyR2, we generated a mouse with 3 amino acid substitutions (RyR2-W3587A/L3591D/F3603A) in exon 75 of the Ryr2 gene, which encodes the CaM-binding site of RyR2. Homozygous mutant mice showed an increased ratio of heart weight to body weight, greatly reduced fractional shortening of the left ventricle, and lethality at 9-16 days of age. Biochemical analysis of hearts of 7- and 10-day-old homozygous mutant mice indicated an impaired CaM inhibition of RyR2 at micromolar Ca(2+) concentrations, reduction in RyR2 protein levels and sarcoplasmic reticulum Ca(2+) sequestration, and upregulation of genes and/or proteins associated with class II histone deacetylase/myocyte enhancer factor-2 and calcineurin signaling pathways. Sustained Ca(2+) transients, often displaying repeated periods of incomplete Ca(2+) removal, were observed in homozygous cardiomyocytes. Taken together, the data indicate that impaired CaM inhibition of RyR2, associated with defective sarcoplasmic reticulum Ca(2+) release and altered gene expression, leads to cardiac hypertrophy and early death.

Pubmed ID: 17431507 RIS Download

Mesh terms: Amino Acid Substitution | Animals | Calmodulin | Cardiomegaly | Mice | Mutagenesis, Site-Directed | Myocardium | Ryanodine Receptor Calcium Release Channel

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Associated grants

  • Agency: NIAMS NIH HHS, Id: AR 018687
  • Agency: NHLBI NIH HHS, Id: HL 073051
  • Agency: NHLBI NIH HHS, Id: HL 49277
  • Agency: NHLBI NIH HHS, Id: HL 71266
  • Agency: NHLBI NIH HHS, Id: R01 HL049277
  • Agency: NHLBI NIH HHS, Id: R01 HL049277-14
  • Agency: NHLBI NIH HHS, Id: R01 HL049277-15
  • Agency: NHLBI NIH HHS, Id: R01 HL049277-16

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