| First Author | Yamaguchi N | Year | 2007 |
| Journal | J Clin Invest | Volume | 117 |
| Issue | 5 | Pages | 1344-53 |
| PubMed ID | 17431507 | Mgi Jnum | J:122033 |
| Mgi Id | MGI:3713015 | Doi | 10.1172/JCI29515 |
| Citation | Yamaguchi N, et al. (2007) Early cardiac hypertrophy in mice with impaired calmodulin regulation of cardiac muscle Ca release channel. J Clin Invest 117(5):1344-53 |
| abstractText | 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. |
