title: Early cardiac hypertrophy in mice with impaired calmodulin regulation of cardiac muscle Ca release channel.
abstract: 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.
authors: Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors: Naohiro
authors: N
authors: Yamaguchi
authors: Nobuyuki
authors: N
authors: Takahashi
authors: Le
authors: L
authors: Xu
authors: Oliver
authors: O
authors: Smithies
authors: Gerhard
authors: G
authors: Meissner
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D002147:Calmodulin / Q000502:physiology*; D006332:Cardiomegaly / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016297:Mutagenesis, Site-Directed; D009206:Myocardium / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics* / Q000378:metabolism*
chemical_list: D002147:Calmodulin; D019837:Ryanodine Receptor Calcium Release Channel