| First Author | Yamaguchi N | Year | 2011 |
| Journal | Am J Physiol Heart Circ Physiol | Volume | 300 |
| Issue | 6 | Pages | H2187-95 |
| PubMed ID | 21421818 | Mgi Jnum | J:170449 |
| Mgi Id | MGI:4946529 | Doi | 10.1152/ajpheart.00719.2010 |
| Citation | Yamaguchi N, et al. (2011) Dysfunctional ryanodine receptor and cardiac hypertrophy: role of signaling molecules. Am J Physiol Heart Circ Physiol 300(6):H2187-95 |
| abstractText | Mice with three amino acid mutations in the calmodulin binding domain of type-2 ryanodine receptor ion channel (Ryr2(ADA/ADA) mice) have impaired intracellular Ca(2+) handling and cardiac hypertrophy with death at an early age. In this report, the role of signaling molecules implicated in cardiac hypertrophy of Ryr2(ADA/ADA) mice was investigated. Calcineurin A-beta (CNA-beta) and nuclear factor of activated T cell (NFAT) signaling were monitored in mice carrying either luciferase transgene driven by NFAT-dependent promoter or knockout of CNA-beta. NFAT transcriptional activity in Ryr2(ADA/ADA) hearts was not markedly upregulated at embryonic day 16.5 compared with wild-type but significantly increased at postnatal days 1 and 10. Ablation of CNA-beta extended the life span of Ryr2(ADA/ADA) mice and enhanced cardiac function without improving sarcoplasmic reticulum Ca(2+) handling or suppressing the expression of genes implicated in cardiac hypertrophy. Embryonic day 16.5 Ryr2(ADA/ADA) mice had normal heart weights with no major changes in Akt1 and class II histone deacetylase phosphorylation and myocyte enhancer factor-2 activity. In contrast, phosphorylation levels of Erk1/2, p90 ribosomal S6 kinases (p90RSKs), and GSK-3beta were increased in hearts of embryonic day 16.5 homozygous mutant mice. The results indicate that an impaired calmodulin regulation of RyR2 was neither associated with an altered CNA-beta/NFAT, class II histone deacetylase (HDAC)/MEF2, nor Akt signaling in embryonic day 16.5 hearts; rather increased Erk1/2 and p90RSK phosphorylation levels likely leading to reduced GSK-3beta activity were found to precede development of cardiac hypertrophy in mice expressing dysfunctional ryanodine receptor ion channel. |
