{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T00:30:36Z","timestamp":1779237036622,"version":"3.51.4"},"reference-count":51,"publisher":"American Physiological Society","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Heart and Circulatory Physiology"],"published-print":{"date-parts":[[2011,6]]},"abstract":"<jats:p>Mice with three amino acid mutations in the calmodulin binding domain of type-2 ryanodine receptor ion channel ( Ryr2<jats:sup>ADA\/ADA<\/jats:sup>mice) have impaired intracellular Ca<jats:sup>2+<\/jats:sup>handling and cardiac hypertrophy with death at an early age. In this report, the role of signaling molecules implicated in cardiac hypertrophy of Ryr2<jats:sup>ADA\/ADA<\/jats:sup>mice was investigated. Calcineurin A-\u03b2 (CNA-\u03b2) 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-\u03b2. NFAT transcriptional activity in Ryr2<jats:sup>ADA\/ADA<\/jats:sup>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-\u03b2 extended the life span of Ryr2<jats:sup>ADA\/ADA<\/jats:sup>mice and enhanced cardiac function without improving sarcoplasmic reticulum Ca<jats:sup>2+<\/jats:sup>handling or suppressing the expression of genes implicated in cardiac hypertrophy. Embryonic day 16.5 Ryr2<jats:sup>ADA\/ADA<\/jats:sup>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-3\u03b2 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-\u03b2\/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-3\u03b2 activity were found to precede development of cardiac hypertrophy in mice expressing dysfunctional ryanodine receptor ion channel.<\/jats:p>","DOI":"10.1152\/ajpheart.00719.2010","type":"journal-article","created":{"date-parts":[[2011,3,19]],"date-time":"2011-03-19T04:51:47Z","timestamp":1300510307000},"page":"H2187-H2195","source":"Crossref","is-referenced-by-count":13,"title":["Dysfunctional ryanodine receptor and cardiac hypertrophy: role of signaling molecules"],"prefix":"10.1152","volume":"300","author":[{"given":"Naohiro","family":"Yamaguchi","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, 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