{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T07:11:33Z","timestamp":1789974693359,"version":"4.0.1"},"reference-count":37,"publisher":"American Physiological Society","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Heart and Circulatory Physiology"],"published-print":{"date-parts":[[2013,7,1]]},"abstract":"<jats:p>The cardiac ryanodine receptor (RyR2) is inhibited by calmodulin (CaM) and S100A1. Simultaneous substitution of three amino acid residues (W3587A, L3591D, F3603A; RyR2<jats:sup>ADA<\/jats:sup>) in the CaM binding domain of RyR2 results in loss of CaM inhibition at submicromolar (diastolic) and micromolar (systolic) Ca<jats:sup>2+<\/jats:sup>, cardiac hypertrophy, and heart failure in Ryr2<jats:sup>ADA\/ADA<\/jats:sup>mice. To address whether cardiac hypertrophy results from the elimination of CaM and S100A1 inhibition at diastolic or systolic Ca<jats:sup>2+<\/jats:sup>, a mutant mouse was generated with a single RyR2 amino acid substitution (L3591D; RyR2<jats:sup>D<\/jats:sup>). Here we report that in single-channel measurements RyR2-L3591D isolated from Ryr2<jats:sup>D\/D<\/jats:sup>hearts lost CaM inhibition at diastolic Ca<jats:sup>2+<\/jats:sup>only, whereas S100A1 regulation was eliminated at both diastolic and systolic Ca<jats:sup>2+<\/jats:sup>. In contrast to the \u223c2-wk life span of Ryr2<jats:sup>ADA\/ADA<\/jats:sup>mice, Ryr2<jats:sup>D\/D<\/jats:sup>mice lived longer than 1 yr. Six-month-old Ryr2<jats:sup>D\/D<\/jats:sup>mice showed a 9% increase in heart weight-to-body weight ratio, modest changes in cardiac morphology, and a twofold increase in atrial natriuretic peptide mRNA levels compared with wild type. After 4-wk pressure overload with transverse aortic constriction, heart weight-to-body weight ratio and atrial natriuretic peptide mRNA levels increased and echocardiography showed changes in heart morphology of Ryr2<jats:sup>D\/D<\/jats:sup>mice compared with sham-operated mice. Collectively, the findings indicate that the single RyR2-L3591D mutation, which distinguishes the effects of diastolic and systolic Ca<jats:sup>2+<\/jats:sup>, alters heart size and cardiac function to a lesser extent in Ryr2<jats:sup>D\/D<\/jats:sup>mice than the triple mutation in Ryr2<jats:sup>ADA\/ADA<\/jats:sup>mice. They further suggest that CaM inhibition of RyR2 at systolic Ca<jats:sup>2+<\/jats:sup>is important for maintaining normal cardiac function.<\/jats:p>","DOI":"10.1152\/ajpheart.00144.2013","type":"journal-article","created":{"date-parts":[[2013,5,11]],"date-time":"2013-05-11T04:13:42Z","timestamp":1368245622000},"page":"H86-H94","source":"Crossref","is-referenced-by-count":32,"title":["Cardiac hypertrophy associated with impaired regulation of cardiac ryanodine receptor by calmodulin and S100A1"],"prefix":"10.1152","volume":"305","author":[{"given":"Naohiro","family":"Yamaguchi","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina; and"},{"name":"Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, South Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asima","family":"Chakraborty","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina; 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