{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T05:40:52Z","timestamp":1777441252490,"version":"3.51.4"},"reference-count":64,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2004,1,12]],"date-time":"2004-01-12T00:00:00Z","timestamp":1073865600000},"content-version":"vor","delay-in-days":11,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2004,1]]},"abstract":"<jats:p>Calcineurin, a Ca<jats:sup>2+<\/jats:sup>\u2013calmodulin\u2010dependent protein phosphatase (PP2B) is one of the links between Ca<jats:sup>2+<\/jats:sup> signals and regulation of gene transcription in cardiac muscle. We studied the Ca<jats:sup>2+<\/jats:sup> signal specificity of calcineurin activation experimentally and with modelling. In the rat atrial preparation, an increase in pacing frequency increased nuclear activity of the calcineurin\u2010sensitive transcription factor, nuclear factor of activated T\u2010cells (NFAT), 2\u2010fold in a cyclosporin A (CsA)\u2010sensitive manner. In line with this, modelling results predicted that the frequency of cardiac Ca<jats:sup>2+<\/jats:sup> transients encodes the stimulus for calcineurin activation. We further observed experimentally that calcineurin inhibition by CsA modulated Ca<jats:sup>2+<\/jats:sup> release in a Ca<jats:sup>2+<\/jats:sup>\u2010dependent manner. CsA had no effect on [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> at a pacing frequency of 1 Hz but it significantly suppressed the amplitude of Ca<jats:sup>2+<\/jats:sup> transients, systolic [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> and time averaged [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> at 6 Hz. Calcineurin had a differential role in the expression of immediate\u2010early genes B\u2010type natriuretic peptide (BNP) and <jats:italic>c\u2010fos<\/jats:italic>. CsA inhibited the pacing\u2010induced BNP gene expression, whereas pacing alone had no effect on the expression of <jats:italic>c\u2010fos<\/jats:italic>. However, in the presence of CsA, <jats:italic>c\u2010fos<\/jats:italic> mRNA levels were significantly augmented by increased pacing frequency. These results show that frequency\u2010dependent calcineurin activation has a specific role in [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> regulation and gene expression, constantly recruited by varying cardiac Ca<jats:sup>2+<\/jats:sup> signals.<\/jats:p>","DOI":"10.1113\/jphysiol.2003.053579","type":"journal-article","created":{"date-parts":[[2003,10,21]],"date-time":"2003-10-21T00:32:03Z","timestamp":1066696323000},"page":"309-320","source":"Crossref","is-referenced-by-count":49,"title":["Pacing\u2010induced calcineurin activation controls cardiac Ca<sup>2+<\/sup> signalling and gene 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