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1 Department of Physiology, Division of Biophysics, Biocentre Oulu, University of Oulu, Finland 2 Department of Pharmacology and Toxicology, Division of Biophysics, Biocentre Oulu, University of Oulu, Finland 3 Department of Physical Sciences, Division of Biophysics, Biocentre Oulu, University of Oulu, Finland 4 Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
Calcineurin, a Ca2+–calmodulin-dependent protein phosphatase (PP2B) is one of the links between Ca2+ signals and regulation of gene transcription in cardiac muscle. We studied the Ca2+ 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-sensitive transcription factor, nuclear factor of activated T-cells (NFAT), 2-fold in a cyclosporin A (CsA)-sensitive manner. In line with this, modelling results predicted that the frequency of cardiac Ca2+ transients encodes the stimulus for calcineurin activation. We further observed experimentally that calcineurin inhibition by CsA modulated Ca2+ release in a Ca2+-dependent manner. CsA had no effect on [Ca2+]i at a pacing frequency of 1 Hz but it significantly suppressed the amplitude of Ca2+ transients, systolic [Ca2+]i and time averaged [Ca2+]i at 6 Hz. Calcineurin had a differential role in the expression of immediate-early genes B-type natriuretic peptide (BNP) and c-fos. CsA inhibited the pacing-induced BNP gene expression, whereas pacing alone had no effect on the expression of c-fos. However, in the presence of CsA, c-fos mRNA levels were significantly augmented by increased pacing frequency. These results show that frequency-dependent calcineurin activation has a specific role in [Ca2+]i regulation and gene expression, constantly recruited by varying cardiac Ca2+ signals.
(Received 18 August 2003;
accepted after revision 16 October 2003;
first published online 17 October 2003)
Corresponding author P. Tavi: Karolinska Institutet, 17177 Stockholm, Sweden. Email: pasi.tavi{at}fyfa.ki.se
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