Premium
Pacing‐induced calcineurin activation controls cardiac Ca 2+ signalling and gene expression
Author(s) -
Tavi Pasi,
Pikkarainen Sampsa,
Ronkainen Jarkko,
Niemelä Perttu,
Ilves Mika,
Weckström Matti,
Vuolteenaho Olli,
Bruton Joseph,
Westerblad Håkan,
Ruskoaho Heikki
Publication year - 2004
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2003.053579
Subject(s) - calcineurin , nfat , phosphatase , gene expression , transcription factor , calmodulin , immediate early gene , endocrinology , medicine , chemistry , biology , microbiology and biotechnology , calcium , gene , transplantation , biochemistry , phosphorylation
Calcineurin, a Ca 2+ –calmodulin‐dependent protein phosphatase (PP2B) is one of the links between Ca 2+ signals and regulation of gene transcription in cardiac muscle. We studied the Ca 2+ 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 Ca 2+ transients encodes the stimulus for calcineurin activation. We further observed experimentally that calcineurin inhibition by CsA modulated Ca 2+ release in a Ca 2+ ‐dependent manner. CsA had no effect on [Ca 2+ ] i at a pacing frequency of 1 Hz but it significantly suppressed the amplitude of Ca 2+ transients, systolic [Ca 2+ ] i and time averaged [Ca 2+ ] 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 [Ca 2+ ] i regulation and gene expression, constantly recruited by varying cardiac Ca 2+ signals.