Pacing-induced calcineurin activation controls cardiac Ca2+ signalling and gene expression.
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.
Tavi
Pasi
P
Department of Physiology, Biocentre Oulu, University of Oulu, Finland. pasi.tavi@fyfa.ki.se
Pikkarainen
Sampsa
S
Ronkainen
Jarkko
J
Niemelä
Perttu
P
Ilves
Mika
M
Weckström
Matti
M
Vuolteenaho
Olli
O
Bruton
Joseph
J
Westerblad
Håkan
H
Ruskoaho
Heikki
H
D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D020013:Calcium Signaling / Q000187:drug effects / Q000235:genetics*; D002304:Cardiac Pacing, Artificial / Q000379:methods*; D016572:Cyclosporine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D065095:Calcineurin Inhibitors; D016572:Cyclosporine; D019703:Calcineurin