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CARDIOVASCULAR |
1 Inserm, U637, Physiopathologie Cardiovasculaire, Montpellier, France
2
University Montpellier 1 and Université de Montpellier 2, IFR3, Montpellier, France
3
Inserm, U769, Signalization et Physiopathologie Cardiaque, Châtenay-Malabry, France
4
University Paris-Sud, IFR141, UMR-S769, Châtenay-Malabry, France
cAMP is a powerful second messenger whose known general effector is protein kinase A (PKA). The identification of a cAMP binding protein, Epac, raises the question of its role in Ca2+ signalling in cardiac myocytes. In this study, we analysed the effects of Epac activation on Ca2+ handling by using confocal microscopy in isolated adult rat cardiomyocytes. [Ca2+]i transients were evoked by electrical stimulation and Ca2+ sparks were measured in quiescent myocytes. Epac was selectively activated by the cAMP analogue 8-(4-chlorophenylthio)-2'-O-methyladenosine-3',5'-cyclic monophosphate (8-CPT). Patch-clamp was used to record the L-type calcium current (ICa), and Western blot to evaluate phosphorylated ryanodine receptor (RyR). [Ca2+]i transients were slightly reduced by 10 µM 8-CPT (F/F0: decreased from 4.7 ± 0.5 to 3.8 ± 0.4, P < 0.05), an effect that was boosted when cells were previously infected with an adenovirus encoding human Epac. ICa was unaltered by Epac activation, so this cannot explain the decreased [Ca2+]i transients. Instead, a decrease in the sarcoplasmic reticulum (SR) Ca2+ load underlies the decrease in the [Ca2+]i transients. This decrease in the SR Ca2+ load was provoked by the increase in the SR Ca2+ leak induced by Epac activation. 8-CPT significantly increased Ca2+ spark frequency (Ca2+ sparks s–1 (100 µm)–1: from 2.4 ± 0.6 to 6.9 ± 1.5, P < 0.01) while reducing their amplitude (F/F0: 1.8 ± 0.02 versus 1.6 ± 0.01, P < 0.001) in a Ca2+/calmodulin kinase II (CaMKII)-dependent and PKA-independent manner. Accordingly, we found that Epac increased RyR phosphorylation at the CaMKII site. Altogether, our data reveal a new signalling pathway by which cAMP governs Ca2+ release and signalling in cardiac myocytes.
(Received 23 March 2007;
accepted after revision 26 June 2007;
first published online 5 July 2007)
Corresponding authors A. M. Gómez: Inserm U637, CHU A. De Villeneuve, 34295 Montpellier, France. Email: agomez{at}montp.inserm.fr. F. Lezoualc'h: Inserm U769, Faculté de Pharmacie, 92296, Châtenay-Malabry, France. Email: frank.lezoualch{at}u-psud.fr
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J. Physiol. 2007 583: 415-416.
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