Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10953841 | Journal of Molecular and Cellular Cardiology | 2012 | 9 Pages |
Abstract
Epac is a guanine nucleotide exchange protein that is directly activated by cAMP, but whose cardiac cellular functions remain unclear. It is important to understand cardiac Epac signaling, because it is activated in parallel to classical cAMP-dependent signaling via protein kinase A. In addition to activating contraction, Ca2Â + is a key cardiac transcription regulator (excitation-transcription coupling). It is unknown how myocyte Ca2Â + signals are decoded in cardiac myocytes to control nuclear transcription. We examine Epac actions on cytosolic ([Ca2Â +]i) and intranuclear ([Ca2Â +]n) Ca2Â + homeostasis, focusing on whether Epac alters [Ca2Â +]n and activates a prohypertrophic program in cardiomyocytes. Adult rat cardiomyocytes, loaded with fluo-3 were viewed by confocal microscopy during electrical field stimulation at 1Â Hz. Acute Epac activation by 8-pCPT increased Ca2Â + sparks and diastolic [Ca2Â +]i, but decreased systolic [Ca2Â +]i. The effects on diastolic [Ca2Â +]i and Ca2Â + spark frequency were dependent on phospholipase C (PLC), inositol 1,4,5 triphosphate receptor (IP3R) and CaMKII activation. Interestingly, Epac preferentially increased [Ca2Â +]n during both diastole and systole, correlating with the perinuclear expression pattern of Epac. Moreover, Epac activation induced histone deacetylase 5 (HDAC5) nuclear export, with consequent activation of the prohypertrophic transcription factor MEF2. These data provide the first evidence that the cAMP-binding protein Epac modulates cardiac nuclear Ca2Â + signaling by increasing [Ca2Â +]n through PLC, IP3R and CaMKII activation, and initiates a prohypertrophic program via HDAC5 nuclear export and subsequent activation of the transcription factor MEF2.
Keywords
NCXET-1PLCRyRPBSIP3R2-APB2-aminoethoxydiphenyl borateEpacPKCband passHdac5GEFn.a.Ca2 +-induced Ca2 + releasesarco/endoplasmic reticulum Ca2 +-ATPaseinositol 1,4,5 triphosphateIP3pKaCaMKIISDSMEF2GFPDAPIBSACa2 +/calmodulin-dependent protein kinase II[Ca2 +]ibovine serum albuminendothelin-1excitation–contractionExcitation–contraction couplingExcitation–transcription couplingRoom temperatureSarcoplasmic reticulumsodium dodecyl sulphateCalcium signalingCalcium concentrationwater immersionmyocyte enhancer factor 2Phosphate buffered salinephospholipase CSERCAVentricular myocyteHistone deacetylase 5protein kinase AProtein kinase CCICRRyanodine receptor
Related Topics
Life Sciences
Biochemistry, Genetics and Molecular Biology
Cell Biology
Authors
Laetitia Pereira, Gema Ruiz-Hurtado, Eric Morel, Anne-Coline Laurent, Mélanie Métrich, Alejandro DomÃnguez-RodrÃguez, Sandra Lauton-Santos, Alexandre Lucas, Jean-Pierre Benitah, Donald M. Bers, Frank Lezoualc'h, Ana M. Gómez,