Epac enhances excitation-transcription coupling in cardiac myocytes

Laetitia Pereira, Gema Ruiz-Hurtado, Eric Morel, Anne Coline Laurent, Mélanie Métrich, Alejandro Domínguez-Rodríguez, Sandra Lauton-Santos, Alexandre Lucas, Jean Pierre Benitah, Donald M Bers, Frank Lezoualc'h, Ana M. Gómez

Research output: Contribution to journalArticlepeer-review

53 Scopus citations


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, Ca 2+ is a key cardiac transcription regulator (excitation-transcription coupling). It is unknown how myocyte Ca 2+ signals are decoded in cardiac myocytes to control nuclear transcription. We examine Epac actions on cytosolic ([Ca 2+] i) and intranuclear ([Ca 2+] n) Ca 2+ homeostasis, focusing on whether Epac alters [Ca 2+] 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 1Hz. Acute Epac activation by 8-pCPT increased Ca 2+ sparks and diastolic [Ca 2+] i, but decreased systolic [Ca 2+] i. The effects on diastolic [Ca 2+] i and Ca 2+ spark frequency were dependent on phospholipase C (PLC), inositol 1,4,5 triphosphate receptor (IP 3R) and CaMKII activation. Interestingly, Epac preferentially increased [Ca 2+] 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 Ca 2+ signaling by increasing [Ca 2+] n through PLC, IP 3R and CaMKII activation, and initiates a prohypertrophic program via HDAC5 nuclear export and subsequent activation of the transcription factor MEF2.

Original languageEnglish (US)
Pages (from-to)283-291
Number of pages9
JournalJournal of Molecular and Cellular Cardiology
Issue number1
StatePublished - Jan 2012


  • Calcium signaling
  • Epac
  • Excitation-contraction coupling
  • Excitation-transcription coupling
  • Ventricular myocyte

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine


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