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Epac in cardiac calcium signaling.
Gema Ruiz-Hurtado1, Eric Morel, Alejandro Domínguez-Rodríguez
1Inserm, U769, Univ. Paris-Sud 11, IFR141, Labex Lermit, Châtenay-Malabry, France.
Journal of Molecular and Cellular Cardiology
|December 11, 2012
Summary
Exchange protein directly activated by cAMP (Epac) regulates cardiac function by modulating intracellular calcium (Ca2+). Epac influences both excitation-contraction and excitation-transcription coupling, impacting cardiac responses to stress.
Area of Science:
- Cardiology
- Molecular Biology
- Cell Physiology
Background:
- Epac, a cAMP effector, is increasingly recognized for its role in cardiac pathophysiology.
- Its functions are less understood compared to Protein Kinase A (PKA), another cAMP effector.
- Emerging evidence links Epac to the regulation of intracellular calcium (Ca2+) in cardiomyocytes.
Purpose of the Study:
- To investigate the role of Epac in modulating cardiac excitation-contraction coupling (ECC) and excitation-transcription coupling (ETC).
- To elucidate the signaling pathways downstream of Epac in cardiac myocytes.
- To understand Epac's contribution to cardiac responses, particularly under stress.
Main Methods:
- Studies in cultured and adult rat cardiomyocytes.
- Analysis of intracellular Ca2+ oscillations and microdomain Ca2+ mobilization.
- Investigation of signaling pathways involving phospholipase C (PLC), Ca2+/calmodulin kinase II (CaMKII), and inositol 1,4,5 trisphosphate receptors (IP3R).
- Assessment of effects on ryanodine receptor (RyR) phosphorylation and gene transcription (MEF2) via HDAC activity.
Main Results:
- Epac increases spontaneous Ca2+ oscillations in cultured cardiomyocytes.
- Epac induces PKA-independent sarcoplasmic reticulum (SR) Ca2+ release via PLC and CaMKII, enhancing RyR phosphorylation and Ca2+ spark probability.
- Epac preferentially elevates nucleoplasmic Ca2+ ([Ca2+]n) by activating IP3R, leading to histone deacetylase (HDAC) nuclear export and myocyte enhancer factor (MEF2) de-repression.
- Epac activation promotes cardiomyocyte hypertrophy and modulates ECC by increasing Ca2+ transient amplitude and contraction.
- Epac's effects are rapid but dependent on time and subcellular microdomains.
Conclusions:
- Epac plays a significant role in cardiac excitation-contraction and excitation-transcription coupling.
- Epac-mediated Ca2+ signaling pathways contribute to arrhythmogenesis and cardiomyocyte hypertrophy.
- Epac is a key regulator of the cardiac response to stress, influencing both rapid mechanical responses and slower transcriptional changes.
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