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Generation of Murine Cardiac Pacemaker Cell Aggregates Based on ES-Cell-Programming in Combination with Myh6-Promoter-Selection
Published on: February 17, 2015
cAMP-Activated EPAC Signaling Is an Integral Component of Cardiac Pacemaker Cell Automaticity
Tatiana M Vinogradova1, Daniel R Riordon1, Dongmei Yang1
1Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD.
Circulation. Arrhythmia and Electrophysiology
|June 25, 2026
Summary
Exchange protein directly activated by cAMP (EPAC) boosts heart rate by enhancing calcium release in sinoatrial node cells. This EPAC-mediated pathway, involving CaMKII, regulates pacemaker function and may offer new therapeutic targets for heart rate disorders.
Area of Science:
- Cardiology
- Molecular Biology
- Cell Physiology
Background:
- Sinoatrial node cell (SANC) automaticity relies on coupled clocks involving ion channels and calcium release (LCRs).
- The link between cyclic adenosine monophosphate (cAMP) and Ca2+/calmodulin dependent protein kinase II (CaMKII) in regulating LCRs is not fully understood.
Purpose of the Study:
- To investigate the role of EPAC in regulating SANC automaticity and LCRs.
- To elucidate the signaling pathway connecting cAMP to CaMKII activity in SANCs.
Main Methods:
- Utilized real-time quantitative polymerase chain reaction, Western blot, immunostaining, whole-cell patch clamp, and line-scan confocal microscopy.
- Employed EPAC inhibitors (CE3F4, HJC0350) and an activator (8-pCPT) in rabbit SANCs.
- Investigated the involvement of protein kinase C (PKC) in the EPAC-mediated pathway.
Main Results:
- EPAC isoforms were active in SANCs, and their inhibition reduced CaMKII activity and L-type Ca2+ current.
- EPAC inhibition decreased LCR amplitude and frequency, slowing SANC firing by ~30%.
- EPAC activation increased LCR amplitude and frequency, accelerating firing by ~18%, via a PKC-dependent pathway involving CaMKII.
Conclusions:
- EPAC is crucial for basal cardiac pacemaker function, accelerating SANC automaticity through CaMKII-dependent phosphorylation.
- EPAC amplifies LCR parameters and shortens the cycle length, regulating heart rate.
- EPAC presents a potential therapeutic target for managing heart rate and sinoatrial node dysfunction.
Keywords:
Ca2+-calmodulin-dependent-protein-kinase-II CaMKIIheart ratephospholambanryanodine receptorsarcoplasmic reticulumsinoatrial nodeMore Related Videos
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