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Electrophysiology of Normal Cardiac Rhythm01:19

Electrophysiology of Normal Cardiac Rhythm

The normal cardiac rhythm is a synchronized electrical activity that facilitates the regular and coordinated contraction of the heart muscle. This process is essential for efficient blood circulation throughout the body. The fundamental elements involved in establishing and maintaining this rhythm include the unique electrical properties of cardiac muscle cells, the sinoatrial (SA) node's pacemaker function, the specialized conducting system, and the ionic mechanisms underlying each phase of...
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G-Protein Gated Ion Channels01:21

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cAMP-dependent Protein Kinase Pathways01:25

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Cyclic Adenosine Monophosphate (cAMP) is an essential second messenger that activates protein kinase A (PKA) and regulates various biological processes. A single epinephrine molecule binds to GPCR and activates several heterotrimeric G proteins, each stimulating multiple adenylyl cyclase, amplifying the signal, and synthesizing large numbers of cAMP molecules. Small changes in cAMP concentration affect PKA activity. The binding of four cAMP molecules induces a conformational change in PKA,...
Calmodulin-dependent Signaling01:16

Calmodulin-dependent Signaling

Calmodulin (CaM) is a calcium-binding protein in eukaryotes that controls various calcium-regulated cellular processes. It has four calcium-binding sites that bind calcium to form the calcium-calmodulin ( Ca2+-CaM) complex. GPCR stimulation increases the calcium levels in the cells that bind to CaM and induces a conformational change.
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Specialized Characteristics of Cardiac Muscles01:27

Specialized Characteristics of Cardiac Muscles

The primary role of cardiac muscles is to propel blood throughout the cardiovascular system. The cardiac muscle cells, or cardiomyocytes, exhibit specialized characteristics that allow them to perform this function.
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Generation of Murine Cardiac Pacemaker Cell Aggregates Based on ES-Cell-Programming in Combination with Myh6-Promoter-Selection
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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
PubMed
Summary
This summary is machine-generated.

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.

Keywords:
heart ratephospholambanpolymerase chain reactionsarcoplasmic reticulumsinoatrial node

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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.