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EPAC1 and 2 inhibit K+ currents via PLC/PKC and NOS/PKG pathways in rat ventricular cardiomyocytes

  • 0UR 4650 PSIR, GIP Cyceron, Caen, France.
American Journal of Physiology. Cell Physiology +

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July 10, 2024

|

July 10, 2024

View abstract on PubMed

Summary

This summary is machine-generated.

Exchange proteins directly activated by cAMP (EPAC) influence heart rhythm by altering action potential duration. Both EPAC1 and EPAC2 regulate potassium currents via parallel signaling pathways, offering potential therapeutic targets for arrhythmias.

Area Of Science

  • Cardiovascular Physiology
  • Molecular Cardiology
  • Cellular Electrophysiology

Background

  • Exchange proteins directly activated by cAMP (EPAC) are implicated in cardiac proarrhythmic signaling.
  • EPAC activation prolongs action potential duration (APD) by decreasing repolarizing potassium current (IKSS).
  • The precise mechanisms underlying EPAC-mediated IKSS reduction remain unclear.

Purpose Of The Study

  • To investigate the roles of EPAC1 and EPAC2 in reducing IKSS.
  • To elucidate the signaling pathways involved in EPAC-mediated effects on IKSS.
  • To assess the contribution of CaMKII, PLC/PKC, and NOS/PKG pathways.

Main Methods

  • Whole-cell patch-clamp technique in isolated rat ventricular myocytes.
  • Pharmacological activation of EPAC1/EPAC2 using 8-CPTAM.
  • Inhibition of EPAC1/EPAC2, CaMKII, PLC/PKC, and NOS/PKG pathways.
  • Intracellular calcium chelation using BAPTA.

Main Results

  • Both EPAC1 and EPAC2 contribute to the EPAC-mediated decrease in APD and IKSS.
  • CaMKII inhibition and BAPTA did not affect the EPAC response.
  • Inhibition of PLC/PKC and NOS/PKG pathways partially prevented the IKSS decrease.
  • Combined inhibition of PKC and PKG fully blocked the EPAC effect on IKSS.

Conclusions

  • EPAC1 and EPAC2 reduce IKSS and prolong APD through parallel PLC/PKC and NOS/PKG signaling pathways.
  • CaMKII is not involved in EPAC-mediated IKSS regulation in ventricular myocytes.
  • EPAC upregulation in cardiac hypertrophy suggests EPAC inhibition as a potential antiarrhythmic strategy.

Keywords:

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