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Myocardial Infarction in Neonatal Mice, A Model of Cardiac Regeneration
07:48

Myocardial Infarction in Neonatal Mice, A Model of Cardiac Regeneration

Published on: May 24, 2016

Phosphoinositide 3-kinase regulates excitation-contraction coupling in neonatal cardiomyocytes

Susan A McDowell1, Eileen McCall, William F Matter

  • 1Cardiovascular Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285-0520, USA.

American Journal of Physiology. Heart and Circulatory Physiology
|October 18, 2003
PubMed

Insights

The phosphoinositide 3-kinase (PI3K) inhibitor LY-294002 reduced heart muscle contraction by decreasing intracellular calcium. This effect is primarily due to reduced calcium influx through L-type calcium channels, not other proteins involved in excitation-contraction coupling.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Cell Physiology

Background:

  • Phosphoinositide 3-kinase (PI3K) signaling plays a crucial role in cardiac function.
  • Understanding the precise mechanisms by which PI3K regulates excitation-contraction (EC) coupling is essential for cardiac research.

Purpose of the Study:

  • To investigate the impact of PI3K inhibition on intracellular calcium handling and steady-state contraction in neonatal rat ventricular myocytes (NRVM).
  • To elucidate the specific molecular targets of PI3K in the regulation of EC coupling.

Main Methods:

  • Utilized the PI3K inhibitor LY-294002 to assess effects on NRVM contraction and intracellular Ca(2+) content.
  • Measured caffeine-releasable Ca(2+) stores as an index of sarcoplasmic reticulum (SR) Ca(2+) content.
  • Investigated the influence of LY-294002 on L-type Ca(2+) channels, SERCA2a, ryanodine receptors, and the Na/Ca exchanger (NCX).

Main Results:

  • LY-294002 dose-dependently decreased steady-state contraction and diminished SR Ca(2+) content in NRVM.
  • LY-294002 attenuated L-type Ca(2+) channel activation by BAY K 8644, indicating reduced Ca(2+) influx.
  • PI3K activity does not appear to sustain SERCA2a function, and its primary effect on EC coupling involves L-type Ca(2+) channels.

Conclusions:

  • The PI3K inhibitor LY-294002 impairs cardiac contraction by reducing intracellular Ca(2+) content, primarily through inhibition of PI3K-mediated L-type Ca(2+) channel activity.
  • These findings highlight a critical role for PI3K in regulating Ca(2+) influx and EC coupling in cardiomyocytes.

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