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Assessment of Myofilament Ca2+ Sensitivity Underlying Cardiac Excitation-contraction Coupling
08:29

Assessment of Myofilament Ca2+ Sensitivity Underlying Cardiac Excitation-contraction Coupling

Published on: August 1, 2016

Calmodulin regulation of excitation-contraction coupling in cardiac myocytes

Dongmei Yang1, Long-Sheng Song, Wei-Zhong Zhu

  • 1National Laboratory of Biomembrane and Membrane Biotechnology, College of Life Sciences, Peking University, Beijing, China.

Circulation Research
|March 1, 2003
PubMed

Insights

A novel calcium-insensitive calmodulin mutant (CaM(1-4)) enhances cardiac contraction by activating Ca2+/CaM-dependent protein kinase II (CaMKII), impacting calcium handling and L-type calcium channels.

Area of Science:

  • Cardiovascular Physiology
  • Molecular Cardiology
  • Calcium Signaling

Background:

  • Calmodulin (CaM) is a crucial calcium (Ca2+) sensor regulating cardiac excitation-contraction (EC) coupling.
  • CaM interacts with key proteins involved in Ca2+ handling within cardiac myocytes.
  • Understanding CaM's role in EC coupling is vital for addressing cardiac dysfunction.

Purpose of the Study:

  • To investigate the effects of a Ca2+-insensitive CaM mutant (CaM(1-4)) on cardiac function.
  • To elucidate the underlying molecular mechanisms, focusing on L-type Ca2+ channels, CaMKII, and phospholamban (PLB).
  • To determine the role of CaMKII in mediating the effects of CaM(1-4).

Main Methods:

  • Adenoviral expression of CaM(1-4) in cultured rat ventricular myocytes.
  • Measurement of Ca2+ transients, contraction, L-type Ca2+ current, and SR Ca2+ content.
  • Assessment of CaMKII activity and PLB phosphorylation; use of CaMKII inhibitors (KN-93).

Main Results:

  • CaM(1-4) overexpression significantly increased Ca2+ transient amplitude and contraction, while abbreviating decay time.
  • CaM(1-4) augmented L-type Ca2+ current, slowed its inactivation, increased CaMKII activity, and enhanced PLB phosphorylation at Thr-17.
  • CaMKII inhibition abolished CaM(1-4)-induced PLB phosphorylation and reversed the positive inotropic and relaxant effects.

Conclusions:

  • CaM modulates cardiac Ca2+ influx, SR Ca2+ release, and Ca2+ recycling during EC coupling.
  • Expression of a Ca2+-insensitive CaM mutant activates CaMKII in cardiac myocytes.
  • CaMKII is essential for the observed alterations in cardiac function induced by CaM(1-4).

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