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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

Protein kinase C and A sites on troponin I regulate myofilament Ca2+ sensitivity and ATPase activity in the mouse

YeQing Pi1, Dahua Zhang, Kara R Kemnitz

  • 1Department of Physiology, University of Wisconsin, Madison, WI 53706 USA.

The Journal of Physiology
|August 19, 2003
PubMed

Insights

Phosphorylation of cardiac troponin I (cTnI) by protein kinase C (PKC) and protein kinase A (PKA) oppositely regulates cardiac muscle function. PKC phosphorylation reduces ATP and calcium needs, enhancing efficiency.

Area of Science:

  • Cardiovascular Physiology
  • Molecular Cardiology
  • Muscle Contraction Regulation

Background:

  • Cardiac troponin I (cTnI) is a key regulator of cardiac muscle contraction.
  • The role of cTnI phosphorylation in modulating cardiac function remains incompletely understood.
  • Distinct kinases, including protein kinase C (PKC) and protein kinase A (PKA), are known to phosphorylate cTnI.

Purpose of the Study:

  • To investigate the functional impact of cTnI phosphorylation at specific sites on cardiac muscle performance.
  • To elucidate the opposing roles of PKC and PKA in regulating actomyosin function via cTnI.
  • To determine if cTnI phosphorylation influences the calcium (Ca2+) and ATP sensitivity of the contractile apparatus.

Main Methods:

  • Generation of transgenic mice with mutated cTnI phosphorylation sites (serines 43/45, threonine 144 for PKC; serines 23/24 for PKA).
  • Assessment of cardiac ATPase rates and myofilament Ca2+ sensitivity following stimulation with PKC activators (PMA, ET-1) or the beta-adrenergic agonist isoproterenol.
  • Analysis of myosin regulatory light chain phosphorylation.

Main Results:

  • PKC activation inhibited ATPase rates and increased Ca2+ sensitivity in wild-type hearts, effects abolished in mice with non-phosphorylatable cTnI at PKC sites.
  • Isoproterenol increased ATPase rates and decreased Ca2+ sensitivity, effects absent in mice with non-phosphorylatable cTnI at PKA sites.
  • Increased myofilament Ca2+ sensitivity was dependent on the presence of phosphorylatable cTnI, while myosin light chain phosphorylation changes were modest.

Conclusions:

  • PKC and PKA exert opposing regulatory effects on actomyosin function through distinct cTnI phosphorylation sites.
  • PKC-mediated cTnI phosphorylation may optimize ATP utilization by reducing Ca2+ and ATP demands of the cardiac contractile apparatus.
  • cTnI phosphorylation is a critical mechanism for fine-tuning cardiac contractility and energy efficiency.

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