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Assessment of Sarcoplasmic Reticulum Calcium Reserve and Intracellular Diastolic Calcium Removal in Isolated Ventricular Cardiomyocytes
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Assessment of Sarcoplasmic Reticulum Calcium Reserve and Intracellular Diastolic Calcium Removal in Isolated Ventricular Cardiomyocytes

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Rad GTPase deletion increases L-type calcium channel current leading to increased cardiac contraction

Janet R Manning1, Guo Yin, Catherine N Kaminski

  • 1Department of Physiology, University of Kentucky College of Medicine, Lexington, KY.

Journal of the American Heart Association
|December 17, 2013
PubMed
Abstract

Insights

Rad GTPase depletion enhances cardiomyocyte function, increasing calcium transients and contraction without causing cardiac hypertrophy. This suggests Rad GTPase as a potential therapeutic target for heart conditions.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Physiology

Background:

  • The small GTPase Rad acts as a negative regulator of voltage-dependent L-type calcium channel current (ICaL).
  • The impact of Rad ablation on cardiomyocyte function remains largely unexplored.
  • This study investigates the functional consequences of Rad depletion in the heart.

Purpose of the Study:

  • To determine if Rad depletion induces positive inotropic effects in cardiomyocytes.
  • To assess whether Rad ablation leads to cardiac hypertrophy.
  • To elucidate the role of Rad GTPase in regulating cardiac contractility and calcium handling.

Main Methods:

  • Isolation and patch-clamp recordings of ventricular myocytes from Rad(-/-) mice.
  • Measurement of L-type calcium channel current (ICaL), action potentials, Ca(2+) transients, and sarcomere shortening.
  • Evaluation of cardiac function in isolated working hearts and single cardiomyocytes.

Main Results:

  • Rad(-/-) myocytes exhibit elevated I(CaL) with faster decay and activation at lower voltages, mimicking beta-adrenergic stimulation.
  • Increased diastolic and twitch calcium levels, enhanced sarcomere shortening, and blunted frequency-dependence of Ca(2+) transients and relaxation were observed in Rad(-/-) cells.
  • Rad(-/-) hearts showed elevated +dP/dt and non-responsiveness to beta-adrenergic stimulation, without signs of hypertrophy despite increased diastolic calcium.

Conclusions:

  • Rad GTPase depletion mimics sympathomimetic beta-adrenergic receptor effects on cardiac function.
  • Targeting Rad GTPase offers a novel therapeutic strategy for positive inotropic support via calcium homeostasis modulation.
  • Rad GTPase inhibition presents a potential treatment for heart failure without inducing detrimental cardiac hypertrophy.
Keywords:
L‐type calcium currentRGKRadinotropyβ‐adrenergic stimulation

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