Related Experiment Video

Updated: Jun 28, 2026

Functional Characterization of Endogenously Expressed Human RYR1 Variants
07:59

Functional Characterization of Endogenously Expressed Human RYR1 Variants

Published on: June 9, 2021

Different actions of RyR2 open and closed channel block explained by a multiscale Ca2+ release model

Derek R Laver1, James Welsh2, Morris Vysma2

  • 1Vanderbilt Center for Arrhythmia Research and Therapeutics, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; School of Biomedical Sciences and Pharmacy, University of Newcastle and Hunter Medical Research Institute, Callaghan, NSW 2308, Australia.

Biophysical Journal
|June 27, 2026
PubMed

Insights

Tetracaine and flecainide differentially affect cardiac calcium handling. Tetracaine increases sarcoplasmic reticulum calcium load, promoting arrhythmias, while flecainide has a sustained anti-arrhythmic action by reducing calcium leak.

Area of Science:

  • Cardiovascular Physiology
  • Molecular Cardiology
  • Computational Biology

Background:

  • Ryanodine receptor 2 (RyR2) channels control cardiac calcium (Ca2+) release from the sarcoplasmic reticulum (SR).
  • Dysfunctional RyR2 activity contributes to cardiac arrhythmias.
  • The impact of RyR2 open probability on sustained arrhythmogenic effects, despite SR Ca2+ autoregulation, remains unclear.

Purpose of the Study:

  • To investigate how RyR2 open probability influences SR Ca2+ load and Ca2+ spark properties under different blocking conditions.
  • To explain the initiation and termination of Ca2+ sparks using a dynamic model of SR Ca2+ handling.
  • To elucidate the distinct effects of closed versus open RyR2 channel blockers on SR Ca2+ dynamics and arrhythmogenesis.

Main Methods:

  • Development of a multiscale, dynamic computational model for SR Ca2+ release and uptake in cardiomyocytes.
  • Incorporation of experimentally determined RyR2 gating kinetics and SERCA2a uptake parameters.
  • Simulation of Ca2+ spark initiation, propagation, and termination under varying RyR2 block conditions.

Main Results:

  • Tetracaine (closed channel blocker) increased SR Ca2+ load and promoted Ca2+ waves.
  • Flecainide (open channel blocker) reduced RyR2 open durations, inhibited RyR2 activity without altering SR Ca2+ load, and exhibited sustained anti-arrhythmic effects.
  • Flecainide increased Ca2+ spark frequency and decreased spark mass, while tetracaine decreased spark frequency but not spark mass.
  • Both blockers acutely inhibited Ca2+ release during sparks, increasing SR load; closed block further reduced spark frequency, leading to greater SR Ca2+ leak inhibition.

Conclusions:

  • RyR2 open probability and channel state (open/closed) critically determine SR Ca2+ load and Ca2+ spark characteristics.
  • Closed RyR2 block leads to a greater increase in SR Ca2+ load and stronger inhibition of Ca2+ leak compared to open RyR2 block.
  • Understanding these distinct mechanisms is crucial for developing targeted anti-arrhythmic therapies.

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