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Optical Mapping of Intra-Sarcoplasmic Reticulum Ca2+ and Transmembrane Potential in the Langendorff-perfused Rabbit Heart
Published on: September 10, 2015
Calsequestrin-mediated mechanism for cellular calcium transient alternans
Juan G Restrepo1, James N Weiss, Alain Karma
1Physics Department and Center for Interdisciplinary Research in Complex Systems, Northeastern University, Boston, Massachusetts, USA. juanga@colorado.edu
Biophysical Journal
|August 5, 2008
Summary
Calcium transient alternans (CTA) can arise from a new mechanism involving the gating of calcium release channels by calsequestrin, independent of sarcoplasmic reticulum calcium load. This offers a complementary explanation for arrhythmogenesis.
Area of Science:
- Cardiology
- Computational Biology
- Biophysics
Background:
- Intracellular calcium transient alternans (CTA) is linked to arrhythmogenesis, but its underlying mechanisms remain unclear.
- Existing models focus on the sarcoplasmic reticulum (SR) calcium load-release relationship, which doesn't fully explain observed CTA.
- Recent findings show SR release units can become refractory independently of calcium content.
Purpose of the Study:
- To investigate a novel mechanism for CTA using a detailed mathematical model.
- To explore the role of luminal gating of ryanodine receptors (RyRs) by calsequestrin (CSQN) in CTA.
- To link microscopic calcium handling properties to whole-cell arrhythmogenic behavior.
Main Methods:
- Developed a physiologically detailed mathematical model of calcium cycling.
- Incorporated spatially distributed dyads with realistic numbers of RyR channels.
- Modeled luminal CSQN buffering and gating based on experimental data.
Main Results:
- The model demonstrates that CSQN-mediated luminal gating of RyRs can cause CTA independently of the release-load relationship.
- CTA can occur with or without diastolic SR calcium alternans, depending on pacing and uptake dynamics.
- The model successfully reproduces experimental data from altered CSQN expression and nanoscopic spark restitution.
Conclusions:
- Luminal gating of RyRs by CSQN presents a complementary mechanism for CTA.
- This multiscale model provides a powerful tool for studying abnormal calcium handling in cardiac disease.
- Understanding these microscopic properties is crucial for investigating the arrhythmogenic role of calcium cycling defects.
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