On the Adjacency Matrix of RyR2 Cluster Structures.
Mark A Walker1, Tobias Kohl2, Stephan E Lehnart2,3
1Institute for Computational Medicine, Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America.
Plos Computational Biology
|November 7, 2015
Summary
The spatial arrangement of ryanodine receptors (RyR2) in cardiac cells influences calcium (Ca2+) spark frequency. The structure of RyR2 clusters predicts spark probability, revealing how function follows structure in heart muscle contraction.
Area of Science:
- Cardiovascular Physiology
- Molecular Cell Biology
- Biophysics
Background:
- Cardiac myocytes rely on calcium (Ca2+) influx for excitation-contraction coupling.
- Ryanodine receptors (RyR2) mediate intracellular Ca2+ release, crucial for muscle contraction.
- Spontaneous RyR2 openings cause localized Ca2+ sparks, influencing cellular function.
Purpose of the Study:
- To develop a theoretical framework linking RyR2 cluster structure to Ca2+ spark initiation probability.
- To investigate how the spatial arrangement of RyR2s impacts the frequency and stability of Ca2+ sparks.
- To explore functional subdomains within RyR2 clusters based on their structure.
Main Methods:
- Developed a stochastic contact network model for Ca2+ spark initiation.
- Utilized super-resolution STED microscopy to obtain realistic RyR2 cluster structures.
- Applied eigendecomposition to a linearized mean-field model of the RyR2 network.
Main Results:
- The maximum eigenvalue (λ1) of the RyR2 cluster adjacency matrix predicts spark probability.
- λ1 defines a stability threshold for Ca2+ spark formation based on RyR2 gating rates.
- Identified functional subdomains within RyR2 clusters with varying Ca2+ sensitivities.
Conclusions:
- RyR2 cluster structure dictates Ca2+ spark initiation probability, demonstrating a structure-function relationship.
- The theoretical model provides insights into cardiac Ca2+ release dynamics.
- This approach offers a general method to infer function from the structure of transmembrane receptor clusters.
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