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On the Adjacency Matrix of RyR2 Cluster Structures
- Source :
- PLoS Computational Biology, Vol 11, Iss 11, p e1004521 (2015), PLoS Computational Biology
- Publication Year :
- 2015
- Publisher :
- Public Library of Science (PLoS), 2015.
-
Abstract
- In the heart, electrical stimulation of cardiac myocytes increases the open probability of sarcolemmal voltage-sensitive Ca2+ channels and flux of Ca2+ into the cells. This increases Ca2+ binding to ligand-gated channels known as ryanodine receptors (RyR2). Their openings cause cell-wide release of Ca2+, which in turn causes muscle contraction and the generation of the mechanical force required to pump blood. In resting myocytes, RyR2s can also open spontaneously giving rise to spatially-confined Ca2+ release events known as “sparks.” RyR2s are organized in a lattice to form clusters in the junctional sarcoplasmic reticulum membrane. Our recent work has shown that the spatial arrangement of RyR2s within clusters strongly influences the frequency of Ca2+ sparks. We showed that the probability of a Ca2+ spark occurring when a single RyR2 in the cluster opens spontaneously can be predicted from the precise spatial arrangements of the RyR2s. Thus, “function” follows from “structure.” This probability is related to the maximum eigenvalue (λ 1) of the adjacency matrix of the RyR2 cluster lattice. In this work, we develop a theoretical framework for understanding this relationship. We present a stochastic contact network model of the Ca2+ spark initiation process. We show that λ 1 determines a stability threshold for the formation of Ca2+ sparks in terms of the RyR2 gating transition rates. We recapitulate these results by applying the model to realistic RyR2 cluster structures informed by super-resolution stimulated emission depletion (STED) microscopy. Eigendecomposition of the linearized mean-field contact network model reveals functional subdomains within RyR2 clusters with distinct sensitivities to Ca2+. This work provides novel perspectives on the cardiac Ca2+ release process and a general method for inferring the functional properties of transmembrane receptor clusters from their structure.<br />Author Summary Many transmembrane receptors have been shown to aggregate into supramolecular clusters that enhance sensitivity to external stimuli in a variety of cell types. Advances in super-resolution microscopy have enabled researchers to study these structures with sufficient detail to distinguish the precise locations of individual receptors. In the heart, efforts have been successful in imaging calcium release channels, which are found in clusters of up to ∼ 100 in the sarcoplasmic reticulum membrane of cardiac myocytes. We showed in a recent study how the precise cluster structure affects the frequency of spontaneous release events known as calcium “sparks.” Here we have developed an analytical model of calcium spark initiation that clearly illustrates how the structure controls spark likelihood. We then applied this model to a collection of channel cluster structures obtained using super-resolution microscopy, revealing spatial gradients in the functional properties of individual channels. This work provides insight into the calcium release process in the heart and a framework for evaluating functional heterogeneity in populations of receptor clusters using structural information alone.
- Subjects :
- Work (thermodynamics)
Biophysics
Cell membranes
Eigenvalues
Eigenvectors
Ion channel gating
Membrane structures
Muscle cells
Network analysis
Gating
030204 cardiovascular system & hematology
Models, Biological
Ryanodine receptor 2
Molecular physics
Mice
03 medical and health sciences
Cellular and Molecular Neuroscience
0302 clinical medicine
Junctional sarcoplasmic reticulum membrane
Genetics
medicine
Cluster (physics)
Animals
Myocytes, Cardiac
Calcium Signaling
Adjacency matrix
Molecular Biology
lcsh:QH301-705.5
Ecology, Evolution, Behavior and Systematics
030304 developmental biology
Physics
0303 health sciences
Ecology
Ryanodine receptor
Systems Biology
Ryanodine Receptor Calcium Release Channel
musculoskeletal system
Myocardial Contraction
Computational Theory and Mathematics
lcsh:Biology (General)
Modeling and Simulation
cardiovascular system
Calcium
medicine.symptom
tissues
Research Article
Muscle contraction
Subjects
Details
- Language :
- English
- ISSN :
- 15537358
- Volume :
- 11
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- PLoS Computational Biology
- Accession number :
- edsair.doi.dedup.....0d1fa33899815dc36d8914e976df965f