Nanoscale analysis of ryanodine receptor clusters in dyadic couplings of rat cardiac myocytes

Hou, Yufeng; Jayasinghe, Izzy; Crossman, DC; Baddeley, David; Soeller, Christian

doi:10.1016/j.yjmcc.2014.12.013

Cited by 74 publications

(136 citation statements)

References 51 publications

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“…Not surprisingly, the number of RyRs/cluster correlates with the physical cluster size (Figure 2B), although there is significant variation, which may reflect differences in relative RyR packing 2, 3, 5. The clusters were typically asymmetric with the major axis roughly 50% longer than the minor axis (Figure 2C), and the major axis tended to be more transverse in orientation (Figure 2D; Figure S5).…”

Section: Resultsmentioning

confidence: 91%

“…First we assume that our mean cluster ΔF/F 0 of 1.39 (Figure 1D) corresponds to the average (or most frequent) RyR cluster size estimated from several prior studies that range mostly between 50 and 150 RyR/cluster, which in some high‐resolution cases were clusters of clusters or superclusters 2, 3, 4, 5, 6, 27. The mean ΔF/F 0 of 1.39 is indicated by a vertical broken line in Figure 1E.…”

Section: Resultsmentioning

confidence: 98%

“…Confocal resolution used here cannot directly resolve individual RyRs within a junctional cluster as is possible with superresolution or electron microscopy 2, 3, 4, 5, 6. However, the relative F‐FKBP fluorescence intensity (ΔF/F 0 ) within 250 nm around the local cluster peak intensity (Figure 1D) provides a direct quantitative readout that is proportional to the number of RyRs within that local cluster (or supercluster; Figure 1E).…”

Section: Resultsmentioning

confidence: 99%

“…RyR sensitivity to cytosolic Ca 2+ ([Ca 2+ ] i ) is increased in genetic diseases (catecholaminergic polymorphic ventricular tachycardia), on increased SR Ca 2+ content, during heart failure, and on certain posttranslational modifications (eg, phosphorylation or oxidation), all of which promote diastolic SR Ca 2+ leak and triggered arrhythmias 1. In cardiac myocytes, RyRs form clusters in which some RyRs are tightly packed in checkerboard arrays (corner to corner) with others clustered in a less organized manner within junctional clefts between the SR and sarcolemma 2, 3, 4, 5, 6. These junctional clefts are cylinders 100 to 200 nm in diameter along transverse tubules and surface sarcolemma, with a depth comparable to the height of the RyR protruding from the SR (≈13 nm).…”

mentioning

confidence: 99%

“…These junctional clefts are cylinders 100 to 200 nm in diameter along transverse tubules and surface sarcolemma, with a depth comparable to the height of the RyR protruding from the SR (≈13 nm). The typical junction (of ≈20 000 in a single myocyte) contains 50 to 250 RyRs, mostly along the transverse tubules,4 and these may correspond to local superclusters 5. Individual RyR cluster size can vary over a continuous distribution (from <10 up to 250 RyRs), but some smaller clusters are quite close to others (eg, at the same junction) and, because of their proximity (within 100 nm), may function as a single junctional cluster.…”

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confidence: 99%

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Size Matters: Ryanodine Receptor Cluster Size Affects Arrhythmogenic Sarcoplasmic Reticulum Calcium Release

Galice

Xie

Yang

et al. 2018

JAHA

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BackgroundRyanodine receptors (RyR) mediate sarcoplasmic reticulum calcium (Ca2+) release and influence myocyte Ca2+ homeostasis and arrhythmias. In cardiac myocytes, RyRs are found in clusters of various sizes and shapes, and RyR cluster size may critically influence normal and arrhythmogenic Ca2+ spark and wave formation. However, the actual RyR cluster sizes at specific Ca2+ spark sites have never been measured in the physiological setting.Methods and ResultsHere we measured RyR cluster size and Ca2+ sparks simultaneously to assess how RyR cluster size influences Ca2+ sparks and sarcoplasmic reticulum Ca2+ leak. For small RyR cluster sizes (<50), Ca2+ spark frequency is very low but then increases dramatically at larger cluster sizes. In contrast, Ca2+ spark amplitude is nearly maximal even at relatively small RyR cluster size (≈10) and changes little at larger cluster size. These properties agreed with computational simulations of RyR gating within clusters.ConclusionsOur study explains how this combination of properties may limit arrhythmogenic Ca2+ sparks and wave propagation (at many junctions) while preserving the efficacy and spatial synchronization of Ca2+‐induced Ca2+‐release during normal excitation‐contraction coupling. However, variations in RyR cluster size among individual junctions and RyR sensitivity could exacerbate heterogeneity of local sarcoplasmic reticulum Ca2+ release and arrhythmogenesis under pathological conditions.

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Section: Resultsmentioning

confidence: 91%

Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Size Matters: Ryanodine Receptor Cluster Size Affects Arrhythmogenic Sarcoplasmic Reticulum Calcium Release

Galice

Xie

Yang

et al. 2018

JAHA

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Junctophilins emerge as novel therapeutic targets

Jiang

Tang

Huang

et al. 2019

Journal Cellular Physiology

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Junctophilins (JPs) emerge to play key role in human pathophysiology. This family includes four subtypes (JP1–4), which are differentially detected in excitable cells. Previous work demonstrated the knockout of JPs that seriously damage physiological functions in skeletal muscle, cardiac, and neurons. Here, we summarize latest papers on the essential function of JPs in some Ca2+‐related diseases and neurological diseases, such as primary muscle disease, cardiomyopathies, Type 2 diabetes, gastrointestinal cancer, Huntington’s disease‐like 2, and Charcot‐Marie‐Tooth disease. Growing evidence suggests that targeting JPs might be a promising therapeutic approach to achieve better clinical efficacy in Ca 2+‐related diseases and neurological diseases.

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A guide to the 3D structure of the ryanodine receptor type 1 by cryoEM

Samsó

2016

Protein Science

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Signal transduction by the ryanodine receptor (RyR) is essential in many excitable cells including all striated contractile cells and some types of neurons. While its transmembrane domain is a classic tetrameric, six-transmembrane cation channel, the cytoplasmic domain is uniquely large and complex, hosting a multiplicity of specialized domains. The overall outline and substructure readily recognizable by electron microscopy make RyR a geometrically well-behaved specimen. Hence, for the last two decades, the 3D structural study of the RyR has tracked closely the technological advances in electron microscopy, cryo-electron microscopy (cryoEM), and computerized 3D reconstruction. This review summarizes the progress in the structural determination of RyR by cryoEM and, bearing in mind the leap in resolution provided by the recent implementation of direct electron detection, analyzes the first near-atomic structures of RyR. These reveal a complex orchestration of domains controlling the channel's function, and help to understand how this could break down as a consequence of disease-causing mutations.

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Nanoscale analysis of ryanodine receptor clusters in dyadic couplings of rat cardiac myocytes

Cited by 74 publications

References 51 publications

Size Matters: Ryanodine Receptor Cluster Size Affects Arrhythmogenic Sarcoplasmic Reticulum Calcium Release

Size Matters: Ryanodine Receptor Cluster Size Affects Arrhythmogenic Sarcoplasmic Reticulum Calcium Release

Junctophilins emerge as novel therapeutic targets

A guide to the 3D structure of the ryanodine receptor type 1 by cryoEM

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