Ultrastructural remodelling of Ca2+ signalling apparatus in failing heart cells

Wu, Haodi; Xu, Ming; Li, Rong-Chang; Guo, Liang; Lai, Ying-Si; Xu, Shili; Li, Sufang; Lu, Quanlong; Li, Linlin; Zhang, Haibo; Zhang, Youyi; Zhang, Chuan-Mao; Wang, Shi Qiang

doi:10.1093/cvr/cvs195

Cited by 70 publications

(91 citation statements)

References 42 publications

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“…Knockdown of JP2 in HL-1 cells results in myocyte hypertrophy [21]. However, it seems that partial silencing of JP2 in cultured adult cardiomyocytes does not alter the morphology of cardiomyocytes [24]. Neither the length nor the width of the cells is changed by JP2 knockdown [24], in close agreement with our results.…”

Section: Discussionsupporting

confidence: 90%

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Morphogenesis of T-tubules in heart cells: the role of junctophilin-2

Han

Wang

et al. 2013

Sci. China Life Sci.

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The T-tubule (TT) system forms the structural basis for excitation-contraction coupling in heart and muscle cells. The morphogenesis of the TT system is a key step in the maturation of heart cells because it does not exist in neonatal cardiomyocytes. In the present study, we quantified the morphological changes in TTs during heart cell maturation and investigated the role of junctophilin-2 (JP2), a protein known to anchor the sarcoplasmic reticulum (SR) to TT, in changes to TT morphological parameters. Analysis of confocal images showed that the transverse elements of TTs increased, while longitudinal elements decreased during the maturation of TTs. Fourier transform analysis showed that the power of ~2 m spatial components increased with cardiomyocytes maturation. These changes were preceded by increased expression of JP2, and were reversed by JP2 knockdown. These findings indicate that JP2 is required for the morphogenesis of TTs during heart development.

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Section: Discussionsupporting

confidence: 90%

“…Absence of JP2 in mice is embryonic lethal [15]. During heart failure, JP2 expression is decreased, leading to reduced density of TT-SR couplons and desynchronized Ca 2+ release in ventricular myocytes [23,24].…”

mentioning

confidence: 99%

Morphogenesis of T-tubules in heart cells: the role of junctophilin-2

Han

Wang

et al. 2013

Sci. China Life Sci.

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“…However, pathological conditions such as heart failure with altered RyR sensitization1 and structure cluster and T‐tubule–SR organization35, 36, 37, 38, 39, 40 could undermine these intrinsically beneficial effects and contribute to cardiac dysfunction and arrhythmogenesis.…”

Section: Discussionmentioning

confidence: 99%

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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“…Taken together, this confirms that the loss of JPH2 profoundly affects the regularity and orientation of the t-system, as seen before, whereas overexpression of JPH2 has a more subtle effect on t-system architecture, promoting a moderate increase in the frequency of longitudinal t-system connections. (2) 11 (2) 12 ( 17 (3) 17 (3) 17 (3) 17 (3) 21 (5) 21 (5) 26 (5) 26 ( The Ca 2+ handling in response to acute JPH2 knockdown has previously been characterised and shown to increase the propensity for spontaneous Ca 2+ release and reduced Ca 2+ amplitude transients (Wu et al, 2012;Landstrom et al, 2011;Van Oort et al, 2011;Takeshima et al, 2000). The observed changes in RyR cluster properties and the increased amount of JPH2 raise the question as to how this affects excitation-contraction coupling in JPH2-OE myocytes.…”

Section: T-tubule System Changes In Cells With Altered Jph2mentioning

confidence: 99%

Junctophilin-2 in the nanoscale organisation and functional signalling of ryanodine receptor clusters in cardiomyocytes

Munro

Jayasinghe

Wang

et al. 2016

Journal of Cell Science

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Signalling nanodomains requiring close contact between the plasma membrane and internal compartments, known as ‘junctions’, are fast communication hubs within excitable cells such as neurones and muscle. Here we have examined two transgenic murine models probing the role of junctophilin-2, a membrane tethering protein crucial for the formation and molecular organisation of sub-microscopic junctions in ventricular muscle cells of the heart. Quantitative single molecule localisation microscopy showed that junctions in animals producing above-normal levels of junctophilin-2 were enlarged, allowing the re-organisation of the primary functional protein within it, the ryanodine receptor (RyR). Although this change was associated with much enlarged RyR clusters that due to their size should be more excitable, functionally it caused a mild inhibition in the calcium signalling output of the junctions (calcium sparks). Analysis of the single molecule densities of both RyR and junctophilin-2 revealed an ∼3-fold increase in the junctophilin-2 to RyR ratio. This molecular rearrangement is compatible with direct inhibition of RyR opening by junctophilin-2 to intrinsically stabilise the calcium signalling properties of the junction and thus the contractile function of the cell.

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Ultrastructural remodelling of Ca2+ signalling apparatus in failing heart cells

Cited by 70 publications

References 42 publications

Morphogenesis of T-tubules in heart cells: the role of junctophilin-2

Morphogenesis of T-tubules in heart cells: the role of junctophilin-2

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

Junctophilin-2 in the nanoscale organisation and functional signalling of ryanodine receptor clusters in cardiomyocytes

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