Selective Modulation of Coupled Ryanodine Receptors During Microdomain Activation of Calcium/Calmodulin-Dependent Kinase II in the Dyadic Cleft

Dries, Eef; Bito, Virginie; Lenaerts, Ilse; Antoons, Gudrun; Sipido, Karin R.; Macquaide, Niall

doi:10.1161/circresaha.113.301896

Cited by 38 publications

(76 citation statements)

References 59 publications

(58 reference statements)

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“…In this study, Ca 2+ influx in cardiomyocytes subjected to TRPV1 activation was significantly increased. To investigate the mechanisms underlying TRPV1‐induced Ca 2+ influx in the development of cardiac hypertrophy, we modulated calcium‐dependent kinase activity by compound KN‐93 for inhibition of CaMKII, which is widely used for this purpose 32. CAP‐induced increase in cardiac hypertrophy was reduced by KN‐93, and this implies that Ca 2+ CaMKII is involved in TRPV1 activation–induced cardiac hypertrophy.…”

Section: Discussionmentioning

confidence: 99%

Mitogen‐Activated Protein Kinase and Intracellular Polyamine Signaling Is Involved in TRPV1 Activation–Induced Cardiac Hypertrophy

Chen

Xin

Liu

et al. 2016

JAHA

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BackgroundThe transient receptor potential vanilloid type 1 (TRPV1) is expressed in the cardiovascular system, and increased TRPV1 expression has been associated with cardiac hypertrophy. Nevertheless, the role of TRPV1 in the pathogenesis of cardiac hypertrophy and the underlying molecular mechanisms remain unclear.Methods and ResultsIn cultured cardiomyocytes, activation of TRPV1 increased cell size and elevated expression of atrial natriuretic peptide mRNA and intracellular calcium level, which was reversed by TRPV1 antagonist capsazepine. Increased expression of phosphorylated calmodulin‐dependent protein kinase IIδ and mitogen‐activated protein kinases were found in TRPV1 agonist capsaicin‐treated cardiomyocytes. Selective inhibitor of calmodulin‐dependent protein kinase IIδ decreased phosphorylation of extracellular signal–regulated kinases and p38. Capsaicin induced an increase in expression of ornithine decarboxylase protein, which is the key enzyme in polyamine biosynthesis in cardiomyocytes. Nevertheless, there was no obvious change of ornithine decarboxylase expression in TRPV1 knockdown cells after capsaicin treatment, and specific inhibitors of calmodulin‐dependent protein kinase IIδ or p38 downregulated the capsaicin‐induced expression of ornithine decarboxylase. Capsazepine alleviated the increase in cross‐sectional area of cardiomyocytes and the ratio of heart weight to body weight and improved cardiac function, including left ventricular internal end‐diastolic and ‐systolic dimensions and ejection fraction and fractional shortening percentages, in mice treated with transverse aorta constriction. Capsazepine also reduced expression of ornithine decarboxylase and cardiac polyamine levels. Transverse aorta constriction induced increases in phosphorylated calmodulin‐dependent protein kinase IIδ and extracellular signal–regulated kinases, and p38 and Serca2a were attenuated by capsazepine treatment.ConclusionsThis study revealed that the mitogen‐activated protein kinase signaling pathway and intracellular polyamines are essential for TRPV1 activation–induced cardiac hypertrophy.

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Section: Discussionmentioning

confidence: 99%

Mitogen‐Activated Protein Kinase and Intracellular Polyamine Signaling Is Involved in TRPV1 Activation–Induced Cardiac Hypertrophy

Chen

Xin

Liu

et al. 2016

JAHA

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“…They are commonly referred to as non-junctional RyRs. The distance between non-junctional RyRs and the sarcolemma ranges up to several micrometers (Dries et al, 2013; Jayasinghe et al, 2009; Torres et al, 2014). The ratio of junctional and non-junctional RyRs depends on species, preparation, method of analysis and the definition of “on-junctional”.…”

Section: Introductionmentioning

confidence: 99%

“…To show similar correlations in patients is more difficult, but recent studies underpin the importance of t-system remodeling as a pathomechanism and potential prognostic factor also in human failing hearts (Crossman et al, 2015; Seidel et al, 2017). At the cellular level, a loss of t-tubules increases the number of non-junctional RyRs, which impairs excitation-contraction coupling because a smaller number of RyR clusters is synchronously activated (Dries et al, 2013; Heinzel et al, 2008; Sachse et al, 2012; Seidel et al, 2017). Additionally, it was suggested that t-tubules may fail to conduct action potentials.…”

Section: Introductionmentioning

confidence: 99%

Remodeling of the transverse tubular system after myocardial infarction in rabbit correlates with local fibrosis: A potential role of biomechanics

Seidel

Sankarankutty

Sachse

2017

Progress in Biophysics and Molecular Biology

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The transverse tubular system (t-system) of ventricular cardiomyocytes is essential for efficient excitation-contraction coupling. In cardiac diseases, such as heart failure, remodeling of the t-system contributes to reduced cardiac contractility. However, mechanisms of t-system remodeling are incompletely understood. Prior studies suggested an association with altered cardiac biomechanics and gene expression in disease. Since fibrosis may alter tissue biomechanics, we investigated the local microscopic association of t-system remodeling with fibrosis in a rabbit model of myocardial infarction (MI). Biopsies were taken from the MI border zone of 6 infarcted hearts and from 6 control hearts. Using confocal microscopy and automated image analysis, we quantified t-system integrity (ITT) and the local fraction of extracellular matrix (fECM). In control, fECM was 18±0.3%. ITT was high and homogeneous (0.07±0.006), and did not correlate with fECM (R2=0.05±0.02). The MI border zone exhibited increased fECM within 3mm from the infarct scar (30±3.5%, p<0.01 vs control), indicating fibrosis. Myocytes in the MI border zone exhibited significant t-system remodeling, with dilated, sheet-like components, resulting in low ITT (0.03±0.008, p<0.001 vs control). While both fECM and t-system remodeling decreased with infarct distance, ITT correlated better with decreasing fECM (R2=0.44) than with infarct distance (R2=0.24, p<0.05). Our results show that t-system remodeling in the rabbit MI border zone resembles a phenotype previously described in human heart failure. T-system remodeling correlated with the amount of local fibrosis, which is known to stiffen cardiac tissue, but was not found in regions without fibrosis. Thus, locally altered tissue mechanics may contribute to t-system remodeling.

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“…Such eagerness can be influenced by spatially heterogeneous posttranslational modifications (eg, RyR phosphorylation or oxidation13), but relatively rapid Ca 2+ diffusion inside the SR network makes it less likely that heterogeneity would exist for local intra‐SR [Ca 2+ ] ([Ca 2+ ] SR ),14, 15 which, like local cleft [Ca 2+ ] i , is a major regulator of RyR gating 16. Moreover, the relationships between Ca 2+ sparks and [Ca 2+ ] SR depletion events at a given site are often self‐similar but vary widely among sites 17.…”

mentioning

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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Selective Modulation of Coupled Ryanodine Receptors During Microdomain Activation of Calcium/Calmodulin-Dependent Kinase II in the Dyadic Cleft

Cited by 38 publications

References 59 publications

Mitogen‐Activated Protein Kinase and Intracellular Polyamine Signaling Is Involved in TRPV1 Activation–Induced Cardiac Hypertrophy

Mitogen‐Activated Protein Kinase and Intracellular Polyamine Signaling Is Involved in TRPV1 Activation–Induced Cardiac Hypertrophy

Remodeling of the transverse tubular system after myocardial infarction in rabbit correlates with local fibrosis: A potential role of biomechanics

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

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