Phosphorylation of RyR<sub>2</sub>and shortening of RyR<sub>2</sub>cluster spacing in spontaneously hypertensive rat with heart failure

Chen‐Izu, Ye; Ward, Christopher W.; Stark, Wayne N.; Bányász, Tamás; Sumandea, Marius P.; Balke, C. William; Izu, Leighton T.; Wehrens, Xander H.T.

doi:10.1152/ajpheart.00562.2007

Cited by 48 publications

(38 citation statements)

References 48 publications

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“…However, several specific aspects of our model are controversial, including the role of RyR2 PKA hyperphosphorylation and calstabin2 depletion in HF. These findings have both been confirmed (18)(19)(20)(21)(22)(23)(24)(25)(26) and challenged in the literature (27)(28)(29)(30)(31).…”

Section: Introductionsupporting

confidence: 63%

Role of chronic ryanodine receptor phosphorylation in heart failure and β-adrenergic receptor blockade in mice

Shan¹,

Betzenhauser²,

Kushnir³

et al. 2010

J. Clin. Invest.

217

255

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Increased sarcoplasmic reticulum (SR) Ca 2+ leak via the cardiac ryanodine receptor/calcium release channel (RyR2) is thought to play a role in heart failure (HF) progression. Inhibition of this leak is an emerging therapeutic strategy. To explore the role of chronic PKA phosphorylation of RyR2 in HF pathogenesis and treatment, we generated a knockin mouse with aspartic acid replacing serine 2808 (mice are referred to herein as RyR2-S2808D +/+ mice). This mutation mimics constitutive PKA hyperphosphorylation of RyR2, which causes depletion of the stabilizing subunit FKBP12.6 (also known as calstabin2), resulting in leaky RyR2. RyR2-S2808D +/+ mice developed age-dependent cardiomyopathy, elevated RyR2 oxidation and nitrosylation, reduced SR Ca 2+ store content, and increased diastolic SR Ca 2+ leak. After myocardial infarction, RyR2-S2808D +/+ mice exhibited increased mortality compared with WT littermates. Treatment with S107, a 1,4-benzothiazepine derivative that stabilizes RyR2-calstabin2 interactions, inhibited the RyR2-mediated diastolic SR Ca 2+ leak and reduced HF progression in WT and RyR2-S2808D +/+ mice. In contrast, β-adrenergic receptor blockers improved cardiac function in WT but not in RyR2-S2808D +/+ mice.Thus, chronic PKA hyperphosphorylation of RyR2 results in a diastolic leak that causes cardiac dysfunction. Reversing PKA hyperphosphorylation of RyR2 is an important mechanism underlying the therapeutic action of β-blocker therapy in HF.

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Section: Introductionsupporting

confidence: 63%

Role of chronic ryanodine receptor phosphorylation in heart failure and β-adrenergic receptor blockade in mice

Shan¹,

Betzenhauser²,

Kushnir³

et al. 2010

J. Clin. Invest.

217

255

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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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“…This degree of resolution is important to identify key residues involved in posttranslational modifications and protein binding. Phosphorylation is a common mechanism to modify protein function, and is known to regulate calcium signaling (6,51). For example, PKA phosphorylation of phospholamban increases Ca 2ϩ entry into the SR, improving cardiac relaxation (5).…”

Section: Posttranslational Modificationsmentioning

confidence: 99%

Molecular evolution of the junctophilin gene family

Garbino

Oort

Dixit

et al. 2009

Physiological Genomics

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Junctophilins (JPHs) are members of a junctional membrane complex protein family important for the physical approximation of plasmalemmal and sarcoplasmic/endoplasmic reticulum membranes. As such, JPHs facilitate signal transduction in excitable cells between plasmalemmal voltagegated calcium channels and intracellular calcium release channels. To determine the molecular evolution of the JPH gene family, we performed a phylogenetic analysis of over 60 JPH genes from over 40 species and compared conservation across species and different isoforms. We found that JPHs are evolutionary highly conserved, in particular the membrane occupation and recognition nexus motifs found in all species. Our data suggest that an ancestral form of JPH arose at the latest in a common metazoan ancestor and that in vertebrates four isoforms arose, probably following two rounds of whole genome duplications. By combining multiple prediction techniques with sequence alignments, we also postulate the presence of new important functional regions and candidate sites for posttranslational modifications. The increasing number of available sequences yields significant insight into the molecular evolution of JPHs. Our analysis is consistent with the emerging concept that JPHs serve dual important functions in excitable cells: structural assembly of junctional membrane complexes and regulation of intracellular calcium signaling pathways.

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Phosphorylation of RyR₂and shortening of RyR₂cluster spacing in spontaneously hypertensive rat with heart failure

Abstract: Chen-Izu Y, Ward CW, Stark Jr. W, Banyasz T, Sumandea MP, Balke CW, Izu LT, Wehrens XH. Phosphorylation of RyR2 and shortening of RyR2 cluster spacing in spontaneously hypertensive rat with heart failure.

Cited by 48 publications

References 48 publications

Role of chronic ryanodine receptor phosphorylation in heart failure and β-adrenergic receptor blockade in mice

Role of chronic ryanodine receptor phosphorylation in heart failure and β-adrenergic receptor blockade in mice

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

Molecular evolution of the junctophilin gene family

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Phosphorylation of RyR2and shortening of RyR2cluster spacing in spontaneously hypertensive rat with heart failure

Abstract: Chen-Izu Y, Ward CW, Stark Jr. W, Banyasz T, Sumandea MP, Balke CW, Izu LT, Wehrens XH. Phosphorylation of RyR2 and shortening of RyR2 cluster spacing in spontaneously hypertensive rat with heart failure.

Cited by 48 publications

References 48 publications

Role of chronic ryanodine receptor phosphorylation in heart failure and β-adrenergic receptor blockade in mice

Role of chronic ryanodine receptor phosphorylation in heart failure and β-adrenergic receptor blockade in mice

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

Molecular evolution of the junctophilin gene family

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Product

Resources

About

Phosphorylation of RyR₂and shortening of RyR₂cluster spacing in spontaneously hypertensive rat with heart failure