Affinage

RYR2

Ryanodine receptor 2 · UniProt Q92736

Length
4967 aa
Mass
564.6 kDa
Annotated
2026-04-28
100 papers in source corpus 40 papers cited in narrative 40 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RyR2 is the principal sarcoplasmic/endoplasmic reticulum Ca²⁺-release channel in cardiomyocytes and neurons, governing excitation–contraction coupling, metabolic signaling, and neuronal excitability. Cryo-EM structures show that channel gating involves breathing motions of the cytoplasmic N-terminal, Helical, and Handle domains coupled to Central domain rotations that dilate the pore (PMID:27708056); calmodulin constitutively binds RyR2 via its C-domain anchored to CaMBD2 while its N-domain acts as a dynamic Ca²⁺ sensor bridging CaMBD2/3, and this tonic inhibition is essential for preventing arrhythmogenic Ca²⁺ leak (PMID:30530841, PMID:24186966). CaMKIIδ phosphorylation at S2814 promotes a pathological open conformation with reduced CaM affinity and SR Ca²⁺ leak driving heart failure, atrial fibrillation, and ventricular tachycardia, while PKA phosphorylation at S2808 uncouples gating from cytosolic Ca²⁺ regulation (PMID:22511749, PMID:22158709, PMID:21274522); gain-of-function mutations enhance store overload-induced Ca²⁺ release and luminal Ca²⁺ sensitivity causing CPVT, whereas loss-of-function mutations abolish SOICR and cause Ca²⁺ release deficiency linked to ventricular fibrillation and left ventricular noncompaction (PMID:16239587, PMID:33825858, PMID:37325910).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2002 Medium

    Early evidence linked distinct RyR2 disease mutations to altered binding of the regulatory protein FKBP12.6, suggesting mutation-class-specific gating defects in CPVT and ARVD2.

    Evidence Quantitative yeast two-hybrid assay of RyR2 point mutations with FKBP12.6

    PMID:12459180

    Open questions at the time
    • Single yeast two-hybrid method without reciprocal or functional validation
    • FKBP12.6 binding changes not confirmed by subsequent reconstituted studies
  2. 2003 High

    Establishing that CaM is an isoform-specific inhibitor of RyR2 at all Ca²⁺ concentrations (unlike RyR1) resolved a key regulatory distinction, showing that Ca²⁺ binding to all four CaM EF-hands is required for inhibition and that apoCaM paradoxically activates the channel.

    Evidence In vitro [³H]ryanodine binding and planar lipid bilayer recordings with systematic Ca²⁺-insensitive CaM point mutants

    PMID:12614169

    Open questions at the time
    • Mechanism by which apoCaM activates versus holoCaM inhibits not structurally resolved
    • In situ binding stoichiometry unknown at this time
  3. 2005 High

    Demonstrating that CPVT mutations across all three RyR2 hotspot regions converge on enhanced store overload-induced Ca²⁺ release (SOICR) and increased luminal Ca²⁺ sensitivity — without FKBP12.6 dissociation — unified the gain-of-function disease mechanism.

    Evidence Stable inducible HEK293 cells expressing six RyR2 mutations, single-channel lipid bilayer recordings, [³H]ryanodine binding, single-cell Ca²⁺ imaging

    PMID:16239587

    Open questions at the time
    • Structural basis for luminal Ca²⁺ sensitivity changes not determined
    • Role of inter-subunit interactions in SOICR regulation unknown
  4. 2009 High

    Two independent advances established CaMKII-S2814 phosphorylation as a critical arrhythmogenic modification: miR-1 was shown to selectively enhance S2814 phosphorylation via PP2A downregulation causing spontaneous Ca²⁺ release, while the R176Q knock-in mouse confirmed that a single gain-of-function mutation causes Ca²⁺ leak and sudden death in vivo.

    Evidence Adenoviral miR-1 overexpression with CaMKII inhibitor rescue in myocytes; R176Q knock-in mice with optical mapping and ECG

    PMID:19131648 PMID:20009080

    Open questions at the time
    • Whether miR-1-dependent regulation operates in human cardiac disease not established
    • R176Q structural mechanism at atomic level unknown
  5. 2011 High

    Two parallel lines of evidence dissected the distinct roles of PKA-S2808 and CaMKII-S2814 phosphorylation: S2808 phosphorylation uncouples RyR2 gating from cytosolic Ca²⁺ (shown by single-channel reconstitution), while S2814 but not S2808 is required for AF in FKBP12.6-KO mice (shown by genetic epistasis).

    Evidence Planar lipid bilayer recordings with PKA/PP1; FKBP12.6−/− × S2814A or S2808A double knock-in mice with AF induction and Ca²⁺ spark measurements

    PMID:20615971 PMID:21274522 PMID:22158709

    Open questions at the time
    • S2808 role remains debated — protective versus pathological context-dependent
    • Endogenous PKC-sensitive kinase co-purifying with RyR2 not identified
  6. 2012 High

    Definitive in vivo evidence established that CaMKII phosphorylation of RyR2-S2814 drives SR Ca²⁺ leak and heart failure progression specifically in pressure-overload (not ischemic) cardiomyopathy.

    Evidence S2814A knock-in mice subjected to transverse aortic constriction with echocardiography, confocal Ca²⁺ imaging, and human HF tissue validation

    PMID:22511749

    Open questions at the time
    • Why S2814A protection is restricted to non-ischemic HF unclear
    • Contribution of other CaMKII substrates not excluded
  7. 2013 High

    Quantifying CaM–RyR2 binding in situ revealed that >90% of Z-line CaM is RyR2-bound at nanomolar affinity, and that disrupting this interaction (RyR2-ADA knock-in) is sufficient for stress-induced arrhythmia; post-MI heart failure reduces CaM–RyR2 affinity ~3-fold.

    Evidence FRET in permeabilized myocytes, RyR2-ADA knock-in mice, confocal Ca²⁺ imaging, in vivo arrhythmia induction

    PMID:23746327 PMID:24186966

    Open questions at the time
    • Molecular basis of reduced CaM affinity in HF not determined
    • CPVT-specific N-terminal destabilization (G230C) not yet linked to CaM binding
  8. 2014 High

    The crystal structure of the human RyR2 N-terminal region (residues 1–606) identified a central stabilizing helix and three-domain architecture, providing a structural framework for understanding how disease mutations destabilize the N-terminus and alter gating.

    Evidence X-ray crystallography, small-angle X-ray scattering, docking into cryo-EM maps

    PMID:25372681

    Open questions at the time
    • Full-length high-resolution open/closed structures not yet available at this time
    • How N-terminal domain movements propagate to the pore unresolved
  9. 2015 High

    Multiple studies converged to show RyR2 functions beyond cardiomyocyte EC-coupling: RyR2-mediated Ca²⁺ release drives mitochondrial Ca²⁺ uptake and PDH-dependent glucose oxidation in the heart, and leaky RyR2 causes ER stress, mitochondrial dysfunction, and impaired insulin secretion in pancreatic β cells.

    Evidence Cardiac Ryr2 haploinsufficient mouse with metabolomics/proteomics/mitochondrial Ca²⁺ imaging; CPVT RyR2 transgenic mice with islet Ca²⁺ imaging, ER stress assays, and pharmacological rescue

    PMID:15044459 PMID:25844899 PMID:26080362 PMID:27621312

    Open questions at the time
    • Specific mitochondrial Ca²⁺ uptake pathway (MCU dependence) downstream of RyR2 not defined
    • Whether β cell RyR2 regulation differs mechanistically from cardiomyocyte regulation unknown
  10. 2016 High

    Near-atomic cryo-EM structures of RyR2 in open and closed states revealed the complete gating mechanism: breathing motions of the cytoplasmic region through NTD/Helical/Handle domains coupled to Central domain outward rotation dilating the pore.

    Evidence Single-particle cryo-EM of porcine RyR2 in two states with site-directed mutagenesis validation

    PMID:27708056

    Open questions at the time
    • Structures lack bound CaM or phosphorylated states
    • Dynamic transitions between states not captured
  11. 2016 High

    CaMKII phosphorylation at S2814 was shown to induce a specific conformational change (increased DPc10 accessibility) that reduces CaM affinity, mechanistically linking phosphorylation to defective CaM inhibition and arrhythmia; dantrolene and excess CaM both rescued the conformation and suppressed VT.

    Evidence S2814D/S2814A knock-in mouse myocytes, FRET-based CaM affinity, DPc10 conformational probe, in vivo VT inducibility

    PMID:27318036

    Open questions at the time
    • Structural basis of DPc10-detected conformational change at atomic resolution unknown
    • Whether dantrolene acts directly on the phospho-S2814 region not established
  12. 2019 High

    Three advances refined CaM–RyR2 regulation: (1) CaM binds constitutively with its C-domain anchored to CaMBD2 and N-domain dynamically sensing Ca²⁺ via CaMBD2/3; (2) CaM inhibition of human RyR2 requires prior phosphorylation at S2808 or S2814; (3) all 14 arrhythmogenic CaM mutations diminish CaM-dependent RyR2 inhibition and enhance SOICR.

    Evidence TAMRA-labeled peptide fluorescence anisotropy; FRET in human failing/healthy hearts with phosphomimetic knock-in mice; HEK293 SOICR assay with 14 CaM mutants

    PMID:30530841 PMID:30928430 PMID:31230402

    Open questions at the time
    • Structural visualization of CaM bound to full-length RyR2 lacking
    • How phosphorylation enables CaM inhibition mechanistically unclear
  13. 2019 High

    RyR2 was placed in a neuronal signaling complex: junctophilin-3/4 tethers a Cav1.3–RyR2–KCa3.1 tripartite complex at PM–ER junctions in hippocampal CA1 neurons to generate the slow afterhyperpolarization, establishing RyR2 as a regulator of neuronal excitability.

    Evidence dSTORM super-resolution imaging, FRET, shRNA knockdown, intracellular antibody infusion, electrophysiology in CA1 neurons

    PMID:31461656

    Open questions at the time
    • Whether CPVT mutations disrupt this neuronal complex not tested
    • Generalizability beyond CA1 neurons unknown
  14. 2020 High

    RyR2 gain-of-function was linked to neurodegeneration: the E4872Q loss-of-function mutation or pharmacological open-time reduction (R-carvedilol) prevented neuronal hyperexcitability, memory impairment, and neuron loss in Alzheimer's mice by upregulating A-type K⁺ current.

    Evidence RyR2-E4872Q knock-in × 5xFAD mice, electrophysiology (IA), behavioral memory tests, R-carvedilol pharmacology

    PMID:32966798

    Open questions at the time
    • Whether RyR2 Ca²⁺ leak directly modulates Kv4/KChIP expression or trafficking unknown
    • Translational relevance to human AD not established
  15. 2021 High

    RyR2 loss-of-function mutations were established as a distinct disease category: E4146K and G4935R abolish SOICR and caffeine activation, with G4935R exerting dominant-negative effects, linking Ca²⁺ release deficiency to ventricular fibrillation and sudden death.

    Evidence HEK293 SOICR assay, single-channel lipid bilayer recordings, [³H]ryanodine binding, co-expression dominant-negative assay

    PMID:33825858

    Open questions at the time
    • In vivo confirmation in knock-in animal models not reported
    • Structural basis for dominant-negative tetramer poisoning not resolved
  16. 2022 High

    Intraluminal redox regulation of RyR2 was identified: Ero1α oxidation of the SR lumen dissociates ERp44 from RyR2-C4806, increasing channel activity and proarrhythmic Ca²⁺ release; Ero1α inhibition reversed this in hypertrophic hearts.

    Evidence Co-IP, C4806 mutagenesis, molecular dynamics, ERroGFP SR redox sensor, Ca²⁺ imaging, optical mapping in Ero1α KO/OE rats

    PMID:35086342

    Open questions at the time
    • Whether other luminal cysteines contribute to redox sensing unknown
    • Relevance to human cardiac hypertrophy not confirmed
  17. 2023 High

    RyR2 loss-of-function was directly linked to a structural heart disease: the I4855M mutation abolishes SOICR and causes left ventricular noncompaction in knock-in mice, expanding RyR2 disease beyond arrhythmia to cardiomyopathy.

    Evidence I4855M knock-in mice, echocardiography, confocal Ca²⁺ imaging, SOICR assay, CaMKII immunoblotting, HEK293 dominant-negative studies

    PMID:37325910

    Open questions at the time
    • Developmental mechanism linking Ca²⁺ release deficiency to noncompaction unknown
    • Whether other LOF mutations cause LVNC not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the high-resolution structure of RyR2 bound to CaM and in phosphorylated states; how phosphorylation at S2808/S2814 mechanistically enables CaM inhibition; the structural basis of luminal Ca²⁺ sensing and SOICR; and whether neuronal and β-cell RyR2 complexes differ in composition and regulation from cardiac RyR2.
  • No cryo-EM structure with CaM or phosphorylated channel
  • Luminal Ca²⁺ sensor identity/mechanism unknown
  • Neuronal RyR2 interactome not systematically defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4 GO:0140299 molecular sensor activity 3
Localization
GO:0005783 endoplasmic reticulum 5 GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-1643685 Disease 5 R-HSA-382551 Transport of small molecules 4 R-HSA-397014 Muscle contraction 3
Partners
CALM1CAMK2DERO1AERP44FKBP1BITGB1JPH3JPH4
Complex memberships
Cav1.3–RyR2–KCa3.1 tripartite complexRyR2 homotetramer

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 Cryo-EM structures of porcine RyR2 in both open and closed states at near-atomic resolution revealed that gating involves a breathing motion of the cytoplasmic region through interdomain movements of NTDs, Helical, and Handle domains, with outward rotations of Central domains leading to dilation of the cytoplasmic gate. Mutational characterization validated the structural model. Single-particle electron cryomicroscopy (open and closed states) + site-directed mutagenesis Science High 27708056
2005 Disease-linked RyR2 mutations from N-terminal, central, and C-terminal regions all enhance store overload-induced Ca2+ release (SOICR) and increase channel sensitivity to luminal (but not cytosolic) Ca2+ activation, representing a common gain-of-function defect. No alteration of FKBP12.6-RyR2 interaction was detected. Stable inducible HEK293 cell lines expressing mutant RyR2, single-channel lipid bilayer recordings, [3H]ryanodine binding, single-cell Ca2+ imaging Circulation Research High 16239587
2009 miR-1 overexpression selectively increases CaMKII-dependent phosphorylation of RyR2 at S2814 (but not PKA site S2808) by downregulating the PP2A regulatory subunit B56α, causing enhanced spontaneous Ca2+ sparks and arrhythmogenic Ca2+ oscillations in rat ventricular myocytes. Adenoviral miR-1 overexpression, Ca2+ imaging, electrophysiology, quantitative immunoblotting, CaMKII inhibitor (KN93) rescue Circulation Research High 19131648
2012 CaMKII phosphorylation of RyR2 at S2814 promotes pathological SR Ca2+ leak and heart failure after transverse aortic constriction. Knock-in mice with S2814A (CaMKII-inactivated) were protected from pressure-overload HF, pulmonary congestion, and SR Ca2+ leak, but not from ischemic HF. S2814A knock-in mice, transverse aortic constriction model, confocal Ca2+ imaging, SR Ca2+ leak measurements, echocardiography Circulation Research High 22511749
2011 CaMKII phosphorylation of RyR2 at S2814 (not S2808) is required for AF induction in FKBP12.6-knockout mice. S2814A knock-in abolished SR Ca2+ leak, delayed afterdepolarizations, and AF susceptibility in FKBP12.6-/- mice. Double knock-in mouse models (FKBP12.6-/- crossed with S2814A or S2808A), Ca2+ spark/wave measurements, patch clamp (DADs), in vivo AF induction Circulation Research High 22158709
2016 CaMKII-dependent phosphorylation of RyR2-S2814 drives a pathological RyR2 conformational shift (increased DPc10 access) with reduced calmodulin affinity and elevated SR Ca2+ leak. Dantrolene and excess CaM both restored normal RyR2 conformation and suppressed ventricular tachycardia in S2814D mice. S2814D and S2814A knock-in mouse myocytes, FRET-based CaM affinity measurements, DPc10 conformational probe, Ca2+ leak assay, in vivo VT inducibility Journal of Molecular and Cellular Cardiology High 27318036
2003 Calmodulin (CaM) inhibits RyR2 at all Ca2+ concentrations (100 nM–1 mM), shifting RyR2 Ca2+ EC50 7–10-fold upward. Ca2+ binding to any of CaM's four Ca2+ sites is required for inhibition. ApoCaM (Ca2+-free mutant) activated RyR2 and acted as competitive inhibitor of wild-type CaM, revealing isoform-specific CaM regulation distinct from RyR1. In vitro [3H]ryanodine binding with Ca2+-insensitive CaM point mutants, planar lipid bilayer single-channel recordings Biochemistry High 12614169
2013 Calmodulin (CaM) binds to RyR2 with high affinity in situ (Kd = 10–20 nM) and >90% of Z-line CaM is RyR2-bound. Disrupting CaM-RyR2 binding (RyR2-ADA/+ knock-in) causes Ca2+ waves and stress-induced ventricular arrhythmia. In post-MI heart failure, CaM-RyR2 affinity is decreased ~3-fold while FKBP12.6-RyR2 affinity is unchanged. FRET in permeabilized myocytes, RyR2-ADA/+ knock-in mice, confocal Ca2+ imaging, in vivo arrhythmia induction Circulation Research High 24186966
2019 CaM binds to four RyR2 CaM-binding domains (CaMBD1a, 1b, 2, 3) in a Ca2+-dependent manner. CaM C-domain anchors to CaMBD2 (Ca2+-saturated under resting conditions) while the N-domain acts as a dynamic Ca2+ sensor bridging CaMBD2 and CaMBD3, supporting a model where CaM stays constitutively bound but changes conformation to regulate RyR2. Fluorescence anisotropy of TAMRA-labeled CaMBD peptides, individual CaM domain titrations across Ca2+ concentrations Biochemical Journal High 30530841
2014 Crystal structure of the human RyR2 N-terminal region (residues 1–606) shows three domains (A, B, C) held together by a network of interactions with a central helix (residues 410–437) playing a key stabilizing role. The anion-binding site present in mouse RyR2 N-terminus is absent in human RyR2. Docking into cryo-EM maps predicts up to 8 Å Cα movements upon gating. X-ray crystallography, small-angle X-ray scattering (solution structure), homology modeling, docking into cryo-EM maps Acta Crystallographica Section D High 25372681
2015 RyR2-mediated Ca2+ release specifically promotes glucose oxidation via pyruvate dehydrogenase (PDH) activation. Ryr2 haploinsufficient (cRyr2Δ50) mice with 50% reduced RyR2 show decreased cytosolic and mitochondrial Ca2+ signals, PDH hyperphosphorylation/inhibition, and reduced glucose oxidation without contractile impairment. Inducible cardiac Ryr2 haploinsufficient mouse model, mitochondrial Ca2+ imaging, metabolomics, proteomics, transcriptomics, PDH phosphorylation assays Journal of Biological Chemistry High 27621312
2010 PKA phosphorylation of RyR2-S2808 contributes to SR Ca2+ leak and dystrophic cardiomyopathy. mdx mice crossed with RyR2-S2808A knock-in had reduced SR Ca2+ leak, preserved fractional shortening, reduced isoproterenol-induced arrhythmia and mortality compared to mdx mice. S2808A knock-in crossed with mdx mice, confocal Ca2+ imaging, echocardiography, survival analysis, SR Ca2+ leak measurements PNAS High 20615971
2015 CaMKIIδ is the specific isoform responsible for β-adrenergic-stimulated RyR2-S2814 phosphorylation and SR Ca2+ leak. CaMKIIδ-KO mice and S2814A mice were both protected from chronic isoproterenol-induced cardiomyopathy and pulmonary congestion, but not from hypertrophy, implicating CaMKIIδ→RyR2-S2814 axis specifically in pathological remodeling. CaMKIIδ-KO and S2814A knock-in mice, chronic isoproterenol infusion, echocardiography, SR Ca2+ leak measurements, immunoblotting Journal of Molecular and Cellular Cardiology High 26080362
2015 RyR2 channel activity (open probability) determines the potency of open-state blockers flecainide and R-propafenone against arrhythmogenic Ca2+ waves. Higher RyR2 activity in CPVT mutant (Casq2-/-, RyR2-R4496C+/-) or caffeine-treated myocytes leads to lower IC50 for open-state but not state-independent (tetracaine) blockers. Permeabilized ventricular myocytes from CPVT mouse models, confocal Ca2+ imaging, concentration-response curves for drug inhibition of Ca2+ waves PLoS ONE High 26121139
2002 ARVD2-associated RyR2 mutations decrease binding of the gating protein FKBP12.6 to RyR2, while VTSIP (CPVT)-associated mutations increase FKBP12.6 binding, as shown by quantitative yeast two-hybrid assay. This suggests ARVD2 mutations increase cytosolic Ca2+ release while VTSIP mutations do not significantly alter Ca2+ levels. Quantitative yeast two-hybrid system with RyR2 point mutations and FKBP12.6 Biochemical and Biophysical Research Communications Medium 12459180
2013 The CPVT-associated RyR2 G230C mutation enhances SOICR propensity, reduces SOICR threshold, increases sensitivity of single channels to both luminal and cytosolic Ca2+, and decreases thermal stability of the N-terminal domain (residues 1–547), suggesting structural destabilization as a disease mechanism. Stable inducible HEK293 cells, single-cell Ca2+ imaging, single-channel lipid bilayer recordings, [3H]ryanodine binding, thermal stability assay of N-terminal fragment Biochemical Journal High 23746327
2022 Ero1α-mediated oxidation of the intra-SR environment causes dissociation of ERp44 from RyR2 intraluminal cysteine C4806, increasing RyR2 Ca2+ channel activity and proarrhythmic Ca2+ release. Site-directed mutagenesis and molecular dynamics confirmed C4806 as the redox-sensitive ERp44-RyR2 interaction site. Ero1α inhibition restored ERp44-RyR2 association and reduced arrhythmias in hypertrophic rat hearts. Co-IP of RyR2-ERp44 complex, site-directed mutagenesis (C4806), molecular dynamics simulations, ERroGFP SR redox sensor, Ca2+ imaging, optical mapping, Ero1α KO/OE Circulation Research High 35086342
2019 Junctophilin proteins (JPH3/4) tether a Cav1.3-RyR2-KCa3.1 tripartite complex at plasma membrane-ER junctions in CA1 hippocampal neurons to enable the slow AHP. shRNA knockdown of JPH3/4 dissociated the complex and reduced IsAHP; antibody infusion into CA1 cells also reduced IsAHP and spike accommodation. dSTORM super-resolution imaging, FRET microscopy, shRNA knockdown, intracellular antibody infusion, electrophysiology Cell Reports High 31461656
2015 RyR2 plays a critical role in pancreatic β cell insulin secretion and glucose homeostasis. CPVT-associated leaky RyR2 mutations in mice caused intracellular Ca2+ leak via oxidized/nitrosylated RyR2, activated ER stress, mitochondrial dysfunction, and decreased fuel-stimulated insulin release. Pharmacological inhibition of Ca2+ leak improved glucose homeostasis. Transgenic mice with CPVT RyR2 mutations, islet Ca2+ imaging, ER stress assays, mitochondrial function assays, insulin secretion assays, pharmacological rescue Journal of Clinical Investigation High 25844899
2004 RyR2 activity is required for β cell survival: inhibiting RyR2 with ryanodine in human and mouse pancreatic β cells markedly increased apoptosis via a caspase-3-independent, calpain-10-dependent pathway. Pharmacological and genetic approaches showed calpain-10 mediates ryanodine-induced apoptosis downstream of RyR2 inhibition. Pharmacological RyR2 inhibition (ryanodine), genetic calpain-10 knockdown, apoptosis assays in primary β cells Journal of Biological Chemistry High 15044459
2014 Doxorubicin and its metabolite doxorubicinol bind directly to RyR2 and SERCA2A, causing initial activation then irreversible inhibition of RyR2 channel activity. Inhibition involves thiol oxidation on RyR2 (reduced by DTT pretreatment, with both drugs reducing thiol group abundance). Doxorubicinol but not doxorubicin inhibited SERCA2A Ca2+ uptake; DTT reversed this to enhancement. Single RyR2 channel recordings (planar lipid bilayer), SERCA2A Ca2+ uptake assay in SR vesicles, thiol group quantification, dithiothreitol rescue Molecular Pharmacology High 25106424
2003 Streptozotocin-induced diabetes increases disulfide bond formation between reactive sulfhydryl groups on RyR2, reducing [3H]ryanodine binding (channel activity). DTT pretreatment partially restored activity; insulin treatment attenuated the oxidative modification. Pyrocoll activation of RyR2 was abolished in diabetic animals, indicating distinct sulfhydryl groups are oxidized. [3H]ryanodine binding assay, thiol-reactive reagent (pyrocoll), DTT rescue, insulin treatment in STZ-diabetic rats Journal of Pharmacology and Experimental Therapeutics Medium 12606683
2015 Palmitoyl-carnitine increases RyR2 oxidation and S-nitrosylation, promotes FKBP12.6 dissociation from RyR2, and increases SR Ca2+ leak in a ROS-dependent manner. This occurs downstream of ANT inhibition and mitochondrial ROS production. ANT inhibitor bongkrekic acid or antioxidant NAC prevented RyR2 oxidation/S-nitrosylation and SR Ca2+ leak. Isolated cardiac mitochondria, cardiomyocyte Ca2+ imaging, RyR2 oxidation/S-nitrosylation immunoblotting, FKBP12.6 co-precipitation, pharmacological rescue Biochimica et Biophysica Acta Medium 25619687
2011 PKA hyperphosphorylation uncouples RyR2 gating from cytosolic Ca2+ regulation: exogenous PKA increases open probability and renders RyR2 insensitive to subactivating Ca2+ concentrations (channel stays open at low [Ca2+]). PP1 treatment reverses this. An endogenous Ca2+-dependent, PKC-sensitive kinase co-purifies with RyR2 and produces identical uncoupling. Planar lipid bilayer single-channel recordings, exogenous PKA and PP1 treatment, endogenous kinase studies, cytosolic Ca2+ manipulation Journal of Membrane Biology Medium 21274522
2020 A RyR2 point mutation E4872Q (reduced open time) prevents neuronal hyperexcitability, hyperactivity, memory impairment, and neuron loss in 5xFAD Alzheimer's disease mice by upregulating hippocampal CA1 A-type K+ current. Pharmacological limiting of RyR2 open time with R-carvedilol (but not racemic carvedilol) also prevented and rescued these deficits even with continued β-amyloid accumulation. RyR2-E4872Q knock-in in 5xFAD mice, electrophysiology (A-type K+ current), memory behavior tests, neuron counting, R-carvedilol pharmacology Cell Reports High 32966798
2020 Ca2+-CaM dependent inactivation of RyR2 is a major determinant of cardiac Ca2+ alternans. CaM gain-of-function (M37Q) promoted Ca2+ alternans and prolonged Ca2+ transient recovery; CaM loss-of-function (1-4) had opposite effects. Numerical modeling incorporating Ca2+-CaM-dependent RyR2 regulation reproduced experimental outcomes across 9 conditions. In vivo adenoviral gene delivery of CaM mutants into mouse LV, confocal Ca2+ imaging in intact Langendorff hearts, mathematical modeling Circulation Research High 33375811
2021 RyR2-mediated Ca2+ release in hippocampal neurons contributes to nuclear Ca2+ signals induced by neuronal activity (gabazine, glutamate uncaging, high-frequency stimulation), CREB phosphorylation, and upregulation of Npas4 and RyR2 expression. Suppressing RyR2-mediated release with ryanodine significantly reduced these activity-dependent molecular events. Primary hippocampal neuron cultures, pharmacological RyR2 inhibition (ryanodine), gabazine/glutamate uncaging, nuclear Ca2+ imaging, CREB phosphorylation immunoblotting, RT-PCR for Npas4/RyR2 PNAS Medium 34389673
2019 CaM inhibition of human RyR2 requires prior phosphorylation: physiological CaM concentrations inhibit RyR2 from failing (phosphorylated) but not healthy human hearts. Phosphomimetic (S2814D, S2808D) mutant cardiomyocytes show CaM-dependent Ca2+ spark regulation, whereas phosphoablated (S2814A, S2808A) mutants do not. Thus phosphorylation of either S2808 or S2814 is necessary and sufficient for CaM inhibitory action on human RyR2. RyR2 isolation from human failing/healthy hearts, FRET (donor-FKBP12.6/acceptor-CaM), ex vivo phosphorylation/dephosphorylation, Ca2+ spark measurements in murine phosphomimetic/phosphoablated knock-in cardiomyocytes Journal of Molecular and Cellular Cardiology High 30928430
2019 All 14 arrhythmogenic calmodulin mutations tested diminish CaM-dependent inhibition of RyR2-mediated Ca2+ release and enhance SOICR in HEK293 cells; many also directly activate RyR2 rather than inhibiting it at elevated cytosolic Ca2+. The mutations alter the Ca2+-dependency of CaM binding to the RyR2 CaM-binding domain. HEK293 stable cell lines expressing human RyR2, single-cell Ca2+ imaging (SOICR assay), permeabilized cell Ca2+ release assay, CaM-binding domain fluorescence assay FEBS Journal High 31230402
2014 Enhanced CaM binding to RyR2 (using GSH-CaM with higher RyR2 affinity) corrects CPVT R2474S channel disorder: reduces Ca2+ spark frequency, DADs, triggered activity, and spontaneous Ca2+ transients in knock-in myocytes. The CPVT mutation reduces apparent CaM affinity for RyR2 in the presence of cAMP. R2474S knock-in mouse myocytes, fluorescent CaM (HiLyte Fluor) binding assay in permeabilized myocytes, patch clamp (DADs, triggered activity), confocal Ca2+ spark imaging Biochemical and Biophysical Research Communications Medium 24755079
2014 Calmodulin F90L mutation (associated with idiopathic ventricular fibrillation) reduces Ca2+-binding affinity and cooperativity, decreases RyR2 interaction, and causes defective modulation of [3H]ryanodine binding, indicating aberrant CaM-RyR2 interaction as the arrhythmogenic mechanism. Protein stability assay, Ca2+-binding fluorimetry, co-sedimentation/pulldown of CaM-RyR2, [3H]ryanodine binding modulation FEBS Letters Medium 25036739
2020 Loss of integrin β1D in ARVC leads to RyR2 Ser-2030 hyperphosphorylation and aberrant Ca2+ handling. Purified integrin β1D directly stabilizes RyR2 by decreasing open probability, mean open time, and increasing mean close time in lipid bilayer recordings. β1D-KO mice develop catecholamine-sensitive polymorphic VT without structural abnormalities. Lipid bilayer single-channel patch clamp with purified integrin β1D protein + RyR2, β1D cardiac KO mice, Ca2+ imaging, Western blotting for RyR2 phosphorylation, protein mass spectrometry Circulation High 32122157
2021 RyR2 loss-of-function mutations E4146K and G4935R are linked to ventricular fibrillation/sudden death. E4146K markedly suppresses caffeine activation, abolishes SOICR, and severely reduces both cytosolic and luminal Ca2+ activation of single channels. G4935R completely abolishes caffeine activation and [3H]ryanodine binding; G4935R exerts dominant-negative impact on wild-type RyR2 in co-expression studies. HEK293 cell Ca2+ release assay (SOICR), single-channel lipid bilayer recordings, [3H]ryanodine binding, co-expression dominant-negative assay Bioscience Reports High 33825858
2016 RyR2 clusters in the periphery of live ventricular myocytes show irregular, dynamic distribution (unlike ordered interior arrays). Peripheral cluster movements are modulated by extracellular Ca2+, RyR2 activator (caffeine), and inhibitor (tetracaine), and peripheral clusters are functionally active for Ca2+ release. GFP-tagged RyR2 knock-in mouse, confocal imaging + TIRF microscopy, time-lapse imaging, simultaneous Ca2+/GFP imaging Biophysical Journal Medium 29401432
2018 In vivo CRISPR/Cas9 (SaCas9) delivered by AAV9 specifically disrupts the disease-causing R176Q RyR2 allele in neonatal cardiomyocytes, normalizes enhanced Ca2+ spark frequency, and completely prevents catecholamine-induced ventricular arrhythmias in CPVT mice. No off-target editing of the wild-type allele was detected. AAV9-delivered SaCas9 in vivo genome editing in R176Q/+ knock-in mice, targeted deep sequencing, confocal Ca2+ spark imaging, in vivo arrhythmia telemetry Circulation Research High 30355031
2009 Gain-of-function RyR2 R176Q mutation causes increased spontaneous Ca2+ release in neonatal cardiomyocytes, increased ventricular ectopy, and higher incidence of sudden death in young knock-in mice, without changes in other Ca2+-handling protein expression levels, indicating that Ca2+ leak through mutant RyR2 underlies arrhythmogenesis. R176Q/+ knock-in mice, optical mapping of membrane potential and Ca2+, surface ECG, intracardiac pacing, RT-PCR/Western blotting Circulation: Arrhythmia and Electrophysiology High 20009080
2023 RyR2 loss-of-function mutation I4855M+/- in mice causes left ventricular noncompaction (LVNC), abolishes SR store overload-induced Ca2+ release, increases peak Ca2+ transient (elevated Ca2+-induced Ca2+ release gain) and end-diastolic Ca2+, with elevated phospho-CaMKII. The I4855M mutation in HEK293 cells inhibited caffeine-induced Ca2+ release and had dominant-negative impact on wild-type RyR2. I4855M+/- knock-in mice, echocardiography, confocal Ca2+ imaging, SOICR assay, CaMKII immunoblotting, HEK293 functional studies Circulation Research High 37325910
2022 CD38 expression on exhausted CD8+ T cells elevates intracellular Ca2+ through RyR2 calcium channel activation, promoting chronic AKT activation and TCF1 loss, leading to terminal exhaustion. RyR2 knockdown in CD8+ T cells maintained TCF1 levels and improved anti-tumor response and anti-PD1 responsiveness in mice. scRNA-seq, genetic CD38/RyR2 knockdown in T cells, intracellular Ca2+ measurements, AKT/TCF1 immunoblotting, in vivo tumor models PNAS Medium 38451948
2019 LINC00472/miR-24/JP2/RyR2 signaling pathway contributes to atrial fibrillation pathogenesis. miR-24 directly binds and negatively regulates JP2, which stabilizes RyR2 expression. Reduced LINC00472 (via promoter methylation in AF patients) increases miR-24, reducing JP2 and consequently RyR2 expression in cardiomyocytes. Dual-luciferase reporter assay, real-time PCR, Western blot, IHC in HCM and H9C2 cells, AF patient samples Biomedicine & Pharmacotherapy Low 31562981
2018 RyR2 mutation R4496C is located in a loop involved in inter-subunit interactions in the tetrameric structure; A165D (CPVT mutation) is in the same loop and disrupts conformational stability, favoring closed-to-open state transition and enhanced SR Ca2+ release. Structural analysis combined with functional studies in A165D knock-in mice confirmed this loop as a common CPVT pathogenic hotspot. A165D knock-in mice, structural analysis docked to cryo-EM RyR2 maps, SR Ca2+ release measurements, DAD recordings in cardiomyocytes Journal of Molecular and Cellular Cardiology Medium 29477366

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2). Human molecular genetics 585 11159936
2001 Mutations of the cardiac ryanodine receptor (RyR2) gene in familial polymorphic ventricular tachycardia. Circulation 556 11157710
2005 Enhanced store overload-induced Ca2+ release and channel sensitivity to luminal Ca2+ activation are common defects of RyR2 mutations linked to ventricular tachycardia and sudden death. Circulation research 284 16239587
2009 The RYR2-encoded ryanodine receptor/calcium release channel in patients diagnosed previously with either catecholaminergic polymorphic ventricular tachycardia or genotype negative, exercise-induced long QT syndrome: a comprehensive open reading frame mutational analysis. Journal of the American College of Cardiology 264 19926015
2009 miR-1 overexpression enhances Ca(2+) release and promotes cardiac arrhythmogenesis by targeting PP2A regulatory subunit B56alpha and causing CaMKII-dependent hyperphosphorylation of RyR2. Circulation research 230 19131648
2016 Structural basis for the gating mechanism of the type 2 ryanodine receptor RyR2. Science (New York, N.Y.) 228 27708056
2005 Catecholaminergic polymorphic ventricular tachycardia: RYR2 mutations, bradycardia, and follow up of the patients. Journal of medical genetics 222 16272262
2012 Role of RyR2 phosphorylation at S2814 during heart failure progression. Circulation research 174 22511749
2015 Calcium release channel RyR2 regulates insulin release and glucose homeostasis. The Journal of clinical investigation 165 25844899
2014 Role of RyR2 phosphorylation in heart failure and arrhythmias: Controversies around ryanodine receptor phosphorylation in cardiac disease. Circulation research 161 24723656
1995 A new locus for arrhythmogenic right ventricular cardiomyopathy (ARVD2) maps to chromosome 1q42-q43. Human molecular genetics 154 8589694
2011 Inhibition of CaMKII phosphorylation of RyR2 prevents induction of atrial fibrillation in FKBP12.6 knockout mice. Circulation research 131 22158709
2014 Adverse effects of doxorubicin and its metabolic product on cardiac RyR2 and SERCA2A. Molecular pharmacology 117 25106424
2004 RyR2 and calpain-10 delineate a novel apoptosis pathway in pancreatic islets. The Journal of biological chemistry 111 15044459
2005 Spectrum and prevalence of cardiac ryanodine receptor (RyR2) mutations in a cohort of unrelated patients referred explicitly for long QT syndrome genetic testing. Heart rhythm 110 16188589
2010 Calmodulin kinase II inhibition prevents arrhythmias in RyR2(R4496C+/-) mice with catecholaminergic polymorphic ventricular tachycardia. Journal of molecular and cellular cardiology 100 20937285
2016 CaMKII-dependent phosphorylation of RyR2 promotes targetable pathological RyR2 conformational shift. Journal of molecular and cellular cardiology 94 27318036
2018 In Vivo Ryr2 Editing Corrects Catecholaminergic Polymorphic Ventricular Tachycardia. Circulation research 77 30355031
2013 Cardiac myocyte Z-line calmodulin is mainly RyR2-bound, and reduction is arrhythmogenic and occurs in heart failure. Circulation research 68 24186966
2015 CaMKIIδ mediates β-adrenergic effects on RyR2 phosphorylation and SR Ca(2+) leak and the pathophysiological response to chronic β-adrenergic stimulation. Journal of molecular and cellular cardiology 66 26080362
2013 'Ryanopathy': causes and manifestations of RyR2 dysfunction in heart failure. Cardiovascular research 64 23408344
2019 Junctophilin Proteins Tether a Cav1-RyR2-KCa3.1 Tripartite Complex to Regulate Neuronal Excitability. Cell reports 57 31461656
2014 Prevalence and significance of rare RYR2 variants in arrhythmogenic right ventricular cardiomyopathy/dysplasia: results of a systematic screening. Heart rhythm 55 25041964
2019 Assessment and Validation of a Phenotype-Enhanced Variant Classification Framework to Promote or Demote RYR2 Missense Variants of Uncertain Significance. Circulation. Genomic and precision medicine 52 31112425
2003 Regulation of the RYR1 and RYR2 Ca2+ release channel isoforms by Ca2+-insensitive mutants of calmodulin. Biochemistry 52 12614169
2023 RYR2-ryanodinopathies: from calcium overload to calcium deficiency. Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology 50 37387319
2019 Iron-deficiency anemia reduces cardiac contraction by downregulating RyR2 channels and suppressing SERCA pump activity. JCI insight 49 30779710
2020 Limiting RyR2 Open Time Prevents Alzheimer's Disease-Related Neuronal Hyperactivity and Memory Loss but Not β-Amyloid Accumulation. Cell reports 48 32966798
2016 A novel RYR2 loss-of-function mutation (I4855M) is associated with left ventricular non-compaction and atypical catecholaminergic polymorphic ventricular tachycardia. Journal of electrocardiology 47 27646203
2015 Palmitoyl-carnitine increases RyR2 oxidation and sarcoplasmic reticulum Ca2+ leak in cardiomyocytes: Role of adenine nucleotide translocase. Biochimica et biophysica acta 46 25619687
2010 Genetic inhibition of PKA phosphorylation of RyR2 prevents dystrophic cardiomyopathy. Proceedings of the National Academy of Sciences of the United States of America 46 20615971
2007 Phosphorylation of RyR2 and shortening of RyR2 cluster spacing in spontaneously hypertensive rat with heart failure. American journal of physiology. Heart and circulatory physiology 46 17630346
2013 Pernicious attrition and inter-RyR2 CICR current control in cardiac muscle. Journal of molecular and cellular cardiology 44 23369697
2021 RyR2 and Calcium Release in Heart Failure. Frontiers in physiology 43 34690808
2020 Integrin β1D Deficiency-Mediated RyR2 Dysfunction Contributes to Catecholamine-Sensitive Ventricular Tachycardia in Arrhythmogenic Right Ventricular Cardiomyopathy. Circulation 43 32122157
2019 The CaMKII inhibitor KN93-calmodulin interaction and implications for calmodulin tuning of NaV1.5 and RyR2 function. Cell calcium 43 31401388
2018 Post-Translational Modifications and Diastolic Calcium Leak Associated to the Novel RyR2-D3638A Mutation Lead to CPVT in Patient-Specific hiPSC-Derived Cardiomyocytes. Journal of clinical medicine 41 30413023
2019 LncRNA-LINC00472 contributes to the pathogenesis of atrial fibrillation (Af) by reducing expression of JP2 and RyR2 via miR-24. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 40 31562981
2002 The binding of the RyR2 calcium channel to its gating protein FKBP12.6 is oppositely affected by ARVD2 and VTSIP mutations. Biochemical and biophysical research communications 40 12459180
2003 Streptozotocin-induced diabetes increases disulfide bond formation on cardiac ryanodine receptor (RyR2). The Journal of pharmacology and experimental therapeutics 39 12606683
2021 Identification of loss-of-function RyR2 mutations associated with idiopathic ventricular fibrillation and sudden death. Bioscience reports 34 33825858
2021 Human RyR2 (Ryanodine Receptor 2) Loss-of-Function Mutations: Clinical Phenotypes and In Vitro Characterization. Circulation. Arrhythmia and electrophysiology 33 34546788
2017 The emerging role of calmodulin regulation of RyR2 in controlling heart rhythm, the progression of heart failure and the antiarrhythmic action of dantrolene. Clinical and experimental pharmacology & physiology 32 27626620
2022 Molecular, Subcellular, and Arrhythmogenic Mechanisms in Genetic RyR2 Disease. Biomolecules 31 35892340
2019 Ca2+-dependent calmodulin binding to cardiac ryanodine receptor (RyR2) calmodulin-binding domains. The Biochemical journal 31 30530841
2019 Ryanodine receptor 2 (RYR2) mutation: A potentially novel neurocardiac calcium channelopathy manifesting as primary generalised epilepsy. Seizure 31 30849713
2014 Enhanced binding of calmodulin to RyR2 corrects arrhythmogenic channel disorder in CPVT-associated myocytes. Biochemical and biophysical research communications 31 24755079
2022 Ero1α-Dependent ERp44 Dissociation From RyR2 Contributes to Cardiac Arrhythmia. Circulation research 30 35086342
2018 CRISPR/Cas9 Gene editing of RyR2 in human stem cell-derived cardiomyocytes provides a novel approach in investigating dysfunctional Ca2+ signaling. Cell calcium 30 29730419
2015 Reconciling depressed Ca2+ sparks occurrence with enhanced RyR2 activity in failing mice cardiomyocytes. The Journal of general physiology 30 26371209
2020 Classification and correlation of RYR2 missense variants in individuals with catecholaminergic polymorphic ventricular tachycardia reveals phenotypic relationships. Journal of human genetics 29 32152366
2015 Channel Activity of Cardiac Ryanodine Receptors (RyR2) Determines Potency and Efficacy of Flecainide and R-Propafenone against Arrhythmogenic Calcium Waves in Ventricular Cardiomyocytes. PloS one 29 26121139
2004 Denaturing HPLC-based approach for detecting RYR2 mutations involved in malignant arrhythmias. Clinical chemistry 29 15131021
2020 Genomic Mapping Identifies Mutations in RYR2 and AHNAK as Associated with Favorable Outcome in Basal-Like Breast Tumors Expressing PD1/PD-L1. Cancers 28 32796628
2016 Cardiac Ryanodine Receptor (Ryr2)-mediated Calcium Signals Specifically Promote Glucose Oxidation via Pyruvate Dehydrogenase. The Journal of biological chemistry 28 27621312
2015 The RyR2-P2328S mutation downregulates Nav1.5 producing arrhythmic substrate in murine ventricles. Pflugers Archiv : European journal of physiology 28 26545784
2021 RyR-mediated Ca2+ release elicited by neuronal activity induces nuclear Ca2+ signals, CREB phosphorylation, and Npas4/RyR2 expression. Proceedings of the National Academy of Sciences of the United States of America 27 34389673
2021 Provocation Testing and Therapeutic Response in a Newly Described Channelopathy: RyR2 Calcium Release Deficiency Syndrome. Circulation. Genomic and precision medicine 27 34949103
2015 Crosstalk between RyR2 oxidation and phosphorylation contributes to cardiac dysfunction in mice with Duchenne muscular dystrophy. Journal of molecular and cellular cardiology 27 26555638
2014 Altered RyR2 regulation by the calmodulin F90L mutation associated with idiopathic ventricular fibrillation and early sudden cardiac death. FEBS letters 27 25036739
2013 The CPVT-associated RyR2 mutation G230C enhances store overload-induced Ca2+ release and destabilizes the N-terminal domains. The Biochemical journal 27 23746327
2020 Ca2+-CaM Dependent Inactivation of RyR2 Underlies Ca2+ Alternans in Intact Heart. Circulation research 26 33375811
2014 Long-term simulated microgravity causes cardiac RyR2 phosphorylation and arrhythmias in mice. International journal of cardiology 26 25227892
2014 Structural insights into the human RyR2 N-terminal region involved in cardiac arrhythmias. Acta crystallographica. Section D, Biological crystallography 26 25372681
2023 The selective RyR2 inhibitor ent-verticilide suppresses atrial fibrillation susceptibility caused by Pitx2 deficiency. Journal of molecular and cellular cardiology 25 37080450
2021 "Ryanopathies" and RyR2 dysfunctions: can we further decipher them using in vitro human disease models? Cell death & disease 24 34725342
2016 An insertion/deletion polymorphism within 3'UTR of RYR2 modulates sudden unexplained death risk in Chinese populations. Forensic science international 24 27987400
2008 Sarcoplasmic reticulum Ca2+ release channel ryanodine receptor (RyR2) plays a crucial role in aconitine-induced arrhythmias. Biochemical pharmacology 24 18439986
2024 Fibroblast Growth Factor Receptor 4 Promotes Triple-Negative Breast Cancer Progression via Regulating Fatty Acid Metabolism Through the AKT/RYR2 Signaling. Cancer medicine 23 39658878
2021 RYR2 Mutations Are Associated With Benign Epilepsy of Childhood With Centrotemporal Spikes With or Without Arrhythmia. Frontiers in neuroscience 23 33897349
2019 Calmodulin inhibition of human RyR2 channels requires phosphorylation of RyR2-S2808 or RyR2-S2814. Journal of molecular and cellular cardiology 23 30928430
2018 Dynamic and Irregular Distribution of RyR2 Clusters in the Periphery of Live Ventricular Myocytes. Biophysical journal 23 29401432
2012 Postmortem genetic testing of the ryanodine receptor 2 (RYR2) gene in a cohort of sudden unexplained death cases. International journal of legal medicine 23 22222782
2019 Diminished inhibition and facilitated activation of RyR2-mediated Ca2+ release is a common defect of arrhythmogenic calmodulin mutations. The FEBS journal 22 31230402
2023 RyR2 inhibition with dantrolene is antiarrhythmic, prevents further pathological remodeling, and improves cardiac function in chronic ischemic heart disease. Journal of molecular and cellular cardiology 21 37285929
2021 Efficacy of RyR2 inhibitor EL20 in induced pluripotent stem cell-derived cardiomyocytes from a patient with catecholaminergic polymorphic ventricular tachycardia. Journal of cellular and molecular medicine 21 34110090
2015 R4496C RyR2 mutation impairs atrial and ventricular contractility. The Journal of general physiology 21 26666913
2009 Sudden infant death syndrome in mice with an inherited mutation in RyR2. Circulation. Arrhythmia and electrophysiology 21 20009080
2018 Pathogenic mechanism of a catecholaminergic polymorphic ventricular tachycardia causing-mutation in cardiac calcium release channel RyR2. Journal of molecular and cellular cardiology 20 29477366
2017 Nationwide experience of catecholaminergic polymorphic ventricular tachycardia caused by RyR2 mutations. Heart (British Cardiac Society) 20 28237968
2004 Dispersion of ventricular mRNA of RyR2 and SERCA2 associated with arrhythmogenesis in rats. Acta pharmacologica Sinica 20 15169625
2015 Medicinal effect and its JP2/RyR2-based mechanism of Smilax glabra flavonoids on angiotensin II-induced hypertrophy model of cardiomyocytes. Journal of ethnopharmacology 19 25926285
2024 CD38-RyR2 axis-mediated signaling impedes CD8+ T cell response to anti-PD1 therapy in cancer. Proceedings of the National Academy of Sciences of the United States of America 18 38451948
2022 Oxidative stress activates Ryr2-Ca2+ and apoptosis to promote PM2.5-induced heart injury of hyperlipidemia mice. Ecotoxicology and environmental safety 18 35091300
2019 Identification of a novel exon3 deletion of RYR2 in a family with catecholaminergic polymorphic ventricular tachycardia. Annals of noninvasive electrocardiology : the official journal of the International Society for Holter and Noninvasive Electrocardiology, Inc 18 30615235
2009 Ryanodine receptor (RyR2) mutations in sudden cardiac death: studies in extended pedigrees and phenotypic characterization in vitro. International journal of cardiology 18 19781797
2024 Inhibitors of Intracellular RyR2 Calcium Release Channels as Therapeutic Agents in Arrhythmogenic Heart Diseases. Annual review of pharmacology and toxicology 17 39374431
2022 How does flecainide impact RyR2 channel function? The Journal of general physiology 17 35713932
2019 CTCF inhibits endoplasmic reticulum stress and apoptosis in cardiomyocytes by upregulating RYR2 via inhibiting S100A1. Life sciences 17 31837328
2013 Postmortem genetic screening of SNPs in RyR2 gene in sudden unexplained nocturnal death syndrome in the southern Chinese Han population. Forensic science international 17 24447446
2005 The cardiac ryanodine receptor (RyR2) and its role in heart disease. Cardiology in review 17 15831148
2019 Ion channel gating in cardiac ryanodine receptors from the arrhythmic RyR2-P2328S mouse. Journal of cell science 16 31028179
2011 Ca²+-dependent phosphorylation of RyR2 can uncouple channel gating from direct cytosolic Ca²+ regulation. The Journal of membrane biology 16 21274522
2023 Increased Ca2+ Transient Underlies RyR2-Related Left Ventricular Noncompaction. Circulation research 15 37325910
2022 Hippocampal dendritic spines express the RyR3 but not the RyR2 ryanodine receptor isoform. Biochemical and biophysical research communications 15 36344175
2020 Impact of NR5A2 and RYR2 3'UTR polymorphisms on the risk of breast cancer in a Chinese Han population. Breast cancer research and treatment 15 32572717
2022 LINC01194 recruits NUMA1 to promote ubiquitination of RYR2 to enhance malignant progression in triple-negative breast cancer. Cancer letters 14 35750275
2014 Non-ventricular, Clinical, and Functional Features of the RyR2(R420Q) Mutation Causing Catecholaminergic Polymorphic Ventricular Tachycardia. Revista espanola de cardiologia (English ed.) 14 25440180
2011 Upregulation of RyR2 in hypoxic/reperfusion injury. Journal of neurotrauma 14 21612318
2009 Genetic variability of RyR2 and CASQ2 genes in an Asian population. Forensic science international 14 19709828