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Showing RYR1 — RYR is a alias.

RYR1

Ryanodine receptor 1 · UniProt P21817

Length
5038 aa
Mass
565.2 kDa
Annotated
2026-06-10
100 papers in source corpus 34 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RYR1 is a homotetrameric intracellular Ca2+ release channel of the skeletal-muscle sarcoplasmic reticulum that converts membrane depolarization into Ca2+ release during excitation-contraction (EC) coupling and additionally sets resting cytosolic Ca2+ through a ryanodine-insensitive leak conformation (PMID:12668474, PMID:20207743). Cryo-EM across functional states defines its gating: Ca2+, ATP, and caffeine bind at interdomain interfaces of the C-terminal activation core, where ATP or Ca2+ alone induces conformational priming while the three activators together bend the S6 segment, displace the S4-S5 linker, and dilate the pore via relaxation of inner-helix/inner-branch bundles along the four-fold axis (PMID:27662087, PMID:19402748); these activators act through a reciprocal allosteric network in which occupancy at one site reshapes the others (PMID:34352272), and even small adenine nucleotides such as AMP and cAMP can drive the long-range rearrangements that open the channel (PMID:37192614). The channel restores skeletal-type EC coupling through two cytoplasmic regions (residues 1924-2446 and 2644-3223) that confer DHPR-dependent voltage gating (PMID:12668474), with FKBP12 binding at Val2461 enhancing EC coupling gain (PMID:12704193). Its activity is tuned by accessory proteins and modifications: CLIC2 binds the clamp region to inhibit opening (PMID:19356589), calmodulin is required for dantrolene inhibition (PMID:25920678), and S-nitrosylation increases temperature sensitivity (PMID:18394989). Pathogenic gain-of-function mutations, exemplified by Y522S, disrupt a hydrophobic helical network and propagate via a ~100 Å lever from the DHPR interface to the Ca2+ activation site, pre-activating the channel and driving a feed-forward cascade of Ca2+ leak, reactive nitrogen species, S-nitrosylation, and heat-triggered contracture underlying malignant hyperthermia (PMID:35867837, PMID:18394989). Conversely, loss of RyR1 protein alone reduces Ca2+ release and force and recapitulates core myopathy features, establishing RyR1 deficiency as causative in RYR1-related myopathy (PMID:31107960, PMID:33176865, PMID:32236737).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1997 Medium

    Establishing that a single ryanodine receptor gene encodes a muscle-expressed channel whose mutation produces a discrete neuromuscular phenotype anchored RYR1 as a muscle Ca2+ release effector.

    Evidence Cloning, expression, and transgene rescue of the unc-68/ryr-1 ortholog in C. elegans

    PMID:9135117

    Open questions at the time
    • Ortholog work does not define mammalian channel structure or gating
    • PKC phosphorylation site functional role not directly tested in mammalian RyR1
  2. 2003 High

    Mapping which RyR1 regions confer DHPR-dependent voltage gating and FKBP12-dependent gain resolved how the channel reads sarcolemmal depolarization.

    Evidence RyR1/RyR3 chimeras and FKBP12-binding mutants reconstituted in dyspedic (RyR1-null) myotubes with Ca2+ imaging and electrophysiology

    PMID:12668474 PMID:12704193

    Open questions at the time
    • Atomic-level DHPR-RyR1 contact interface not resolved
    • How the two cytoplasmic regions cooperate mechanically not defined
  3. 2005 High

    Localizing FKBP12 to a defined site and generating the first MH knock-in mouse connected accessory-protein binding and a specific mutation to channel sensitization in vivo.

    Evidence Cryo-EM difference mapping of FKBP12 on RyR1; Y522S knock-in mouse with contracture and single-channel assays

    PMID:16284304 PMID:16405911

    Open questions at the time
    • Y522S structural mechanism not yet resolved at this stage
    • Downstream consequences of leak not yet defined
  4. 2008 High

    Defining a Ca2+ leak → reactive nitrogen species → S-nitrosylation feed-forward loop explained how a gain-of-function mutation produces heat-triggered contractures.

    Evidence Y522S knock-in mouse with S-nitrosylation biochemistry, contracture measurement, and N-acetylcysteine rescue

    PMID:18394989

    Open questions at the time
    • Identity of the RNS-producing source within muscle not fully defined
    • Whether the same loop operates for all MH mutations untested
  5. 2009 High

    Resolving the open-versus-closed conformational transition and identifying an inhibitory CLIC2 binding site established the physical basis of pore gating and a negative regulator.

    Evidence Cryo-EM of RyR1-FKBP12 in open/closed states with single-channel validation; CLIC2 binding with ryanodine binding, Ca2+ efflux, single-channel, and cryo-EM

    PMID:19356589 PMID:19402748

    Open questions at the time
    • Resolution insufficient for side-chain-level gating mechanism
    • Physiological context of CLIC2 regulation in muscle unclear
  6. 2010 High

    Showing that RyR1 sets resting cytosolic Ca2+ and basal sarcolemmal influx via a non-gating leak conformation expanded its role beyond depolarization-evoked release.

    Evidence Pharmacological/molecular dissection in dyspedic myotubes with RyR1 re-expression and Ca2+ imaging

    PMID:20207743

    Open questions at the time
    • Structural basis of the leak conformation not defined
    • Regulators of basal influx coupling unidentified
  7. 2015 High

    Demonstrating an absolute calmodulin requirement for dantrolene inhibition resolved why prior single-channel studies failed and clarified a pharmacological mechanism.

    Evidence Single-channel lipid bilayer recordings ± physiological CaM; cardiomyocyte Ca2+ wave assays

    PMID:25920678

    Open questions at the time
    • Molecular site of CaM-dependent dantrolene action not mapped
    • Whether all MH mutants retain CaM-dependent dantrolene sensitivity untested
  8. 2016 High

    High-resolution multi-state cryo-EM defined the ligand-binding sites and the priming-versus-opening logic of Ca2+, ATP, and caffeine, providing the structural gating model.

    Evidence Cryo-EM single-particle reconstruction of ligand-bound functional states

    PMID:27662087

    Open questions at the time
    • Dynamics between captured states not directly observed
    • How disease mutations distort these states not yet integrated
  9. 2018 Medium

    Microsecond single-channel recording revealed additional closed states and a possible second Ca2+ site, refining the gating-state landscape beyond static structures.

    Evidence CMOS-integrated suspended lipid bilayer recording at >500 kHz

    PMID:29432144

    Open questions at the time
    • Proposed second Ca2+ site not structurally localized
    • Single method, single lab
  10. 2020 Medium

    Connecting mutation-driven leak to patient-tissue protease activity and showing structure-based variant pathogenicity prediction linked the mechanism to RYR1-related myopathy diagnosis.

    Evidence Ex vivo patient muscle biopsy leak/protease assays with S107 rescue and cryo-EM variant mapping

    PMID:32236737

    Open questions at the time
    • Generalizability of S107 rescue across variants not established
    • Causal link between protease activity and clinical myopathy progression not proven
  11. 2022 High

    Resolving the Y522S structure defined a ~100 Å allosteric lever coupling the DHPR interface to the Ca2+ activation site, explaining mutation-induced pre-activation at atomic resolution.

    Evidence Cryo-EM of mutant RyR1 in nanodiscs with Ca2+ activation assays

    PMID:35867837

    Open questions at the time
    • Whether the same lever explains other clamp-region mutations untested
    • Structure of the lever in the full DHPR-coupled complex unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RyR1 leak is integrated across muscle, vascular, immune, and metabolic contexts and whether a unified structural classification predicts clinical severity across all variants remains open.
  • No unified structural-to-clinical severity model spanning gain-of-function and loss-of-function variants
  • Tissue-specific roles (T cells, vascular smooth muscle, thermogenesis) not mechanistically reconciled with the muscle channel model

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 3
Localization
GO:0005783 endoplasmic reticulum 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-1643685 Disease 3 R-HSA-397014 Muscle contraction 3 R-HSA-162582 Signal Transduction 2
Partners
AKAP18CALM1CHERPCLIC2FKBP12ORAI1STIM1TRPC3
Complex memberships
DHPR-RyR1 EC coupling junctionRYR1-ORAI1-STIM1 clusterRyR1-FKBP12 complex

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 Cryo-EM structures of RyR1 in multiple functional states revealed the structural basis of channel gating: binding sites for Ca2+, ATP, and caffeine were identified at interdomain interfaces of the C-terminal domain. ATP or Ca2+ alone induces conformational 'priming' without pore dilation, while all three activators together enable pore opening via bending of the S6 transmembrane segment, displacement of the S4-S5 linker, and global conformational changes in the cytosolic assembly. Cryo-EM single-particle reconstruction at high resolution with ligand-bound functional states Cell High 27662087
2009 Cryo-EM analysis of RyR1-FKBP12 in closed and open states at 10.2 Å resolution revealed that gating involves coordinated movement of cytoplasmic and transmembrane domains: distal cytoplasmic domains move toward the transmembrane domain while central cytoplasmic domains move away; the inner helices and cytoplasmic inner branches form two right-handed bundles that relax along the 4-fold axis to open the pore, producing ~4 Å diameter increase at the ion gate. Cryo-electron microscopy and single-particle image processing; single-channel electrophysiology PLoS biology High 19402748
2022 High-resolution cryo-EM of the MH/CCD mutation Y522S (rabbit homolog Y523S) in RyR1 showed that Tyr acts as a 'spacer' within an α-helical bundle; the Y523S substitution disrupts the hydrophobic network, rearranges α-helices, and propagates conformational changes via an ~100 Å-long lever that links the DHPR interaction site to the Ca2+ activation site, producing channel pre-activation and ~20-fold increased Ca2+ potency. Cryo-EM structure determination of purified mutant RyR1 reconstituted in nanodiscs; functional Ca2+ activation assays Proceedings of the National Academy of Sciences of the United States of America High 35867837
2020 Cryo-EM of RyR1 in native SR membranes revealed helix-like densities traversing the bilayer ~5 nm from the RyR1 transmembrane domain and sarcoplasmic extensions linking RyR1 to a calsequestrin network; RyR1 activation in native membranes is associated with changes in membrane curvature and movement of sarcoplasmic extensions. Cryo-EM of native SR membrane preparations; comparison of closed and open states in situ EMBO reports High 32147968
2005 Cryo-EM difference mapping at 16 Å resolution located FKBP12 at a specific site on RyR1 in a unique orientation, with Gln3 of FKBP12 participating directly in the interaction; the orientation places part of the FK506 binding site toward RyR1, explaining how FK506 dissociates FKBP12 from RyR1. Cryo-electron microscopy and single-particle image processing; 3D difference mapping fitted with atomic model of FKBP12 Journal of molecular biology High 16405911
2008 The Y522S malignant hyperthermia mutation in RyR1 causes Ca2+ leak that drives increased generation of reactive nitrogen species (RNS), leading to S-nitrosylation of mutant RyR1, which increases its temperature sensitivity for activation and produces muscle contractures upon heat exposure. This establishes a feed-forward mechanism linking Ca2+ leak → RNS → S-nitrosylation → enhanced RyR1 activation. Y522S RyR1 knock-in mouse model; biochemical S-nitrosylation assays; in vitro contracture measurements; N-acetylcysteine treatment Cell High 18394989
2003 FKBP12 binding to RyR1 at Val2461 enhances the gain of skeletal muscle excitation-contraction (EC) coupling. RyR1 mutants that cannot bind FKBP12 (V2461G, V2461I) show ~50% reduction in voltage-gated Ca2+ release; co-expression of FKBP12.6 with V2461I (which binds FKBP12.6 but not FKBP12) restores normal voltage-gated Ca2+ release. Expression of FKBP12-binding mutant RyR1 in RyR1-knockout (dyspedic) myotubes; fluorescence Ca2+ imaging; electrophysiology The Journal of biological chemistry High 12704193
2003 Multiple domains of RyR1 are required for skeletal-type excitation-contraction (EC) coupling with the α1S-DHPR. Using RyR1/RyR3 chimeras expressed in dyspedic myotubes, two critical RyR1 regions were identified: residues 1924–2446 and 2644–3223, each independently capable of restoring skeletal-type EC coupling. RyR1/RyR3 chimeric cDNAs expressed in dyspedic (RyR1-null) myotubes; functional Ca2+ imaging and electrophysiology Biophysical journal High 12668474
2009 CLIC2 binds to RyR1 in the clamp-shaped region between domains 5 and 6, induces conformational changes separating domains 9 and 10, and inhibits channel activity by increasing mean closed time and decreasing open probability; CLIC2 also increases ryanodine binding affinity and reduces Ca2+ efflux from SR vesicles. 3H-ryanodine binding assay; Ca2+ efflux from SR vesicles; single-channel recording in lipid bilayers; cryo-electron microscopy Journal of molecular biology High 19356589
2021 Cryo-EM structures of RyR1 bound to ATP-γ-S, ADP, AMP, adenosine, adenine, and cAMP revealed that AMP is the smallest ATP derivative capable of inducing long-range (>170 Å) structural rearrangements associated with channel activation; cAMP also induces these structural changes and increases channel opening, identifying it as a potential endogenous modulator. Cryo-EM structure determination; single-channel electrophysiology Structure (London, England : 1993) High 37192614
2021 3H-ryanodine ligand binding and molecular dynamics simulations demonstrated that Ca2+, ATP, and caffeine regulate RyR1 through a network of allosteric interactions: ATP and caffeine binding affect the conformation of the Ca2+-binding site, and Ca2+ binding reciprocally affects the ATP- and caffeine-binding site conformations in the C-terminal activation core. 3H-ryanodine ligand-binding assays; molecular dynamics simulations The Journal of biological chemistry Medium 34352272
2015 Calmodulin (CaM) is essential for dantrolene inhibition of RyR1: dantrolene inhibits RyR1 (and RyR2) single channels only when physiological CaM (100 nM) is present (Emax ~52% inhibition of Po); without CaM, dantrolene has no effect, explaining why prior single-channel studies failed to detect inhibition. Single-channel recordings in lipid bilayers; cardiomyocyte Ca2+ wave assays Molecular pharmacology High 25920678
2006 TRPC3 functionally couples with RyR1: knockdown of TRPC3 in skeletal myotubes significantly reduces the gain of excitation-contraction coupling and the amplitude of caffeine-induced RyR1-mediated Ca2+ release without altering SR Ca2+ content, and concomitantly up-regulates TRPC1, calsequestrin, triadin, and junctophilin 1. Retroviral siRNA knockdown; Mn2+ influx assay (Fura-2); Ca2+ imaging (Fluo-4); immunoblot The Journal of biological chemistry Medium 16484216
2011 RyR1 knockdown in human myoblasts concomitantly downregulates the α1 subunit of DHPR and other EC coupling proteins, while upregulating IP3 receptors; however, this IP3R upregulation does not compensate for loss of RyR1-mediated Ca2+ release, demonstrating that RyR1 deficiency disrupts the entire EC coupling machinery. siRNA knockdown of RyR1 in immortalized human myoblasts; immunoblot; Ca2+ imaging; co-expression analysis Human mutation Medium 23553787
2010 RyR1 expression accounts for more than half of total resting free Ca2+ concentration in skeletal myotubes, not through active channel gating but via a ryanodine-insensitive Ca2+ leak conformation; RyR1 expression also regulates basal sarcolemmal Ca2+ influx. Pharmacological and molecular perturbations in dyspedic (RyR1/RyR3-null) myotubes with RyR1 re-expression; Ca2+ imaging The Journal of biological chemistry High 20207743
2011 CHERP (calcium homeostasis endoplasmic reticulum protein) was identified as a novel RyR1 interacting protein: CHERP co-purifies with affinity-tagged RyR1 by metal affinity chromatography, co-localizes with endogenous RyR1 in the SR of rat soleus muscle, and siRNA suppression of CHERP affects Ca2+ release from the ER via RyR1. Affinity purification/LC-MS; co-purification Western blot; immunofluorescence co-localization; siRNA knockdown with Ca2+ release assay The Journal of biological chemistry Medium 21454501
2006 RYR1 alleles in skeletal muscle undergo polymorphic, tissue-specific, and developmentally regulated epigenetic silencing via hypermethylation; 5-aza-deoxycytidine treatment of patient myoblasts reactivated the silenced allele, demonstrating DNA methylation as the mechanism. Silencing is maternally inherited, suggesting imprinting. Transcription analysis in patient muscle, fibroblasts, and lymphoblastoid cells; segregation analysis; 5-aza-deoxycytidine demethylation experiment American journal of human genetics Medium 17033962
2021 AKAP18δ anchors and directly regulates CaMKIIδ activity at RYR through two distinct regions: an N-terminal region inhibits CaMKIIδ (sharing homology with a CaMKII inhibitor peptide), while the C-terminal region activates CaMKIIδ by lowering Ca2+ threshold and inducing CaM trapping; AKAP18δ-C facilitates faster Ca2+ release through RYR. Peptide arrays; co-immunoprecipitation; pull-downs; FRET-based CaMKII activity assays; SR vesicle Ca2+ imaging; proximity ligation; surface plasmon resonance Circulation research Medium 34814703
2020 Pathogenic RYR1 variants in muscle biopsies from individuals with RYR1-related myopathies cause pathologic SR calcium leak and increased calcium-activated protease activity; ex vivo treatment with S107 (a Rycal RyR-stabilizing molecule) normalized both the leak and protease activity. Variant pathogenicity can be predicted by 3D co-localization on the cryo-EM RyR1 structure. Ex vivo skeletal muscle biopsy biochemical assays; S107 pharmacological treatment; cryo-EM structure mapping of variants Acta neuropathologica Medium 32236737
2021 A single session of sprint interval training triggers RyR1 protein oxidation and nitrosylation leading to calstabin1 dissociation in human muscle and in vitro models; this acute Ca2+ leak increases mitochondrial Ca2+ uptake, decreases pyruvate dehydrogenase phosphorylation, and enhances NADH-linked mitochondrial respiratory capacity. Countering Ca2+ leak or preventing mitochondrial Ca2+ uptake blunts these adaptations. Human muscle biopsies; mouse myotube and fiber Ca2+ imaging; proteomics; pharmacological Ca2+ leak inhibition; mitochondrial respiration assays Nature communications Medium 34893614
2015 CUG-BP1 directly mediates aberrant alternative splicing of RyR1 ASI (exon 70) in skeletal muscle atrophy: gain- and loss-of-function of CUG-BP1 in vivo altered RyR1 ASI splicing pattern, affected Ca2+ release activity in single myofibers, and CUG-BP1 silencing significantly reduced the extent of atrophy. In vivo gain/loss-of-function experiments; Ca2+ imaging in single myofibers; gene silencing Scientific reports Medium 26531141
2009 In vitro contracture test (IVCT) caffeine threshold and tension values correlate with each other and with MH/CCD phenotype severity across 504 individuals from 204 MH families; the specific RYR1 variant was a significant determinant of the severity of each laboratory phenotype (P<0.0001). In vitro contracture test (pharmacological muscle contracture); genotype-phenotype correlation in large clinical cohort British journal of anaesthesia Medium 19648156
2005 Heterozygous expression of the Y522S RyR1 mutation in mice produces MH susceptibility with enhanced sensitivity to activation by temperature, caffeine, and voltage; homozygous expression is lethal perinatally. The mutation does not cause uncompensated SR Ca2+ store depletion at rest but specifically increases RyR1 channel activation sensitivity. RyR1 Y522S knock-in mouse model; in vitro contracture tests; single-channel electrophysiology; Ca2+ imaging FASEB journal High 16284304
2019 In a recessive RYR1-RM mouse model (Ryr1TM/Indel), RYR1 protein levels are reduced to 20% of normal (despite only 50% reduction in transcript), accompanied by significantly reduced electrically evoked Ca2+ release and force production, and decreased triad number, demonstrating that RyR1 deficiency per se causes severely impaired EC coupling. CRISPR/Cas9 knock-in mouse; biochemical quantification; Ca2+ imaging in muscle fibers; force production assays; histopathology Human molecular genetics High 31107960
2020 Tamoxifen-induced muscle-specific deletion of RYR1 in adult mice produces a 50% reduction in RyR1 protein, progressive muscle weakness and atrophy, reduced Ca2+ release amplitude proportional to protein reduction, abnormal mitochondria distribution, and membrane remodeling, demonstrating that RyR1 reduction alone is sufficient to recapitulate Central Core Disease features. Inducible muscle-specific Cre/lox RYR1 deletion mouse; Ca2+ flux measurements in isolated fibers; histopathology; protein quantification Acta neuropathologica communications High 33176865
2018 In T cells, RYR1 forms preformed clusters with ORAI1 and STIM1 in subplasmalemmal microdomains; upon TCR stimulation, NAADP-evoked Ca2+ release through RYR1 cooperates with ORAI1/STIM to rapidly increase Ca2+ microdomains within the first second of activation, initiating spread of Ca2+ signals and full T cell activation. Super-resolution microscopy; co-immunoprecipitation; FRET; live-cell Ca2+ microdomain imaging; RYR1 siRNA knockdown Science signaling Medium 30563862
2016 Gain-of-function RYR1 mutations (particularly Y522S) lead to higher frequency of subplasmalemmal Ca2+ sparks in vascular smooth muscle cells, producing more negative resting membrane potential and prolonged bleeding times; treatment with dantrolene reversed both Ca2+ sparks and the bleeding phenotype in mice and one patient. RYR1 Y522S knock-in mouse; primary vascular smooth muscle cell Ca2+ spark imaging; bleeding time assay; dantrolene pharmacological rescue Science signaling Medium 27382027
2020 In RYR1 Y524S (YS) knock-in mice, adaptive thermogenesis from brown adipose tissue (BAT) exacerbates the lethal heat response; YS mice have increased BAT thermogenic capacity; elevated blood lactate (from Ca2+-driven muscle metabolism) promotes brown adipogenesis, establishing a mechanism linking RYR1 Ca2+ dysregulation to systemic thermogenic amplification. YS knock-in mouse; BAT thermogenesis measurements; blood lactate assays; brown adipogenesis cell culture experiments Nature communications Medium 33037202
2006 In myotonic dystrophy, CUG-BP1 drives preferential expression of the juvenile RyR1 ASI(-) isoform (lacking alternatively spliced insert, exon 70) in adults; ASI(-) RyR1 is less active than adult ASI(+) isoform. Mutations in RyR regulators (e.g., calsequestrin) disrupt protein-protein interactions within the RyR complex, altering Ca2+ homeostasis. Isoform expression analysis; functional channel activity comparison; domain peptide competition assays Journal of muscle research and cell motility Low 16909197
2009 Functional assays in immortalized B-lymphoblastoid cells expressing RYR1 variants showed that N-terminal and central region variants (p.Arg530His, p.Arg2163Pro, p.Asn2342Ser, p.Glu2371Gly, p.Arg2454His) cause hyperactivation of RyR1 (increased acidification rate in response to 4-CmC), while p.Cys4664Arg causes a leaky channel and depletion of intracellular Ca2+ stores. 4-CmC stimulation; extracellular acidification rate measurement in lymphoblastoid cell lines Human mutation Medium 19191333
2017 HEK293 cell functional assays demonstrated that RyR1 channels containing variants p.R2336H, p.R2355W, p.E3104K, p.G3990V, and p.V4849I show increased caffeine sensitivity (gain-of-function) compared with wild-type RyR1, supporting their pathogenicity in MH; p.D3986E did not differ from wild type. Mutagenesis; expression in HEK293 cells; caffeine-induced Ca2+ release assay with fluorescent Ca2+ indicator British journal of anaesthesia Medium 28403410
2012 Oxidative stress (H2O2) in cardiomyocytes markedly reduces CaM-RyR2 binding affinity, causes RyR2 domain unzipping (measured by F-DPc10 biosensor), and increases Ca2+ sparks/waves; dantrolene reverses domain unzipping, restores CaM-RyR2 affinity, and reduces Ca2+ leak, without affecting RyR2 oxidation levels. FKBP12.6-RyR2 binding is not affected by H2O2. Fluorescent CaM and FKBP12.6 biosensors; domain-peptide biosensor (F-DPc10); Ca2+ spark/wave imaging in cardiomyocytes Journal of molecular and cellular cardiology Medium 26092277
2018 Single-channel recordings of RyR1 at microsecond resolution using CMOS-integrated lipid bilayers revealed multiple closed states not evident with conventional recordings, suggesting an additional Ca2+ binding site distinct from the activation site; closed-state flicker events as fast as 35 ns were detected. CMOS-integrated suspended lipid bilayer single-channel recording at >500 kHz bandwidth Proceedings of the National Academy of Sciences of the United States of America Medium 29432144
1997 In C. elegans, the ryanodine receptor gene ryr-1 (unc-68) encodes a 5071 aa protein expressed in body-wall and pharyngeal muscles; a Ser1444Asn substitution at a putative PKC phosphorylation site causes ketamine-dependent convulsions followed by paralysis, and unc-68(e540) contains a splice acceptor mutation creating a premature stop codon. Full-length ryr-1 injection rescued unc-68(e540), confirming identity. Mutant isolation; gene cloning; promoter/lacZ expression; rescue by transgene injection Journal of molecular biology Medium 9135117

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Mutations in RYR1 in malignant hyperthermia and central core disease. Human mutation 381 16917943
2016 Structural Basis for Gating and Activation of RyR1. Cell 321 27662087
2008 RyR1 S-nitrosylation underlies environmental heat stroke and sudden death in Y522S RyR1 knockin mice. Cell 292 18394989
2020 Therapy for Stage IV Non-Small-Cell Lung Cancer Without Driver Alterations: ASCO and OH (CCO) Joint Guideline Update. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 262 31990617
2021 Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations: ASCO and OH (CCO) Joint Guideline Update. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 261 33591844
2008 Roles of IP3R and RyR Ca2+ channels in endoplasmic reticulum stress and beta-cell death. Diabetes 191 19033399
2013 Mutations in RYR1 are a common cause of exertional myalgia and rhabdomyolysis. Neuromuscular disorders : NMD 163 23628358
2005 Heat- and anesthesia-induced malignant hyperthermia in an RyR1 knock-in mouse. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 156 16284304
2009 Coordinated movement of cytoplasmic and transmembrane domains of RyR1 upon gating. PLoS biology 145 19402748
2007 Molecular mechanisms and phenotypic variation in RYR1-related congenital myopathies. Brain : a journal of neurology 142 17483490
2015 RYR1-related myopathies: a wide spectrum of phenotypes throughout life. European journal of neurology 119 25960145
2011 Amyloid β-peptide oligomers stimulate RyR-mediated Ca2+ release inducing mitochondrial fragmentation in hippocampal neurons and prevent RyR-mediated dendritic spine remodeling produced by BDNF. Antioxidants & redox signaling 119 20712397
1998 Identification of novel mutations in the ryanodine-receptor gene (RYR1) in malignant hyperthermia: genotype-phenotype correlation. American journal of human genetics 107 9497245
2022 Use of Adjuvant Bisphosphonates and Other Bone-Modifying Agents in Breast Cancer: ASCO-OH (CCO) Guideline Update. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 98 35041467
2013 Genotype-phenotype correlations in recessive RYR1-related myopathies. Orphanet journal of rare diseases 98 23919265
2012 Oxidative stress and successful antioxidant treatment in models of RYR1-related myopathy. Brain : a journal of neurology 97 22418739
2015 Oxidation of ryanodine receptor (RyR) and calmodulin enhance Ca release and pathologically alter, RyR structure and calmodulin affinity. Journal of molecular and cellular cardiology 96 26092277
2009 Genetic variation in RYR1 and malignant hyperthermia phenotypes. British journal of anaesthesia 89 19648156
2015 Golden age of RyR and GABA-R diamide and isoxazoline insecticides: common genesis, serendipity, surprises, selectivity, and safety. Chemical research in toxicology 86 25688713
2006 Epigenetic allele silencing unveils recessive RYR1 mutations in core myopathies. American journal of human genetics 85 17033962
2017 Oxidative stress induces stem cell proliferation via TRPA1/RyR-mediated Ca2+ signaling in the Drosophila midgut. eLife 80 28561738
2006 Functional coupling between TRPC3 and RyR1 regulates the expressions of key triadic proteins. The Journal of biological chemistry 79 16484216
2005 Structural characterization of the RyR1-FKBP12 interaction. Journal of molecular biology 78 16405911
1994 Detection of a novel RYR1 mutation in four malignant hyperthermia pedigrees. Human molecular genetics 74 7849712
1995 Discordance, in a malignant hyperthermia pedigree, between in vitro contracture-test phenotypes and haplotypes for the MHS1 region on chromosome 19q12-13.2, comprising the C1840T transition in the RYR1 gene. American journal of human genetics 67 7762556
2018 ORAI1, STIM1/2, and RYR1 shape subsecond Ca2+ microdomains upon T cell activation. Science signaling 66 30563862
2016 Review of RyR1 pathway and associated pathomechanisms. Acta neuropathologica communications 65 27855725
2016 Critical Role of Intracellular RyR1 Calcium Release Channels in Skeletal Muscle Function and Disease. Frontiers in physiology 62 26793121
2015 Next-generation Sequencing of RYR1 and CACNA1S in Malignant Hyperthermia and Exertional Heat Illness. Anesthesiology 61 25658027
2015 Essential Role of Calmodulin in RyR Inhibition by Dantrolene. Molecular pharmacology 61 25920678
2003 FKBP12 binding to RyR1 modulates excitation-contraction coupling in mouse skeletal myotubes. The Journal of biological chemistry 61 12704193
2017 Aging Impairs Hippocampal- Dependent Recognition Memory and LTP and Prevents the Associated RyR Up-regulation. Frontiers in aging neuroscience 60 28484388
2007 Congenital neuromuscular disease with uniform type 1 fiber and RYR1 mutation. Neurology 57 17538032
2018 Regulation of the RyR channel gating by Ca2+ and Mg2. Biophysical reviews 55 29926426
2004 Redox regulation of RyR-mediated Ca2+ release in muscle and neurons. Biological research 54 15709680
2020 Intracellular calcium leak as a therapeutic target for RYR1-related myopathies. Acta neuropathologica 48 32236737
1997 An abnormal ketamine response in mutants defective in the ryanodine receptor gene ryr-1 (unc-68) of Caenorhabditis elegans. Journal of molecular biology 48 9135117
2016 A Feed-Forward Mechanism Involving the NOX Complex and RyR-Mediated Ca2+ Release During Axonal Specification. The Journal of neuroscience : the official journal of the Society for Neuroscience 47 27798190
2002 Mutation screening in the ryanodine receptor 1 gene (RYR1) in patients susceptible to malignant hyperthermia who show definite IVCT results: identification of three novel mutations. Acta anaesthesiologica Scandinavica 45 12059893
2021 AKAP18δ Anchors and Regulates CaMKII Activity at Phospholamban-SERCA2 and RYR. Circulation research 43 34814703
2013 RyR1 deficiency in congenital myopathies disrupts excitation-contraction coupling. Human mutation 43 23553787
2010 RyR1-mediated Ca2+ leak and Ca2+ entry determine resting intracellular Ca2+ in skeletal myotubes. The Journal of biological chemistry 43 20207743
2009 CLIC2-RyR1 interaction and structural characterization by cryo-electron microscopy. Journal of molecular biology 43 19356589
2012 Hierarchical accumulation of RyR post-translational modifications drives disease progression in dystrophic cardiomyopathy. Cardiovascular research 41 23263329
2018 Atypical periodic paralysis and myalgia: A novel RYR1 phenotype. Neurology 39 29298851
2018 Correlation of phenotype with genotype and protein structure in RYR1-related disorders. Journal of neurology 39 30155738
2009 Polyol pathway impairs the function of SERCA and RyR in ischemic-reperfused rat hearts by increasing oxidative modifications of these proteins. Journal of molecular and cellular cardiology 39 20025885
2019 'Dusty core disease' (DuCD): expanding morphological spectrum of RYR1 recessive myopathies. Acta neuropathologica communications 38 30611313
2020 Structure of RyR1 in native membranes. EMBO reports 37 32147968
2017 Common and variable clinical, histological, and imaging findings of recessive RYR1-related centronuclear myopathy patients. Neuromuscular disorders : NMD 37 28818389
2021 Acute RyR1 Ca2+ leak enhances NADH-linked mitochondrial respiratory capacity. Nature communications 36 34893614
2003 RyR1/RyR3 chimeras reveal that multiple domains of RyR1 are involved in skeletal-type E-C coupling. Biophysical journal 36 12668474
2002 Morphology and molecular composition of sarcoplasmic reticulum surface junctions in the absence of DHPR and RyR in mouse skeletal muscle. Biophysical journal 35 12023238
2000 Selectively suppressed Ca2+-induced Ca2+ release activity of alpha-ryanodine receptor (alpha-RyR) in frog skeletal muscle sarcoplasmic reticulum: potential distinct modes in Ca2+ release between alpha- and beta-RyR. The Journal of biological chemistry 35 11054412
1993 Exclusion of malignant hyperthermia susceptibility (MHS) from a putative MHS2 locus on chromosome 17q and of the alpha 1, beta 1, and gamma subunits of the dihydropyridine receptor calcium channel as candidates for the molecular defect. Human molecular genetics 35 8395939
2016 An RYR1 mutation associated with malignant hyperthermia is also associated with bleeding abnormalities. Science signaling 34 27382027
2011 Dominant and recessive RYR1 mutations in adults with core lesions and mild muscle symptoms. Muscle & nerve 32 21674524
2020 Nox4 - RyR1 - Nox2: Regulators of micro-domain signaling in skeletal muscle. Redox biology 31 32506037
2011 Novel missense mutations and unexpected multiple changes of RYR1 gene in 75 malignant hyperthermia families. Clinical genetics 31 20681998
1992 High-resolution physical mapping of four microsatellite repeat markers near the RYR1 locus on chromosome 19q13.1 and apparent exclusion of the MHS locus from this region in two malignant hyperthermia susceptible families. Genomics 28 1427902
2022 Molecular mechanism of the severe MH/CCD mutation Y522S in skeletal ryanodine receptor (RyR1) by cryo-EM. Proceedings of the National Academy of Sciences of the United States of America 27 35867837
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
2019 Mouse model of severe recessive RYR1-related myopathy. Human molecular genetics 27 31107960
2006 Novel regulators of RyR Ca2+ release channels: insight into molecular changes in genetically-linked myopathies. Journal of muscle research and cell motility 27 16909197
2017 Intracellular calcium release through IP3R or RyR contributes to secondary axonal degeneration. Neurobiology of disease 25 28709993
2006 RyR isoforms and fibre type-specific expression of proteins controlling intracellular calcium concentration in skeletal muscles. Journal of muscle research and cell motility 25 16874451
2021 Structural and functional interactions between the Ca2+-, ATP-, and caffeine-binding sites of skeletal muscle ryanodine receptor (RyR1). The Journal of biological chemistry 24 34352272
2017 Importance of Altered Levels of SERCA, IP3R, and RyR in Vascular Smooth Muscle Cell. Biophysical journal 24 28122214
2016 Structures of the colossal RyR1 calcium release channel. Current opinion in structural biology 24 27687475
2009 Functional characterization of ryanodine receptor (RYR1) sequence variants using a metabolic assay in immortalized B-lymphocytes. Human mutation 24 19191333
2021 Neuronal junctophilins recruit specific CaV and RyR isoforms to ER-PM junctions and functionally alter CaV2.1 and CaV2.2. eLife 23 33769283
2020 Adaptive thermogenesis enhances the life-threatening response to heat in mice with an Ryr1 mutation. Nature communications 23 33037202
2019 Lead exposure-induced cognitive impairment through RyR-modulating intracellular calcium signaling in aged rats. Toxicology 23 30905827
2007 Time course of changes in the expression of DHPR, RyR(2), and SERCA2 after myocardial infarction in the rat left ventricle. Molecular and cellular biochemistry 23 17516033
2022 Ryanodine receptor 1 (RYR1) mutations in two patients with tubular aggregate myopathy. The European journal of neuroscience 22 35666680
2022 Neuromuscular symptoms in patients with RYR1-related malignant hyperthermia and rhabdomyolysis. Brain communications 22 36751502
2021 Genome-wide identification, characterization and expression analysis of the carotenoid cleavage oxygenase (CCO) gene family in Saccharum. Plant physiology and biochemistry : PPB 22 33691250
2020 Identification of drug modifiers for RYR1-related myopathy using a multi-species discovery pipeline. eLife 22 32223895
2010 Influence of different ammonium, lactate and glutamine concentrations on CCO cell growth. Cytotechnology 22 21069459
2012 Proteins within the intracellular calcium store determine cardiac RyR channel activity and cardiac output. Clinical and experimental pharmacology & physiology 21 22524859
2019 Homozygous/compound heterozygote RYR1 gene variants: Expanding the clinical spectrum. American journal of medical genetics. Part A 19 30652412
2024 Genome-wide identification and in-silico expression analysis of CCO gene family in sunflower (Helianthus annnus) against abiotic stress. Plant molecular biology 18 38568355
2023 RyR-mediated calcium release in hippocampal health and disease. Trends in molecular medicine 18 37957056
2014 Adaptation and cultivation of permanent fish cell line CCO in serum-free medium and influence of protein hydrolysates on growth performance. Cytotechnology 18 24993608
2023 Anthranilic Diamides Containing Monofluoroalkene Amide Linkers as Potential Insect RyR Activators: Design, Synthesis, Bio-evaluation, and Computational Study. Journal of agricultural and food chemistry 17 36735252
2023 Allosteric modulation of ryanodine receptor RyR1 by nucleotide derivatives. Structure (London, England : 1993) 17 37192614
2022 RYR1-Related Rhabdomyolysis: A Spectrum of Hypermetabolic States Due to Ryanodine Receptor Dysfunction. Current pharmaceutical design 17 34348614
2020 In vivo RyR1 reduction in muscle triggers a core-like myopathy. Acta neuropathologica communications 17 33176865
2019 Targeting RyR Activity Boosts Antisense Exon 44 and 45 Skipping in Human DMD Skeletal or Cardiac Muscle Culture Models. Molecular therapy. Nucleic acids 17 31678734
2017 Assessing the pathogenicity of RYR1 variants in malignant hyperthermia. British journal of anaesthesia 17 28403410
2011 Identification of novel ryanodine receptor 1 (RyR1) protein interaction with calcium homeostasis endoplasmic reticulum protein (CHERP). The Journal of biological chemistry 17 21454501
2023 Cysteines 1078 and 2991 cross-linking plays a critical role in redox regulation of cardiac ryanodine receptor (RyR). Nature communications 16 37495581
2021 The effect of statins on RyR and RyR-associated disease. Journal of applied physiology (Bethesda, Md. : 1985) 16 34166122
2019 An unusual ryanodine receptor 1 (RYR1) phenotype: Mild calf-predominant myopathy. Neurology 16 30842289
2018 Single-channel recordings of RyR1 at microsecond resolution in CMOS-suspended membranes. Proceedings of the National Academy of Sciences of the United States of America 16 29432144
2006 Ryanodine receptor type 1 (RyR1) possessing malignant hyperthermia mutation R615C exhibits heightened sensitivity to dysregulation by non-coplanar 2,2',3,5',6-pentachlorobiphenyl (PCB 95). Neurotoxicology 16 17023049
2015 CUG-BP1 regulates RyR1 ASI alternative splicing in skeletal muscle atrophy. Scientific reports 15 26531141
2023 Successful Correction by Prime Editing of a Mutation in the RYR1 Gene Responsible for a Myopathy. Cells 14 38201236
2022 InsP3R-RyR Ca2+ channel crosstalk facilitates arrhythmias in the failing human ventricle. Basic research in cardiology 14 36378362
2017 RYR1 causing distal myopathy. Molecular genetics & genomic medicine 14 29178655

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