ryanodine receptor calcium release channel


Summary: A tetrameric calcium release channel in the SARCOPLASMIC RETICULUM membrane of SMOOTH MUSCLE CELLS, acting oppositely to SARCOPLASMIC RETICULUM CALCIUM-TRANSPORTING ATPASES. It is important in skeletal and cardiac excitation-contraction coupling and studied by using RYANODINE. Abnormalities are implicated in CARDIAC ARRHYTHMIAS and MUSCULAR DISEASES.

Top Publications

  1. Böhm J, Leshinsky Silver E, Vassilopoulos S, Le Gras S, Lerman Sagie T, Ginzberg M, et al. Samaritan myopathy, an ultimately benign congenital myopathy, is caused by a RYR1 mutation. Acta Neuropathol. 2012;124:575-81 pubmed publisher
    ..Our results suggest an aberrant ECC as the primary cause of this disease, and broaden the clinical consequences of RYR1 defects. ..
  2. Itzhaki I, Maizels L, Huber I, Gepstein A, Arbel G, Caspi O, et al. Modeling of catecholaminergic polymorphic ventricular tachycardia with patient-specific human-induced pluripotent stem cells. J Am Coll Cardiol. 2012;60:990-1000 pubmed publisher
    ..As such, it represents a promising paradigm to study disease mechanisms, optimize patient care, and aid in the development of new therapies. ..
  3. Sun L, Cui L, Rui C, Yan X, Yang D, Yuan H. Modulation of the expression of ryanodine receptor mRNA from Plutella xylostella as a result of diamide insecticide application. Gene. 2012;511:265-73 pubmed publisher
    ..However, the relative expression levels of the RyRs from larvae were dependent on the insecticide concentration and gradually increased with increasing insecticide concentrations...
  4. Liu X, Betzenhauser M, Reiken S, Meli A, Xie W, Chen B, et al. Role of leaky neuronal ryanodine receptors in stress-induced cognitive dysfunction. Cell. 2012;150:1055-67 pubmed publisher
    ..Thus, neuronal RyR2 remodeling contributes to stress-induced cognitive dysfunction. Leaky RyR2 could be a therapeutic target for treatment of stress-induced cognitive dysfunction. ..
  5. Oulès B, Del Prete D, Greco B, Zhang X, Lauritzen I, Sevalle J, et al. Ryanodine receptor blockade reduces amyloid-? load and memory impairments in Tg2576 mouse model of Alzheimer disease. J Neurosci. 2012;32:11820-34 pubmed
  6. Respress J, van Oort R, Li N, Rolim N, Dixit S, Dealmeida A, et al. Role of RyR2 phosphorylation at S2814 during heart failure progression. Circ Res. 2012;110:1474-83 pubmed publisher
    ..However, the importance of CaMKII phosphorylation of ryanodine receptors (RyR2) in HF development and associated diastolic sarcoplasmic reticulum Ca(2+) leak is unclear...
  7. Wang J, Li Y, Han Z, Zhu Y, Xie Z, Wang J, et al. Molecular characterization of a ryanodine receptor gene in the rice leaffolder, Cnaphalocrocis medinalis (Guenée). PLoS ONE. 2012;7:e36623 pubmed publisher
    ..Our results imply that alternative splicing may be a major means of generating functional diversity in C. medinalis RyR channel...
  8. Guo T, Gillespie D, Fill M. Ryanodine receptor current amplitude controls Ca2+ sparks in cardiac muscle. Circ Res. 2012;111:28-36 pubmed publisher
    ..The inherent positive feedback of CICR is normally well-controlled. Understanding this control mechanism is a priority because its malfunction has life-threatening consequences...
  9. Chakroborty S, Kim J, Schneider C, Jacobson C, Molgo J, Stutzmann G. Early presynaptic and postsynaptic calcium signaling abnormalities mask underlying synaptic depression in presymptomatic Alzheimer's disease mice. J Neurosci. 2012;32:8341-53 pubmed publisher
    ..Because AD is increasingly recognized as a "synaptic disease," calcium-mediated signaling alterations may serve as a proximal trigger for the synaptic degradation driving the cognitive loss in AD. ..

More Information


  1. Yuchi Z, Lau K, Van Petegem F. Disease mutations in the ryanodine receptor central region: crystal structures of a phosphorylation hot spot domain. Structure. 2012;20:1201-11 pubmed publisher
    ..Docking into cryo-electron microscopy maps suggests a putative location in the clamp region, implying that mutations and phosphorylation may affect the allosteric motions within this area. ..
  2. Wang L, Myles R, De Jesus N, Ohlendorf A, Bers D, Ripplinger C. Optical mapping of sarcoplasmic reticulum Ca2+ in the intact heart: ryanodine receptor refractoriness during alternans and fibrillation. Circ Res. 2014;114:1410-21 pubmed publisher
    ..Sarcoplasmic reticulum (SR) Ca(2+) cycling is key to normal excitation-contraction coupling but may also contribute to pathological cardiac alternans and arrhythmia...
  3. Boncompagni S, Thomas M, Lopez J, Allen P, Yuan Q, Kranias E, et al. Triadin/Junctin double null mouse reveals a differential role for Triadin and Junctin in anchoring CASQ to the jSR and regulating Ca(2+) homeostasis. PLoS ONE. 2012;7:e39962 pubmed publisher
    ..These data suggest that in skeletal muscle the disruption of Tdn/CASQ link has a more profound effect on jSR architecture and myoplasmic Ca(2+) regulation than Jct/CASQ association...
  4. Porta M, Diaz Sylvester P, Neumann J, Escobar A, Fleischer S, Copello J. Coupled gating of skeletal muscle ryanodine receptors is modulated by Ca2+, Mg2+, and ATP. Am J Physiol Cell Physiol. 2012;303:C682-97 pubmed publisher
  5. Tencerová B, Zahradnikova A, Gaburjakova J, Gaburjakova M. Luminal Ca2+ controls activation of the cardiac ryanodine receptor by ATP. J Gen Physiol. 2012;140:93-108 pubmed publisher
  6. Yarotskyy V, Dirksen R. Temperature and RyR1 regulate the activation rate of store-operated Ca²+ entry current in myotubes. Biophys J. 2012;103:202-11 pubmed publisher
  7. Janiek R, Polakova E, Pavelkova J, Zahradnik I, Zahradnikova A. Calcium spike variability in cardiac myocytes results from activation of small cohorts of ryanodine receptor 2 channels. J Physiol. 2012;590:5091-106 pubmed publisher
    ..We conclude that the variability of the elementary calcium release events supports a calcium signalling mechanism that arises from stochastics of RyR2 gating and from inactivation of local origin. ..
  8. Sharma P, Ishiyama N, Nair U, Li W, Dong A, Miyake T, et al. Structural determination of the phosphorylation domain of the ryanodine receptor. FEBS J. 2012;279:3952-64 pubmed publisher
  9. Laver D, Kong C, Imtiaz M, Cannell M. Termination of calcium-induced calcium release by induction decay: an emergent property of stochastic channel gating and molecular scale architecture. J Mol Cell Cardiol. 2013;54:98-100 pubmed publisher
  10. Zissimopoulos S, Viero C, Seidel M, Cumbes B, White J, Cheung I, et al. N-terminus oligomerization regulates the function of cardiac ryanodine receptors. J Cell Sci. 2013;126:5042-51 pubmed publisher
    ..Our findings suggest that the N-terminus interactions mediating tetramer assembly are involved in RyR channel closure, identifying a crucial role for this structural association in the dynamic regulation of intracellular Ca(2+) release...
  11. Gillespie D, Fill M. Pernicious attrition and inter-RyR2 CICR current control in cardiac muscle. J Mol Cell Cardiol. 2013;58:53-8 pubmed publisher
    ..Moreover, we aggregate RyR data into a working scheme of inter-RyR CICR current control of sparks and a potential inter-RyR CICR termination mechanism that we call pernicious attrition...
  12. Tian X, Liu Y, Liu Y, Wang R, Wagenknecht T, Liu Z, et al. Ligand-dependent conformational changes in the clamp region of the cardiac ryanodine receptor. J Biol Chem. 2013;288:4066-75 pubmed publisher
    ..Our data demonstrate that conformational changes in the clamp region of RyR are ligand-dependent and suggest the existence of multiple ligand dependent RyR activation mechanisms associated with distinct conformational changes. ..
  13. Raina S, Tsai J, Samso M, Fessenden J. FRET-based localization of fluorescent protein insertions within the ryanodine receptor type 1. PLoS ONE. 2012;7:e38594 pubmed publisher
    ..More accurate point-to-point distance information may be obtained using complementary orthogonal labeling systems that rely on fluorescent probes that bind directly to amino acid side chains. ..
  14. Venetucci L, Denegri M, Napolitano C, Priori S. Inherited calcium channelopathies in the pathophysiology of arrhythmias. Nat Rev Cardiol. 2012;9:561-75 pubmed publisher
    ..The identification of mutations associated with 'calcium-handling diseases' has led to an improved understanding of the role of calcium in cardiac physiology. ..
  15. Dulhunty A, Wium E, Li L, Hanna A, Mirza S, Talukder S, et al. Proteins within the intracellular calcium store determine cardiac RyR channel activity and cardiac output. Clin Exp Pharmacol Physiol. 2012;39:477-84 pubmed publisher
    ..Herein, we discuss known interactions between the RyR, triadin, junctin and CSQ with emphasis on the cardiac isoforms of the proteins. Where there is little known about the cardiac isoforms, we discuss evidence from skeletal isoforms...
  16. Santiago D, Rios E, Shannon T. Isoproterenol increases the fraction of spark-dependent RyR-mediated leak in ventricular myocytes. Biophys J. 2013;104:976-85 pubmed publisher
    ..Working together, the increased Ca(2+) sensitivity and the greater spark width found during isoproterenol treatment may increase the probability of Ca(2+) wave generation...
  17. Ramachandran S, Chakraborty A, Xu L, Mei Y, Samso M, Dokholyan N, et al. Structural determinants of skeletal muscle ryanodine receptor gating. J Biol Chem. 2013;288:6154-65 pubmed publisher
    ..Our integrated computational and experimental approach significantly advances the understanding of the structure and function of an unusually large ion channel. ..
  18. Marx S, Marks A. Dysfunctional ryanodine receptors in the heart: new insights into complex cardiovascular diseases. J Mol Cell Cardiol. 2013;58:225-31 pubmed publisher
    ..Correcting these defects using either genetic manipulation (knock-in) in mice, or specific and novel small molecules ameliorates the RyR2 dysfunction, reducing the progression to heart failure and the incidence of arrhythmias. ..
  19. Van Petegem F. Ryanodine receptors: structure and function. J Biol Chem. 2012;287:31624-32 pubmed publisher
    ..With the advent of high-resolution structures of individual domains, many of these can be mapped onto the three-dimensional structure. ..
  20. Mason S, Viero C, Euden J, Bannister M, West D, Chen S, et al. The contribution of hydrophobic residues in the pore-forming region of the ryanodine receptor channel to block by large tetraalkylammonium cations and Shaker B inactivation peptides. J Gen Physiol. 2012;140:325-39 pubmed publisher
  21. Kujala K, Paavola J, Lahti A, Larsson K, Pekkanen Mattila M, Viitasalo M, et al. Cell model of catecholaminergic polymorphic ventricular tachycardia reveals early and delayed afterdepolarizations. PLoS ONE. 2012;7:e44660 pubmed publisher
    ..This cell model shows aberrant Ca(2+) cycling characteristic of CPVT and in addition to DADs it displays EADs. This cell model for CPVT provides a platform to study basic pathology, to screen drugs, and to optimize drug therapy. ..
  22. Klein A, Jungbluth H, Clement E, Lillis S, Abbs S, Munot P, et al. Muscle magnetic resonance imaging in congenital myopathies due to ryanodine receptor type 1 gene mutations. Arch Neurol. 2011;68:1171-9 pubmed publisher
    ..Our results suggest that muscle MRI is a powerful predictor of RYR1 involvement in patients with a congenital myopathy, especially if they carry a dominant mutation or recessive mutations without ophthalmoparesis. ..
  23. Vega A, Ramos Mondragón R, Calderón Rivera A, Zarain Herzberg A, Avila G. Calcitonin gene-related peptide restores disrupted excitation-contraction coupling in myotubes expressing central core disease mutations in RyR1. J Physiol. 2011;589:4649-69 pubmed publisher
    ..Taken together, our data show that in the C2C12 model system, changes in excitation-contraction coupling induced by the expression of RyR1 channels bearing CCD mutations Y523S or I4897T can be reversed by CGRP. ..
  24. Lanner J, Georgiou D, Joshi A, Hamilton S. Ryanodine receptors: structure, expression, molecular details, and function in calcium release. Cold Spring Harb Perspect Biol. 2010;2:a003996 pubmed publisher
    ..This chapter examines the current concepts of the structure, function and regulation of RyRs and assesses the current state of understanding of their roles in associated disorders. ..
  25. Wei L, Salahura G, Boncompagni S, Kasischke K, Protasi F, Sheu S, et al. Mitochondrial superoxide flashes: metabolic biomarkers of skeletal muscle activity and disease. FASEB J. 2011;25:3068-78 pubmed publisher
    ..Together, these results demonstrate that mSOF activity is a highly sensitive biomarker of mitochondrial respiration and the cellular metabolic state of muscle during physiological activity and pathological oxidative stress ..
  26. Xu X, Yano M, Uchinoumi H, Hino A, Suetomi T, Ono M, et al. Defective calmodulin binding to the cardiac ryanodine receptor plays a key role in CPVT-associated channel dysfunction. Biochem Biophys Res Commun. 2010;394:660-6 pubmed publisher
    ..In conclusion, CPVT mutation causes defective inter-domain interaction, significant reduction in the ability of CaM binding to the RyR2, spontaneous Ca(2+) leak, and then lethal arrhythmia. ..
  27. Bannister R, Esteve E, Eltit J, Pessah I, Allen P, Lopez J, et al. A malignant hyperthermia-inducing mutation in RYR1 (R163C): consequent alterations in the functional properties of DHPR channels. J Gen Physiol. 2010;135:629-40 pubmed publisher
    ..Our present results indicate that mutations in RYR1 can alter DHPR activity and raise the possibility that this altered DHPR function may contribute to MH episodes...
  28. Sarma S, Li N, van Oort R, Reynolds C, Skapura D, Wehrens X. Genetic inhibition of PKA phosphorylation of RyR2 prevents dystrophic cardiomyopathy. Proc Natl Acad Sci U S A. 2010;107:13165-70 pubmed publisher
  29. Gant J, Chen K, Norris C, Kadish I, Thibault O, Blalock E, et al. Disrupting function of FK506-binding protein 1b/12.6 induces the Ca²+-dysregulation aging phenotype in hippocampal neurons. J Neurosci. 2011;31:1693-703 pubmed publisher
    ..Thus, disruption of FKBP1b recapitulated much of the Ca(2+)-dysregulation aging phenotype in young rat hippocampus, supporting a novel hypothesis that declining FKBP function plays a major role in unhealthy brain aging. ..
  30. Gonzalez D, Treuer A, Castellanos J, Dulce R, Hare J. Impaired S-nitrosylation of the ryanodine receptor caused by xanthine oxidase activity contributes to calcium leak in heart failure. J Biol Chem. 2010;285:28938-45 pubmed publisher
    ..The reversal of this phenotype by inhibition of xanthine oxidase has important pathophysiologic and therapeutic implications. ..
  31. Jiang J, Zhou Y, Zou J, Chen Y, Patel P, Yang J, et al. Site-specific modification of calmodulin Ca²(+) affinity tunes the skeletal muscle ryanodine receptor activation profile. Biochem J. 2010;432:89-99 pubmed publisher
    ..These results indicate further that targeting CaM's Ca²(+) affinity may be a valid strategy to tune the activation profile of CaM-regulated ion channels...
  32. Song D, Lee J, Youn H, Eom S, Kim D. Ryanodine receptor assembly: a novel systems biology approach to 3D mapping. Prog Biophys Mol Biol. 2011;105:145-61 pubmed publisher
    ..In this paper, we have attempted to establish a 3D-map for the assembly of RyRs by considering published cryo-EM data, available X-ray crystallographic information and molecular modeling methods. ..
  33. Kobayashi S, Yano M, Uchinoumi H, Suetomi T, Susa T, Ono M, et al. Dantrolene, a therapeutic agent for malignant hyperthermia, inhibits catecholaminergic polymorphic ventricular tachycardia in a RyR2(R2474S/+) knock-in mouse model. Circ J. 2010;74:2579-84 pubmed
    ..6±0.2). The increase in SpF seen in KI cardiomyocytes was attenuated by 1.0µmol/L dantrolene (SpF: 3.6±0.5, P<0.01). Dantrolene prevents CPVT, presumably by inhibiting Ca(2+) leak through the RyR2. ..
  34. Clark J, Kinnear N, Kalujnaia S, Cramb G, Fleischer S, Jeyakumar L, et al. Identification of functionally segregated sarcoplasmic reticulum calcium stores in pulmonary arterial smooth muscle. J Biol Chem. 2010;285:13542-9 pubmed publisher
    ..The other is located centrally, receives Ca(2+) via SERCA2a, and likely releases Ca(2+) via RyR3 and RyR2 to initiate vasoconstriction. ..
  35. Belevych A, Terentyev D, Terentyeva R, Ho H, Gyorke I, Bonilla I, et al. Shortened Ca2+ signaling refractoriness underlies cellular arrhythmogenesis in a postinfarction model of sudden cardiac death. Circ Res. 2012;110:569-77 pubmed publisher
  36. Yuen B, Boncompagni S, Feng W, Yang T, Lopez J, Matthaei K, et al. Mice expressing T4826I-RYR1 are viable but exhibit sex- and genotype-dependent susceptibility to malignant hyperthermia and muscle damage. FASEB J. 2012;26:1311-22 pubmed publisher
    ..These data demonstrate that an MHS mutation within the S4-S5 cytoplasmic linker of RYR1 confers genotype- and sex-dependent susceptibility to pharmacological and environmental stressors that trigger fulminant MH and promote myopathy. ..
  37. Diaz Sylvester P, Porta M, Copello J. Modulation of cardiac ryanodine receptor channels by alkaline earth cations. PLoS ONE. 2011;6:e26693 pubmed publisher
    ..In summary, RyR2 luminal and cytosolic surfaces have at least two sets of M(2+) binding sites (specific for Ca(2+) and unspecific for Ca(2+)/Mg(2+)) that dynamically modulate channel activity and gating status, depending on SR voltage...
  38. Olojo R, Hernández Ochoa E, Ikemoto N, Schneider M. Effects of conformational peptide probe DP4 on bidirectional signaling between DHPR and RyR1 calcium channels in voltage-clamped skeletal muscle fibers. Biophys J. 2011;100:2367-77 pubmed publisher
    ..However, DP4 augmented DHPR Ca²? current density without affecting its voltage-dependence. Our results demonstrate that the conformational changes induced by DP4 regulate both orthograde E-C coupling and retrograde RyR1-DHPR signaling. ..
  39. Acsai K, Antoons G, Livshitz L, Rudy Y, Sipido K. Microdomain [Ca²?] near ryanodine receptors as reported by L-type Ca²? and Na+/Ca²? exchange currents. J Physiol. 2011;589:2569-83 pubmed publisher
    ..Comparable [Ca²?]nrs at +10 mV and -20 mV suggests that, although the number of activated release sites differs at these potentials, local gradients at release sites can reach similar values. ..
  40. Tang Y, Tian X, Wang R, Fill M, Chen S. Abnormal termination of Ca2+ release is a common defect of RyR2 mutations associated with cardiomyopathies. Circ Res. 2012;110:968-77 pubmed publisher
  41. Lanner J, Georgiou D, Dagnino Acosta A, Ainbinder A, Cheng Q, Joshi A, et al. AICAR prevents heat-induced sudden death in RyR1 mutant mice independent of AMPK activation. Nat Med. 2012;18:244-51 pubmed publisher
    ..Our findings suggest that AICAR is probably effective in prophylactic treatment of humans with enhanced susceptibility to exercise- and/or heat-induced sudden death associated with RYR1 mutations. ..
  42. Prosser B, Ward C, Lederer W. X-ROS signaling: rapid mechano-chemo transduction in heart. Science. 2011;333:1440-5 pubmed publisher
    ..X-ROS signaling thus provides a mechanistic explanation for the mechanotransduction of Ca(2+) release in the heart and offers fresh therapeutic possibilities...
  43. Andersson D, Betzenhauser M, Reiken S, Meli A, Umanskaya A, Xie W, et al. Ryanodine receptor oxidation causes intracellular calcium leak and muscle weakness in aging. Cell Metab. 2011;14:196-207 pubmed publisher
    ..Taken together, these data indicate that leaky RyR1 contributes to age-related loss of muscle function...
  44. Lobo P, Kimlicka L, Tung C, Van Petegem F. The deletion of exon 3 in the cardiac ryanodine receptor is rescued by ? strand switching. Structure. 2011;19:790-8 pubmed publisher
    ..Despite the rescue, the deletion affects interfaces with other RYR2 domains. We propose that relative movement of the NTD is allosterically coupled to the pore region. ..
  45. Scriven D, Asghari P, Schulson M, Moore E. Analysis of Cav1.2 and ryanodine receptor clusters in rat ventricular myocytes. Biophys J. 2010;99:3923-9 pubmed publisher
    ..2 showed no preferential localization and were broadly distributed. These results provide a wealth of morphometric data that are essential for understanding intracellular Ca2+ regulation and modeling Ca2+ dynamics. ..
  46. Goussakov I, Chakroborty S, Stutzmann G. Generation of dendritic Ca2+ oscillations as a consequence of altered ryanodine receptor function in AD neurons. Channels (Austin). 2011;5:9-13 pubmed
    ..As the temporal entrainment of Ca(2+) signals influences many downstream cellular and synaptic functions, these abnormal oscillatory patterns may be associated with the structural and functional breakdown of synapses in AD. ..
  47. van Oort R, McCauley M, Dixit S, Pereira L, Yang Y, Respress J, et al. Ryanodine receptor phosphorylation by calcium/calmodulin-dependent protein kinase II promotes life-threatening ventricular arrhythmias in mice with heart failure. Circulation. 2010;122:2669-79 pubmed publisher
    ..our results suggest that Ca(2+)/calmodulin-dependent protein kinase II phosphorylation of RyR2 Ca(2+) release channels at S2814 plays an important role in arrhythmogenesis and sudden cardiac death in mice with heart failure. ..
  48. Bevilacqua J, Monnier N, Bitoun M, Eymard B, Ferreiro A, Monges S, et al. Recessive RYR1 mutations cause unusual congenital myopathy with prominent nuclear internalization and large areas of myofibrillar disorganization. Neuropathol Appl Neurobiol. 2011;37:271-84 pubmed publisher
  49. Kang G, Giovannone S, Liu N, Liu F, Zhang J, Priori S, et al. Purkinje cells from RyR2 mutant mice are highly arrhythmogenic but responsive to targeted therapy. Circ Res. 2010;107:512-9 pubmed publisher
  50. Zhang H, Sun S, Herreman A, De Strooper B, Bezprozvanny I. Role of presenilins in neuronal calcium homeostasis. J Neurosci. 2010;30:8566-80 pubmed publisher
    ..These results indicate that disruption of ER Ca(2+) leak function of presenilins may play an important role in AD pathogenesis. ..
  51. Zahradnikova A, Valent I, Zahradnik I. Frequency and release flux of calcium sparks in rat cardiac myocytes: a relation to RYR gating. J Gen Physiol. 2010;136:101-16 pubmed publisher
    ..This mechanism clarifies the unexpectedly low calcium release flux during elementary release events and unifies the theory of calcium signaling in resting and contracting cardiac myocytes. ..
  52. Liu Z, Wang R, Tian X, Zhong X, Gangopadhyay J, Cole R, et al. Dynamic, inter-subunit interactions between the N-terminal and central mutation regions of cardiac ryanodine receptor. J Cell Sci. 2010;123:1775-84 pubmed publisher
  53. Schredelseker J, Shrivastav M, Dayal A, Grabner M. Non-Ca2+-conducting Ca2+ channels in fish skeletal muscle excitation-contraction coupling. Proc Natl Acad Sci U S A. 2010;107:5658-63 pubmed publisher
    ..1-RyR1 protein-protein interaction with a relatively small and slow influx of external Ca(2+) in tetrapods. Finally, the Ca(V)1.1 Ca(2+) influx was completely eliminated in higher teleost fishes. ..