ID:RYR1_HUMAN DESCRIPTION: RecName: Full=Ryanodine receptor 1; Short=RYR-1; Short=RyR1; AltName: Full=Skeletal muscle calcium release channel; AltName: Full=Skeletal muscle ryanodine receptor; AltName: Full=Skeletal muscle-type ryanodine receptor; AltName: Full=Type 1 ryanodine receptor; FUNCTION: Calcium channel that mediates the release of Ca(2+) from the sarcoplasmic reticulum into the cytoplasm and thereby plays a key role in triggering muscle contraction following depolarization of T-tubules. Repeated very high-level exercise increases the open probability of the channel and leads to Ca(2+) leaking into the cytoplasm. Can also mediate the release of Ca(2+) from intracellular stores in neurons, and may thereby promote prolonged Ca(2+) signaling in the brain. Required for normal embryonic development of muscle fibers and skeletal muscle. Required for normal heart morphogenesis, skin development and ossification during embryogenesis (By similarity). SUBUNIT: Homotetramer. Can also form heterotetramers with RYR2. Interacts with CALM; CALM with bound calcium inhibits the RYR1 channel activity. Interacts with S100A1. Interacts with FKBP1A; this stabilizes the closed conformation of the channel. Interacts with CACNA1S; interaction with CACNA1S is important for activation of the RYR1 channel. Interacts with CACNB1. Interacts with TRDN and ASPH; these interactions stimulate RYR1 channel activity (By similarity). Identified in a complex composed of RYR1, PDE4D, PKA, FKBP1A and protein phosphatase 1 (PP1). Repeated very high-level exercise decreases interaction with PDE4D and protein phosphatase 1 (PP1). INTERACTION: P54296:MYOM2; NbExp=2; IntAct=EBI-1221290, EBI-5357134; SUBCELLULAR LOCATION: Sarcoplasmic reticulum membrane; Multi-pass membrane protein. Membrane; Multi-pass membrane protein (Probable). Note=The number of predicted transmembrane domains varies between orthologs, but both N-terminus and C-terminus seem to be cytoplasmic. TISSUE SPECIFICITY: Skeletal muscle and brain (cerebellum and hippocampus). DOMAIN: The calcium release channel activity resides in the C- terminal region while the remaining part of the protein constitutes the 'foot' structure spanning the junctional gap between the sarcoplasmic reticulum (SR) and the T-tubule (By similarity). PTM: Channel activity is modulated by phosphorylation. Phosphorylation at Ser-2843 may increase channel activity. Repeated very high-level exercise increases phosphorylation at Ser-2843. PTM: Activated by reversible S-nitrosylation. Repeated very high- level exercise increases S-nitrosylation. DISEASE: Defects in RYR1 are the cause of malignant hyperthermia susceptibility type 1 (MHS1) [MIM:145600]. MH is an autosomal dominant pharmacogenetic disorder of skeletal muscle and is one of the main causes of death due to anesthesia. In susceptible people, an MH episode can be triggered by all commonly used inhalational anesthetics such as halothane and by depolarizing muscle relaxants such as succinylcholine. The clinical features of the myopathy are hyperthermia, accelerated muscle metabolism, contractures, metabolic acidosis, tachycardia and death, if not treated with the postsynaptic muscle relaxant, dantrolene. Susceptibility to MH can be determined with the 'in vitro' contracture test (IVCT): observing the magnitude of contractures induced in strips of muscle tissue by caffeine alone and halothane alone. Patients with normal response are MH normal (MHN), those with abnormal response to caffeine alone or halothane alone are MH equivocal (MHE(C) and MHE(H) respectively). DISEASE: Defects in RYR1 are a cause of central core disease of muscle (CCD) [MIM:117000]. CCD is an autosomal dominant congenital myopathy, but a severe autosomal recessive form also exists. Both clinical and histological variability is observed. Affected individuals typically display hypotonia and proximal muscle weakness in infancy, leading to the delay of motor milestones. The clinical course of the disorder is usually slow or nonprogressive in adulthood, and the severity of the symptoms may vary from normal to significant muscle weakness. Microscopic examination of CCD-affected skeletal muscle reveals a predominance of type I fibers containing amorphous-looking areas (cores) that do not stain with oxidative and phosphorylase histochemical techniques. DISEASE: Defects in RYR1 are the cause of multiminicore disease with external ophthalmoplegia (MMDO) [MIM:255320]; also known as multicore myopathy with external ophthalmoplegia or minicore myopathy with external ophthalmoplegia. MMD is a clinically heterogeneous neuromuscular disorder. General features include neonatal hypotonia, delayed motor development, and generalized muscle weakness and amyotrophy, which may progress slowly or remain stable. Muscle biopsy shows multiple, poorly circumscribed, short areas of sarcomere disorganization and mitochondria depletion (areas termed minicores) in most muscle fibers. Typically, no dystrophic signs, such as muscle fiber necrosis or regeneration or significant endomysial fibrosis, are present in multiminicore disease. DISEASE: Defects in RYR1 are a cause of congenital myopathy with fiber-type disproportion (CFTD) [MIM:255310]; also known as congenital fiber-type disproportion myopathy (CFTDM). CFTD is a genetically heterogeneous disorder in which there is relative hypotrophy of type 1 muscle fibers compared to type 2 fibers on skeletal muscle biopsy. However, these findings are not specific and can be found in many different myopathic and neuropathic conditions. DISEASE: Note=Defects in RYR1 may be a cause of Samaritan myopathy, a congenital myopathy with benign course. Patients display severe hypotonia and respiratory distress at birth. Unlike other congenital myopathies, the health status constantly improves and patients are minimally affected at adulthood. MISCELLANEOUS: Channel activity is modulated by the alkaloid ryanodine that binds to the open Ca-release channel with high affinity. At low concentrations, ryanodine maintains the channel in an open conformation. High ryanodine concentrations inhibit channel activity. Channel activity is regulated by calmodulin (CALM). The calcium release is activated by increased cytoplasmic calcium levels, by nitric oxyde (NO), caffeine and ATP. Channel activity is inhibited by magnesium ions, possibly by competition for calcium binding sites (By similarity). MISCELLANEOUS: Coexpression of normal and mutant Thr-4898 RYR1 in a 1:1 ratio, produces RYR1 channels with normal halothane and caffeine sensitivities, but maximal levels of Ca(2+) release are reduced by 67%. Binding of [3H]ryanodine indicates that the heterozygous channel is activated by Ca(2+) concentrations 4-fold lower than normal. Single-cell analysis of cotransfected cells shows a significantly increased resting cytoplasmic Ca(2+) level and a significantly reduced luminal Ca(2+) level. These data indicated a leaky channel, possibly caused by a reduction in the Ca(2+) concentration required for channel activation. Comparison with 2 other coexpressed mutant/normal channels suggests that the Thr-4898 mutation produces one of the most abnormal RYR1 channels that has been investigated, and this level of abnormality is reflected in the severe and penetrant phenotype of affected CCD individuals. SIMILARITY: Belongs to the ryanodine receptor (TC 1.A.3.1) family. RYR1 subfamily. SIMILARITY: Contains 3 B30.2/SPRY domains. SIMILARITY: Contains 5 MIR domains. WEB RESOURCE: Name=GeneReviews; URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/RYR1"; WEB RESOURCE: Name=Wikipedia; Note=Ryanodine receptor entry; URL="http://en.wikipedia.org/wiki/Ryanodine_receptor"; WEB RESOURCE: Name=Wikipedia; Note=RYR1 entry; URL="http://en.wikipedia.org/wiki/RYR1"; WEB RESOURCE: Name=Leiden Muscular Dystrophy pages Ryanodine receptor 1 (skeletal) (RYR1); Note=Leiden Open Variation Database (LOVD); URL="http://www.dmd.nl/nmdb2/home.php?select_db=RYR1";
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on P21817
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Biological Process: GO:0001666 response to hypoxia GO:0003151 outflow tract morphogenesis GO:0006811 ion transport GO:0006816 calcium ion transport GO:0006874 cellular calcium ion homeostasis GO:0006936 muscle contraction GO:0007275 multicellular organism development GO:0014808 release of sequestered calcium ion into cytosol by sarcoplasmic reticulum GO:0031000 response to caffeine GO:0034220 ion transmembrane transport GO:0043588 skin development GO:0043931 ossification involved in bone maturation GO:0048741 skeletal muscle fiber development GO:0051209 release of sequestered calcium ion into cytosol GO:0051289 protein homotetramerization GO:0051480 regulation of cytosolic calcium ion concentration GO:0055085 transmembrane transport GO:0070588 calcium ion transmembrane transport GO:0071277 cellular response to calcium ion GO:0071313 cellular response to caffeine GO:1903779 regulation of cardiac conduction
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Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
