Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P21817 (RyR1)
 1,154 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ryanodine receptor (RyR) is the Ca(2+)-induced Ca(2+) release channel in cells. RyR1 and RyR2 are its isoforms expressed in the skeletal and cardiac muscles, respectively. Their missense mutations, which are clustered in three regions that correspond to each other, cause hereditary disorders such as malignant hyperthermia and central core disease in skeletal muscle and catecholaminergic polymorphic ventricular tachycardia in cardiac muscle. Their pathogeneses, however, are not well understood. The following hypotheses are favorably discussed in this article: phenotypes with RyR1 and RyR2 mutations are mainly caused by dysregulations of their functions through the interdomain interaction and luminal Ca(2+), respectively.
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PMID:Distinct mechanisms for dysfunctions of mutated ryanodine receptor isoforms. 1806 58

Ryanodine receptors (RyR) are Ca(2+) channels that mediate Ca(2+) release from intracellular stores in response to diverse intracellular signals. In RINm5F insulinoma cells, caffeine, and 4-chloro-m-cresol (4CmC), agonists of RyR, stimulated Ca(2+) entry that was independent of store-operated Ca(2+) entry, and blocked by prior incubation with a concentration of ryanodine that inactivates RyR. Patch-clamp recording identified small numbers of large-conductance (gamma(K) = 169 pS) cation channels that were activated by caffeine, 4CmC or low concentrations of ryanodine. Similar channels were detected in rat pancreatic beta-cells. In RINm5F cells, the channels were blocked by cytosolic, but not extracellular, ruthenium red. Subcellular fractionation showed that type 3 IP(3) receptors (IP(3)R3) were expressed predominantly in endoplasmic reticulum, whereas RyR2 were present also in plasma membrane fractions. Using RNAi selectively to reduce expression of RyR1, RyR2, or IP(3)R3, we showed that RyR2 mediates both the Ca(2+) entry and the plasma membrane currents evoked by agonists of RyR. We conclude that small numbers of RyR2 are selectively expressed in the plasma membrane of RINm5F pancreatic beta-cells, where they mediate Ca(2+) entry.
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PMID:Functional ryanodine receptors in the plasma membrane of RINm5F pancreatic beta-cells. 1911 7

Ryanodine receptors (RyRs) are ion channels that regulate muscle contraction by releasing calcium ions from intracellular stores into the cytoplasm. Mutations in skeletal muscle RyR (RyR1) give rise to congenital diseases such as central core disease. The absence of high-resolution structures of RyR1 has limited our understanding of channel function and disease mechanisms at the molecular level. Here, we report a structural model of the pore-forming region of RyR1. Molecular dynamics simulations show high ion binding to putative pore residues D4899, E4900, D4938, and D4945, which are experimentally known to be critical for channel conductance and selectivity. We also observe preferential localization of Ca(2+) over K(+) in the selectivity filter of RyR1. Simulations of RyR1-D4899Q mutant show a loss of preference to Ca(2+) in the selectivity filter as seen experimentally. Electrophysiological experiments on a central core disease mutant, RyR1-G4898R, show constitutively open channels that conduct K(+) but not Ca(2+). Our simulations with G4898R likewise show a decrease in the preference of Ca(2+) over K(+) in the selectivity filter. Together, the computational and experimental results shed light on ion conductance and selectivity of RyR1 at an atomistic level.
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PMID:A structural model of the pore-forming region of the skeletal muscle ryanodine receptor (RyR1). 1939 Jun 14

Ryanodine receptors (RyRs) are large homotetrameric protein complexes that mediate the release of intracellular stores of calcium. Mammals possess three gene copies, RyR1, RyR2, and RyR3 that are expressed in a variety of tissue types. Teleost fish express RyR1a and RyR1b genes that are expressed in slow twitch skeletal muscle and fast twitch skeletal muscles respectively. Here we report the results of a survey of the genome of bichir (Polypterus ornatipinnis), considered the most basal ray-finned fish, for its RyR genes. The bichir genome encodes four RyR genes, RyR1a, RyR1b, RyR2, and RyR3 that phylogenetically cluster with their vertebrate orthologs. Quantitative real time PCR shows fibre type-specific expression of the RyR1a and RyR1b genes. The RyR3 gene, however, is down regulated in bichir in contrast to derived teleosts including zebrafish in which the RyR1 and RyR3 genes are co-expressed at equivalent levels.
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PMID:A comparative study of ryanodine receptor (RyR) gene expression levels in a basal ray-finned fish, bichir (Polypterus ornatipinnis) and the derived euteleost zebrafish (Danio rerio). 1975 69

Ryanodine receptors (RyRs) are a family of Ca2+ channel proteins that mediate the massive release of Ca2+ from the endoplasmic reticulum into the cytoplasma. In the present study, we manipulated the incorporation of RyR1 into RBC membrane and investigated its influences on the intracellular Ca2+ ([Ca2+](in)) level and the biomechanical properties in RBCs. The incorporation of RyR1 into RBC membranes was demonstrated by both immunofluorescent staining and the change of [Ca2+](in) of RBCs. In the presence of RyR1, [Ca2+](in) showed biphasic changes, i.e., it increased with the extracellular Ca2+ ([Ca2+](ex)) up to 5muM and then decreased with the further increase of [Ca2+](ex). However, [Ca2+](in) remained constant in the absence of the RyR1. The results of biomechanical measurements on RBCs, including deformability, osmotic fragility, and membrane microviscosity, reflected similar biphasic changes of [Ca2+](in) mediated by RyR1 with the increases of [Ca2+](ex). Therefore, it is believed that RyR1 can incorporate into RBC membrane in vitro, and mediate Ca2+ influx, and then regulate RBC biomechanical properties. This information suggests that RBCs may serve as a model to study the function of RyR1 as a Ca2+ release channel.
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PMID:Ryanodine receptor 1 mediates Ca2+ transport and influences the biomechanical properties in RBCs. 1976 2

Ryanodine receptors (RyRs) are channels governing the release of Ca(2+) from the sarcoplasmic or endoplasmic reticulum. They are required for the contraction of both skeletal (RyR1) and cardiac (RyR2) muscles. Mutations in both RyR1 and RyR2 have been associated with severe genetic disorders, but high-resolution data describing the disease variants in detail have been lacking. Here we present the crystal structures of the N-terminal domains of both RyR2 (1-217) and RyR1 (9-205) at 2.55 A and 2.9 A, respectively. The domains map in a hot spot region for disease mutations. Both structures consist of a core beta trefoil domain flanked by an alpha helix. Crystal structures of two RyR2 disease mutants, A77V (2.2 A) and V186M (1.7 A), show that the mutations cause distinct local changes in the surface of the protein. A RyR2 deletion mutant causes significant changes in the thermal stability. The disease positions highlight two putative binding interfaces required for normal RyR function.
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PMID:Crystal structures of the N-terminal domains of cardiac and skeletal muscle ryanodine receptors: insights into disease mutations. 1991 85

Functional coupling between clustered membrane receptors has been identified as a novel mechanism to improve signaling performance in a number of physiological processes. The potential role of defective inter-receptor coupling in the pathogenesis of disease, however, has not previously been explored. Ryanodine receptors (RyRs), the primary calcium release channel of muscle, usually form ordered two-dimensional arrays in the sarcoplasmic reticulum membranes. Mutations in RyRs are known to cause a number of severe diseases both in skeletal muscle and in heart. Here we present a model demonstrating how impaired functional coupling between neighboring mutant RyR1(R615C) channels may contribute to the pharmacogenetic skeletal muscle sensitivity, malignant hyperthermia (MH). We find that purified RyR1(R615C) from MH susceptible porcine skeletal muscle shows significantly reduced oligomerization when compared to RyR1(WT), indicating a potential loss of intrinsic intermolecular control. The MH-triggering volatile anesthetic, halothane, activates RyR1(R615C) and RyR1(WT) to a similar extent, using [(3)H]ryanodine binding as a measure of activation. Modeling RyR1 array function with parameters modified to simulate the loss of functional inter-RyR coupling recapitulates the MH molecular phenotype-RyR1 channels leaky to Ca(2+) at rest and long open-times following exposure to halothane. Our work suggests that a defect in inter-RyR1 coupling is a novel direction for research into the pathogenesis of MH.
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PMID:Impaired interaction between skeletal ryanodine receptors in malignant hyperthermia. 2002 68

Ryanodine receptors (RyRs) are high conductance intracellular cation channels that release calcium ions from stores such as the endoplasmic reticulum and sarcoplasmic reticulum. Although RyRs are expressed in many cell types, their roles have only been extensively characterised in tissues in which they are abundant: RyR1 is essential for excitation-contraction coupling in skeletal muscle; whereas RyR2 is required for the analogous signal transduction pathway in heart. Defects in RyR1 cause malignant hyperthermia and a spectrum of myopathies in skeletal muscle; whereas RyR2 dysregulation can result in fatal cardiac arrhythmias and is involved in heart failure. Altered RyR gating has been implicated in a range of other diseases, including epilepsy, neurodegeneration, pain and cancer. RyRs interact with a range of toxic substances, providing insights into their functional and structural properties. Consequently, these channel complexes represent potential therapeutic targets for treatment of numerous diseases. Furthermore, strategies for combating multicellular parasites and agricultural pests could exploit pharmacological differences between their RyRs and those of vertebrates. However, available pharmacological tools for manipulation of RyR gating are generally unsuitable for clinical, veterinary or agricultural use, owing to their lack of selectivity, inappropriate solubility in the aqueous or lipid environment, or generation of side-effects. The expression, subcellular distribution and gating of RyRs is modified by a wide variety of cellular proteins, some of which are expressed in a developmentally or tissue-restricted manner. This commentary examines the possibility of manipulating the expression and function of such proteins in order develop new drugs acting on RyR channel complexes.
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PMID:Ryanodine receptor calcium channels and their partners as drug targets. 2009 79

Preeclampsia (PE) is characterized by maternal hypertension, proteinuria, oedema and, in 30% of cases, by intrauterine growth retardation. Causes are still unknown; however, epidemiological and clinical studies have suggested alterations in maternal calcium metabolism. We suggested that in PE, calcium transport by the syncytiotrophoblast (ST) is disturbed. From total placental tissues, we studied the expression of: calcium channels (TRPV5, TRPV6 [transient receptor potential vanilloid]), calcium binding proteins (CaBP-9K, CaBP-28K), plasma membrane calcium ATPase (PMCA)1,2,3,4 pumps, ATP synthase, genes implicated in Ca(2+) release [inositol-1,4,5-triphosphate receptor (IP3R)1,2,3; Ryanodine receptor (RyR)1,2,3] and replenishment (SERCA1,2,3 [sarcoendoplasmic reticulum Ca(2+) ATPases]) from endoplasmic reticulum, channels implicated in mitochondrial Ca(2+) accumulation (VDAC1,2,3 [voltage-dependent anion channels]) and a marker of oxidative stress (hOGG1 [Human 8-oxoguanine-DNA glycosylase 1]), as well as the influence of these variations on calcium transport in primary ST cultures. The mRNA and protein levels were thereby examined by real-time PCR and Western blot analysis, respectively, in two different groups of pregnant women with similar gestational age: a normal group (n= 16) and a PE group (n= 8), diagnosed by a clinician. Our study showed a significant decrease in calcium transport by the ST cultured from preeclamptic placentas. We found a significant (P < 0.05) decrease in mRNA levels of TRPV5, TRPV6, CaBP-9K, CaBP-28K, PMCA1, PMCA4, ATP synthase, IP3R1, IP3R2, RyR1, RyR2 and RyR3 in PE group compared to normal one. We also noted a significant decrease in protein levels of TRPV5, TRPV6, CaBP-9K, CaBP-28K and PMCA1/4 in PE group. In contrast, SERCA1, SERCA2, SERCA3, VDAC3 and hOGG1 mRNA expressions were significantly increased in PE placentas. Calcium homeostasis and transport through placenta is compromised in preeclamptic pregnancies and it appears to be affected by a lack of ATP and an excess of oxidative stress.
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PMID:Alteration of calcium homeostasis in primary preeclamptic syncytiotrophoblasts: effect on calcium exchange in placenta. 2017 61

Ryanodine receptors (RyR) are intracellular Ca2+-permeable channels that provide the sarcoplasmic reticulum Ca2+ release required for skeletal and cardiac muscle contractions. RyR1 underlies skeletal muscle contraction, and RyR2 fulfills this role in cardiac muscle. Over the past 20 years, numerous mutations in both RyR isoforms have been identified and linked to skeletal and cardiac diseases. Malignant hyperthermia, central core disease, and catecholaminergic polymorphic ventricular tachycardia have been genetically linked to mutations in either RyR1 or RyR2. Thus, RyR channelopathies are both of interest because they cause significant human diseases and provide model systems that can be studied to elucidate important structure-function relationships of these ion channels.
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PMID:Ryanodine receptor channelopathies. 2017 62


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