Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024591 (malignant hyperthermia)
 2,353 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The tissue distribution of mRNA for ryanodine receptor (ryr) isoforms in various porcine tissues has been determined using the reverse transcription-polymerase chain reaction (RT-PCR). First strand cDNA was synthesized from total tissue RNA with reverse transcriptase and random hexamer primers. PCR primers were selected to amplify an approximately 500-base pair segment from homologous regions near the 5' end of the skeletal (ryr1), cardiac (ryr2), or brain (ryr3) ryr cDNA sequences. The specific amplification of each of the ryr isoforms was confirmed by restriction enzyme mapping and DNA sequencing. A ryr1 RT-PCR product was identified in skeletal muscle and esophagus, a ryr2 RT-PCR product was identified in cardiac muscle, aorta and esophagus, and a ryr3 RT-PCR product was identified in skeletal and cardiac muscle, aorta, esophagus, adrenal gland, small intestine, and lung. All three ryr isoforms were identified throughout the brain, including the parietal, frontal, and temporal lobes of the cerebrum, thalamus/hypothalamus, cerebellum, and brain stem. The normal (Arg615) and mutant (Cys615) ryr1 alleles were expressed in the brains of normal and malignant hyperthermia susceptible pigs, respectively. These results thus demonstrate expression of two ryr isoforms in each type of striated muscle, and all ryr isoforms in a number of regions of the nervous system. The wide distribution of ryr1 in the brain provides a possible neurogenic etiology of malignant hyperthermia.
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PMID:Tissue distribution of ryanodine receptor isoforms and alleles determined by reverse transcription polymerase chain reaction. 798 22

Recent findings on the ryanodine receptor of vertebrates, a Ca-release channel protein for the caffeine- and ryanodine-sensitive Ca pools, are reviewed in this article. Three distinct genes, i.e., ryr1, ryr2, and ryr3, express different isoforms in specific locations: Ryr1 in skeletal muscle and Purkinje cells of cerebellum; Ryr2 in cardiac muscle and brain, especially cerebellum; Ryr3 in skeletal muscle of nonmammalian vertebrates, the corpus striatum, and limbic cortex of brain, smooth muscles, and the other cells in vertebrates. While only one isoform (Ryr1) is expressed in mammalian skeletal muscles, two isoforms (alpha- and beta-isoforms expressed by ryr1 and ryr3, respectively) are found in nonmammalian vertebrate skeletal muscles. Although the coexistence of two isoforms may merely be related to differentiation and specialization, the biological significance remains to be clarified. Ryanodine receptors in vertebrate skeletal muscles are believed to mediate two different modes of Ca release: Ca(2+)-induced Ca release and action potential-induced Ca release. All results obtained so far with any isoform of ryanodine receptor are related to Ca(2+)-induced Ca release and show very similar characteristics. Ca(2+)-induced Ca release, however, cannot be the underlying mechanism of Ca release on skeletal muscle activation. Susceptibility of the ryanodine receptor's ryanodine-binding activity to modification by physical factors, such as osmolality of the medium, might be related to action potential-induced Ca release. A hypothesis of molecular interaction in view of the plunger model of action potential-induced Ca release is discussed, suggesting that the model could be compatible with Ryr1 and Ryr3, but incompatible with Ryr2. The functional relevance of ryanodine receptor isoforms, especially Ryr3, in brain also remains to be clarified. Among ryr1 gene-related diseases, malignant hyperthermia was the first to be identified; however, there is still the possibility of involvement of the other genes. Central core disease has been added to the list recently. A molecular approach for the diagnosis and treatment of diseases is now in progress.
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PMID:Role of ryanodine receptors. 800 96

General anaesthetics exhibit a relatively close relationship between their pharmacological potency and their lipid solubility and may thus act by non-specific perturbation of biomembranes. However, more recent data on anaesthetic action suggests that inhalational drugs such as halothane bind directly to hydrophobic protein domains, thereby modulating important receptor functions. In support of this protein theory of anaesthetic action our native gel analysis presented here shows that halothane induces oligomerization of the skeletal muscle ryanodine receptor (RyR) 1 Ca(2+)-release channel, but not its cardiac RyR-2 isoform. Thus, inhalational anaesthetics are not only able to influence protein-protein interactions directly but also appear to differentiate between protein isoforms and/or configurations. This suggests that distinct peptide binding sites exist for these pharmacological agents. In addition, similar mutations in the RyR-2 isoform, which would trigger an episode of malignant hyperthermia in skeletal muscle fibres via abnormal RyR-1 isoforms, would probably not induce an increase in cardiac Ca(2+)-release upon administration of halothane.
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PMID:Isoform-specific interactions between halothane and the ryanodine receptor Ca(2+)-release channel: implications for malignant hyperthermia and the protein theory of anaesthetic action. 1064 91

Arrhythmogenic right ventricular dysplasia type 2 (ARVD2, OMIM 600996) is an autosomal dominant cardiomyopathy, characterized by partial degeneration of the myocardium of the right ventricle, electrical instability and sudden death. The disease locus was mapped to chromosome 1q42--q43. We report here on the physical mapping of the critical ARVD2 region, exclusion of two candidate genes (actinin 2 and nidogen), elucidation of the genomic structure of the cardiac ryanodine receptor gene (RYR2) and identification of RYR2 mutations in four independent families. In myocardial cells, the RyR2 protein, activated by Ca(2+), induces the release of calcium from the sarcoplasmic reticulum into the cytosol. RyR2 is the cardiac counterpart of RyR1, the skeletal muscle ryanodine receptor, involved in malignant hyperthermia (MH) susceptibility and in central core disease (CCD). The RyR2 mutations detected in the present study occurred in two highly conserved regions, strictly corresponding to those where mutations causing MH or CCD are clustered in the RYR1 gene. The detection of RyR2 mutations causing ARVD2, reported in this paper, opens the way to pre-symptomatic detection of carriers of the disease in childhood, thus enabling early monitoring and treatment.
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PMID:Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2). 1115 36

The cardiac ryanodine receptor (RyR2), the major calcium release channel on the sarcoplasmic reticulum (SR) in cardiomyocytes, has recently been shown to be involved in at least two forms of sudden cardiac death (SCD): (1) Catecholaminergic polymorphic ventricular tachycardia (CPVT) or familial polymorphic VT (FPVT); and (2) Arrhythmogenic right ventricular dysplasia type 2 (ARVD2). Eleven RyR2 missense mutations have been linked to these diseases. All eleven RyR2 mutations cluster into 3 regions of RyR2 that are homologous to the three malignant hyperthermia (MH)/central core disease (CCD) mutation regions of the skeletal muscle ryanodine receptor/calcium release channel RyR1. MH/CCD RyR1 mutations have been shown to alter calcium-induced calcium release. Sympathetic nervous system stimulation leads to phosphorylation of RyR2 by protein kinase A (PKA). PKA phosphorylation of RyR2 activates the channel. In conditions associated with high rates of SCD such as heart failure RyR2 is PKA hyperphosphorylated resulting in "leaky" channels. SR calcium leak during diastole can generate "delayed after depolarizations" that can trigger fatal cardiac arrhythmias (e.g., VT). We propose that RyR2 mutations linked to genetic forms of catecholaminergic-induced SCD may alter the regulation of the channel resulting in increased SR calcium leak during sympathetic stimulation.
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PMID:Involvement of the cardiac ryanodine receptor/calcium release channel in catecholaminergic polymorphic ventricular tachycardia. 1180 5

Familial polymorphic (catecholaminergic) ventricular tachycardia is an arrhythmogenic cardiac disorder caused by mutations of the myocardial isoform of the ryanodine receptor gene (RyR2). Mutations of the corresponding gene in the skeletal muscle (RyR1) predispose its carriers to malignant hyperthermia upon use of volatile anesthetics or succinylcholine, which further deteriorate the inherited intracellular calcium release disorder. We report a series of patients with cardiac RyR defects who underwent general anesthesia without complications. Succinylcholine and volatile anesthetics did not have a clinically significant effect on RyR2 defects.
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PMID:Volatile anesthetics and succinylcholine in cardiac ryanodine receptor defects. 1527 19

Ryanodine receptor (RyR), a homotetrameric Ca2+ release channel, is one of the main actors in the generation of Ca2+ signals that trigger muscle contraction. Three genes encode three isoforms of RyRs, which have tissue-restricted distribution. RyR1 and RyR2 are typical of muscle cells, with RyR1 originally considered the skeletal muscle type and RyR2 the cardiac type. However, RyR1 and RyR2 have recently been found in numerous other cell types, including, for instance, peripheral B and T lymphocytes. In contrast, RyR3 is widely distributed among cells. RyR1 and RyR2 are localized in a specialized portion of the sarcoplasmic reticulum (SR), the terminal cisternae, which is the portion of the SR Ca2+ store that releases Ca2+ to control the process of muscle contraction. A specific role for RyR3 has not yet been established: probably, its co-expression with the other RyR isoforms contributes to qualitatively modulate Ca2+-dependent processes in muscle cells and in neurons. Several mutations in the genes encoding RyR1 and RyR2 have been identified in autosomal dominant diseases of skeletal and cardiac muscle, such as malignant hyperthermia (MH), central core disease (CCD), catecholaminergic polymorphic ventricular tachycardia (CPVT), and arrhythmogenic right ventricular dysplasia type 2 (ARVD2). More recently, CCD cases with recessive inheritance have also been described. MH is a pharmacogenetic disease, but the others manifest as congenital myopathies. Even if their clinical phenotypes are well established, particularly in skeletal muscle, the molecular mechanisms that generate the conditions are not clear. A number of studies on cellular models have attempted to elucidate the molecular defects associated with the different mutations, but the problem of understanding how mutations in the same gene generate such an array of diverse pathological traits and diseases of widely different degrees of severity is still open. This review will consider the molecular and cellular effects of RyR mutations, summarizing recent data in the literature on Ca2+ dysregulation, which may lead to a better understanding of the functioning of RyRs.
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PMID:Ryanodine receptor defects in muscle genetic diseases. 1533 72

Ryanodine receptors (RyR) are the Ca2+ release channels of sarcoplasmic reticulum that provide the majority of the [Ca2+] necessary to induce contraction of cardiac and skeletal muscle cells. In their cellular environment, RyRs are exquisitely regulated by a variety of cytosolic factors and accessory proteins so that their output signal (Ca2+) induces cell contraction without igniting signaling pathways that eventually lead to contractile dysfunction or pathological cellular remodeling. Here we review how dysfunction of RyRs, most commonly expressed as enhanced Ca2+ release at rest (skeletal muscle) or during diastole (cardiac muscle), appears to be the fundamental mechanism underlying several genetic or acquired syndromes. In skeletal muscle, malignant hyperthermia and central core disease result from point mutations in RYR1, the skeletal isoform of RyRs. In cardiac muscle, RYR2 mutations lead to catecholaminergic polymorphic ventricular tachycardia and other cardiac arrhythmias. Lastly, an altered phosphorylation of the RyR2 protein may be involved in some forms of congestive heart failure.
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PMID:Ryanodine receptor channelopathies. 1533 75

Ryanodine receptors (RyRs) are the major sarcoplasmic reticulum calcium-release channels required for excitation-contraction coupling in skeletal and cardiac muscle. Mutations in RyRs have been linked to several human diseases. Mutations in the cardiac isoform of RyR2 are associated with catecholaminergic polymorphic ventricular arrhythmias (CPVT), and arrhythmogenic right ventricular dysplasia type 2 (ARVD2), whereas mutations in the skeletal muscle isoform (RyR1) are linked to malignant hyperthermia (MH) and central core disease (CCD). RyRs are modulated by several other proteins, including the FK506 binding proteins (FKBPs), FKBP12 and FKBP12.6. These immunophilins appear to stabilize a closed state of the channel and are important for cooperative interactions among the subunits of RyRs. This review discusses the regulation of RyRs by FKBPs and the possibility that defective modulation of RyR2 by FKBP12.6 could play a role in heart failure, CPVT, and ARVD2. Also discussed are the consequences of FKBP12 depletion to skeletal muscle and the possibility of FKBP12 involvement in certain forms of MH or CCD.
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PMID:Regulation of ryanodine receptors by FK506 binding proteins. 1545 14

Here we review the current knowledge about the mutations of the gene encoding the cardiac ryanodine receptor (RyR2) that cause cardiac arrhythmias. Similarities between the mutations identified in the RyR2 gene and those found in the gene RyR1 that cause malignant hyperthermia and central core disease are discussed. In vitro functional characterization of RyR1 and RyR2 mutants is reviewed, with a focus on the contribution that in vitro expression studies have made to our understanding of related human diseases.
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PMID:Cardiac and skeletal muscle disorders caused by mutations in the intracellular Ca2+ release channels. 1607 44


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