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)

It has been presumed that alteration in the concentrations of second messengers leads to alterations in the function of the ryanodine receptor. Consequently, we have determined the basal content of cyclic AMP and inositol phosphates in skeletal and cardiac muscle of malignant hyperthermia (MH) susceptible (MHS) and healthy normal control (MHN) swine. Since alpha 1- and beta-adrenoceptors are linked to these second messenger systems, the densities of alpha 1- and beta-adrenoceptors were also determined. In skeletal as well as cardiac muscle, a higher basal concentration of almost all of the inositol phosphates was found. Of all inositol phosphates measured, the presumed second messenger inositol 1,4,5-trisphosphate (1,4,5-IP3) was mostly concentrated in both tissues. Each MHS sample contained more 1,4,5-IP3 than the highest value observed in MHN muscle, indicating that a threshold of 1,4,5-IP3 concentration for determination of MHS or MHN status can be defined. In addition, MHS skeletal muscle contained more cAMP than MHN, whereas there was no difference between MHS and MHN in cardiac muscle. The changes observed in the different inositol phosphate and cAMP contents were not accompanied by an altered alpha 1- or beta-adrenoceptor density in skeletal or cardiac muscle between MHS and MHN. However, the total number of beta-adrenoceptors of MHN and MHS was significantly higher in cardiac (about 80 fmol/mg protein) than skeletal muscles (about 30 fmol/mg protein). The cardiac muscles revealed about 80% beta 1- and beta 2- and 20% beta 2-adrenoceptors, whereas skeletal muscles were characterized by over 95% beta 2-adrenoceptors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Biochemical changes in malignant hyperthermia susceptible swine: cyclic AMP, inositol phosphates, alpha 1, beta 1- and beta 2-adrenoceptors in skeletal and cardiac muscle. 821 23

The ryanodine receptors (RYR) are a family of intracellular Ca2+ release channels that were first identified in the terminal cistenae of the sarcoplasmic reticulum of the skeletal and cardiac muscle. Mutations within the skeletal muscle isoform were shown to cause malignant hyperthermia in swine and man. We have analysed the genomic structure of the porcine skeletal muscle ryanodine receptor and its expression using chimeric reporter gene constructs consisting of the RYR1 gene promoter and the chloramphenicol acetyltransferase gene after transfection in muscle and non-muscle cells.
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PMID:[Structure and expression of the porcine skeletal muscle ryanodine receptor gene]. 903 69

In this review, potential roles for the endogenous sphingolipid, sphingosine, and its derivatives are described for muscle cells. Sphingosine modulates the function of important calcium channels in muscle, including the ryanodine receptor (RyR) calcium release channel of the sarcoplasmic reticulum (SR). Sphingosine blocks calcium release through the SR ryanodine receptor and reduces the activity of single skeletal muscle RyR channels reconstituted into planar lipid bilayers. Sphingosine-blocked calcium release is coincident with the inhibitory effects of sphingosine on [3H]ryanodine binding to the RyR. The sphingomyelin signal transduction pathway has also been identified in both skeletal and cardiac muscle. A neutral form of sphingomyelinase (nSMase) enzyme has been localized to the junctional transverse tubule membrane. The high turnover of the SMase is responsible for the production of ceramide and sphingosine. HPLC analyses indicate that significant resting levels of sphingosine are present in muscle tissue. A model of excitation-contraction coupling is presented suggesting a potential role for this endogenous sphingolipid in normal muscle function. Putative roles for sphingolipid mediators in skeletal muscle dysfunction are also discussed. We hypothesize that sphingosine plays important roles in malignant hyperthermia and during the development of muscle fatigue.
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PMID:The role of sphingolipids in the control of skeletal muscle function: a review. 1093 63

Transient elevations of intracellular Ca2+ play a signalling role in such complex cellular functions as contraction, secretion, fertilization, proliferation, metabolism, heartbeat and memory. However, prolonged elevation of Ca2+ above about 10 microM is deleterious to a cell and can activate apoptosis. In muscle, there is a narrow window of Ca2+ dysregulation in which abnormalities in Ca2+ regulatory proteins can lead to disease, rather than apoptosis. Key proteins in the regulation of muscle Ca2+ are the voltage-dependent, dihydropyridine-sensitive, L-type Ca2+ channels located in the transverse tubule and Ca2+ release channels in the junctional terminal cisternae of the sarcoplasmic reticulum. Abnormalities in these proteins play a key role in malignant hyperthermia (MH), a toxic response to anesthetics, and in central core disease (CCD), a muscle myopathy. Sarco(endo)plasmic reticulum Ca2+ ATPases (SERCAs) return sarcoplasmic Ca2+ to the lumen of the sarcoplasmic reticulum. Loss of SERCA1a Ca2+ pump function is one cause of exercise-induced impairment of the relaxation of skeletal muscle, in Brody disease. Phospholamban expressed in cardiac muscle and sarcolipin expressed in skeletal muscle regulate SERCA activity. Studies with knockout and transgenic mice show that gain of inhibitory function of phospholamban alters cardiac contractility and could be a causal feature in some cardiomyopathies. Calsequestrin, calreticulin, and a series of other acidic, lumenal, Ca2+ binding proteins provide a buffer for Ca2+ stored in the sarcoplasmic reticulum. Overexpression of cardiac calsequestrin leads to cardiomyopathy and ablation of calreticulin alters cardiac development.
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PMID:Ca2+ signalling and muscle disease. 1095 Nov 87

1. The conventional approach to understanding the structure and properties of ion channels has been to use physiological characterization. 2. Purification and molecular cloning of ion channel genes has enabled more detailed structure-function analyses to be undertaken. 3. An alternative approach to the identification of genes of pathophysiological importance has been the use of genetic linkage approaches and positional cloning or positional candidate analysis of ion channel genes. 4. Using genetic approaches, mutations have been described that cause inherited neurological disorders of neurons (e.g. epilepsy, migraine, deafness, ataxia and startle disease), skeletal muscle (myotonia, malignant hyperthermia, periodic paralysis and myasthenia) and cardiac muscle (long QT syndrome and ventricular fibrillation). 5. For each disease, gene structure-function analyses of the mutant alleles have provided further insights into the biology of ion channels. 6. The present brief review examines the methods used in genetic linkage studies and positional cloning of disease genes. Understanding how ion channel gene mutations give rise to dysfunctional channels will be important in defining and treating the episodic and chronic channelopathies.
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PMID:Genetics, an alternative way to discover, characterize and understand ion channels. 1115 44

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

Identification of the genetic basis of human diseases linked to dysfunctional free calcium (Ca2+) signaling has triggered an explosion of interest in the functional characterization of the molecular components regulating intracellular Ca2+ homeostasis. There is a growing appreciation of the central role of intracellular ryanodine-sensitive Ca2+ release channel (RyR) regulation in skeletal and cardiac muscle pathologies, including malignant hyperthermia, heart failure, and sudden cardiac death. The use of cloned RyR isoforms and recombinant expression techniques has greatly facilitated the elucidation of the molecular basis of RyR Ca2+ release functionality. This review will focus on the recombinant techniques used in the functional characterization of recombinant RyR isoforms and the insights that these approaches have yielded in unraveling the mechanistic basis of RyR channel functionality.
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PMID:Toward a molecular understanding of the structure-function of ryanodine receptor Ca2+ release channels: perspectives from recombinant expression systems. 1585 32

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


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