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)

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

Ca2+ ions play a pivotal role in a wide array of cellular processes ranging from fertilization to cell death. In skeletal muscle, a mechanical interaction between plasma membrane dihydropyridine receptors (DHPRs, L-type Ca2+ channels) and Ca2+ release channels (ryanodine receptors, RyR1s) of the sarcoplasmic reticulum orchestrates a complex, bi-directional Ca2+ signaling process that converts electrical impulses in the sarcolemma into myoplasmic Ca2+ transients during excitation-contraction coupling. Mutations in the genes that encode the two proteins that coordinate this electrochemical conversion process (the DHPR and RyR1) result in a variety of skeletal muscle disorders including malignant hyperthermia (MH), central core disease (CCD), multiminicore disease, nemaline rod myopathy, and hypokalemic periodic paralysis. Although RyR1 and DHPR disease mutations are thought to alter excitability and Ca2+ homeostasis in skeletal muscle, only recently has research begun to probe the molecular mechanisms by which these genetic defects lead to distinct clinical and histopathological manifestations. This review focuses on recent advances in determining the impact of MH and CCD mutations in RyR1 on muscle Ca2+ signaling and how these effects contribute to disease-specific aspects of these disorders.
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PMID:Dynamic alterations in myoplasmic Ca2+ in malignant hyperthermia and central core disease. 1533 73

Malignant hyperthermia (MH) and central core disease (CCD) are disorders of skeletal muscle Ca2+ homeostasis that are linked to mutations in the type 1 ryanodine receptor (RyR1). Certain RyR1 mutations result in an MH-selective phenotype (MH-only), whereas others result in a mixed phenotype (MH + CCD). We characterized effects on Ca2+ handling and excitation-contraction (EC) coupling of MH-only and MH + CCD mutations in RyR1 after expression in skeletal myotubes derived from RyR1-null (dyspedic) mice. Compared to wild-type RyR1-expressing myotubes, MH + CCD- and MH-only-expressing myotubes exhibited voltage-gated Ca2+ release (VGCR) that activated at more negative potentials and displayed a significantly higher incidence of spontaneous Ca2+ oscillations. However, maximal VGCR was reduced only for MH + CCD mutants (Y4795C, R2435L, and R2163H) in which spontaneous Ca2+ oscillations occurred with significantly longer duration (Y4795C and R2435L) or higher frequency (R2163H). Notably, myotubes expressing these MH + CCD mutations in RyR1 exhibited both increased [Ca2+]i and reduced sarcoplasmic reticulum (SR) Ca2+ content. We conclude that MH-only mutations modestly increase basal release-channel activity in a manner insufficient to alter net SR Ca2+ content ("compensated leak"), whereas the mixed MH + CCD phenotype arises from mutations that enhance basal activity to a level sufficient to promote SR Ca2+ depletion, elevate [Ca2+]i, and reduce maximal VGCR ("decompensated leak").
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PMID:Distinct effects on Ca2+ handling caused by malignant hyperthermia and central core disease mutations in RyR1. 1534 86

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

Malignant hyperthermia (MH) is a rare, potentially lethal disorder of skeletal muscle calcium homeostasis characterized by muscle contracture and life-threatening hypermetabolic crisis following exposure to halogenated anesthetics and depolarizing muscle relaxants. Susceptibility to MH results from mutations in calcium channel proteins that mediate excitation-contraction coupling, with the ryanodine receptor calcium release channel (RyR1) representing the major locus. The mode of inheritance appears to be autosomal dominant with variable penetrance. The authors report the death of a 60-year-old white male with a history of low back pain. He had undergone 2 back surgeries previously, the first occurring 10 years prior to his current presentation. Both previous procedures were done under generalized anesthetic with no complications. Recently, he developed stenosis and presented for fusion of vertebrae L3 and L4. The procedure was performed under general anesthetic including sevoflurane, with no intraoperative complications. The anesthesiologist noted that, near the end of the 2-hour procedure, the decedent's CO2 levels were slightly elevated. After the procedure, the decedent was extubated, the temperature probe which had been recording normal values was removed, and he was rolled from ventral to dorsal position. He immediately became hypotensive and bradycardic. Lifesaving interventions were begun. Subsequently, he went into cardiac arrest, at which time the temperature probe was reinserted into the trachea, where it read a body temperature of 109 degrees F. Malignant hyperthermia protocol was initiated, and interventions continued for over 2 hours, at which time they failed. At autopsy, the abdomen contained 1800 mL of blood, and bilateral hematomas were present in the psoas muscles. The authors present this case of clinically apparent malignant hyperthermia, discuss how to approach such a case, the gross and microscopic findings, ancillary studies, and a review of the literature.
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PMID:Pathologic findings in malignant hyperthermia: a case report and review of literature. 1557 23

Malignant hyperthermia (MH) and central core disease (CCD) are inherited human disorders of skeletal muscle Ca2+ homeostasis. Both MH and CCD are linked to mutations and/or deletions in the gene encoding the skeletal muscle ryanodine receptor (RyR1), the intracellular Ca2+ release channel, which is essential to excitation-contraction (EC) coupling. Our knowledge on how mutations in RyR1 disrupt intracellular Ca2+ homeostasis and EC coupling, eventually leading to MH and CCD has been recently improved, thanks to multidisciplinary studies ranging from clinical, single channel recordings, patch-clamp experiments, and molecular biology. This review presents a brief historical perspective, on how pioneer studies resulted in associating MH and CCD to RyR1. The review is also focused on discussing novel results in regard to pathophysiological consequences of specific MH/CCD RyR1 mutant proteins, which are representative of the different cellular mechanisms that are linked to either phenotype.
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PMID:Intracellular Ca2+ dynamics in malignant hyperthermia and central core disease: established concepts, new cellular mechanisms involved. 1558 92

Interdomain interactions between N-terminal and central domains serving as a "domain switch" are believed to be essential to the functional regulation of the skeletal muscle ryanodine receptor-1 Ca(2+) channel. Mutational destabilization of the domain switch in malignant hyperthermia (MH), a genetic sensitivity to volatile anesthetics, causes functional instability of the channel. Dantrolene, a drug used to treat MH, binds to a region within this proposed domain switch. To explore its mechanism of action, the effect of dantrolene on MH-like channel activation by the synthetic domain peptide DP4 or anti-DP4 antibody was examined. A fluorescence probe, methylcoumarin acetate, was covalently attached to the domain switch using DP4 as a delivery vehicle. The magnitude of domain unzipping was determined from the accessibility of methylcoumarin acetate to a macromolecular fluorescence quencher. The Stern-Volmer quenching constant (K(Q)) increased with the addition of DP4 or anti-DP4 antibody. This increase was reversed by dantrolene at both 37 and 22 degrees C and was unaffected by calmodulin. [(3)H]Ryanodine binding to the sarcoplasmic reticulum and activation of sarcoplasmic reticulum Ca(2+) release, both measures of channel activation, were enhanced by DP4. These activities were inhibited by dantrolene at 37 degrees C, yet required the presence of calmodulin at 22 degrees C. These results suggest that the mechanism of action of dantrolene involves stabilization of domain-domain interactions within the domain switch, preventing domain unzipping-induced channel dysfunction. We suggest that temperature and calmodulin primarily affect the coupling between the domain switch and the downstream mechanism of regulation of Ca(2+) channel opening rather than the domain switch itself.
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PMID:Dantrolene stabilizes domain interactions within the ryanodine receptor. 1561 Nov 17

In the present study, the effects of 3,5-di-t-butylcatechol (DTCAT) on ryanodine receptor Ca(2+) channel (RyRC) of skeletal muscle sarcoplasmic reticulum (SR) vesicles were investigated, both by monitoring extravesicular Ca(2+) concentration directly with the Ca(2+) indicator dye arsenazo III and by studying the high-affinity [(3)H]ryanodine binding. DTCAT stimulated Ca(2+) release from junctional (terminal cisternae) vesicles in a concentration-dependent manner, with a threshold activating concentration of 30 microM and a pEC(50) value of 3.43+/-0.03 M. The release of Ca(2+) induced by DTCAT was antagonized in a concentration-dependent manner by ruthenium red, thus indicating that RyRC is involved in the mechanism of stimulation. A structure-activity relationship analysis carried out on a limited number of compounds suggested that both hydroxy and t-butyl groups in DTCAT were important for the activation of RyRC. DTCAT inhibited [(3)H]ryanodine binding to SR vesicles with a K(i) of 232.5 microM, thus indicating that it acted directly at the skeletal muscle ryanodine receptor binding site to stimulate Ca(2+) release. In conclusion, the ability of DTCAT to release Ca(2+) from TC vesicles of skeletal muscle is noteworthy in view of its possible use as an alternative compound to either caffeine or halothane for performing the "In vitro contracture test" to diagnose the susceptibility of some patients to develop malignant hyperthermia under particular pharmacological treatments.
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PMID:3,5-di-t-butylcatechol (DTCAT) as an activator of rat skeletal muscle ryanodine receptor Ca2+ channel (RyRC). 1565 39

Ryanodine receptor (RyR) type 1 (RyR1) exhibits a markedly lower gain of Ca(2+)-induced Ca(2+) release (CICR) activity than RyR type 3 (RyR3) in the sarcoplasmic reticulum (SR) of mammalian skeletal muscle (selective stabilization of the RyR1 channel), and this reduction in the gain is largely eliminated using 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid (CHAPS). We have investigated whether the hypothesized interdomain interactions within RyR1 are involved in the selective stabilization of the channel using [(3)H]ryanodine binding, single-channel recordings, and Ca(2+) release from the SR vesicles. Like CHAPS, domain peptide 4 (DP4, a synthetic peptide corresponding to the Leu(2442)-Pro(2477) region of RyR1), which seems to destabilize the interdomain interactions, markedly stimulated RyR1 but not RyR3. Their activating effects were saturable and nonadditive. Dantrolene, a potent inhibitor of RyR1 used to treat malignant hyperthermia, reversed the effects of DP4 or CHAPS in an identical manner. These findings indicate that RyR1 is activated by DP4 and CHAPS through a common mechanism that is probably mediated by the interdomain interactions. DP4 greatly increased [(3)H]ryanodine binding to RyR1 with only minor alterations in the sensitivity to endogenous CICR modulators (Ca(2+), Mg(2+), and adenine nucleotide). However, DP4 sensitized RyR1 four- to six-fold to caffeine in the caffeine-induced Ca(2+) release. Thus the gain of CICR activity critically determines the magnitude and threshold of Ca(2+) release by drugs such as caffeine. These findings suggest that the low CICR gain of RyR1 is important in normal Ca(2+) handling in skeletal muscle and that perturbation of this state may result in muscle diseases such as malignant hyperthermia.
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PMID:Postulated role of interdomain interactions within the type 1 ryanodine receptor in the low gain of Ca2+-induced Ca2+ release activity of mammalian skeletal muscle sarcoplasmic reticulum. 1567 76

Malignant hyperthermia (MH) and central core disease (CCD) are caused by mutations in the RYR1 gene encoding the skeletal muscle isoform of the ryanodine receptor (RyR1), a homotetrameric Ca(2+) release channel. Rabbit RyR1 mutant cDNAs carrying mutations corresponding to those in human RyR1 that cause MH and CCD were expressed in HEK-293 cells, which do not have endogenous RyR, and in primary cultures of rat skeletal muscle, which express rat RyR1. Analysis of intracellular Ca(2+) pools was performed using aequorin probes targeted to the lumen of the endo/sarcoplasmic reticulum (ER/SR), to the mitochondrial matrix, or to the cytosol. Mutations associated with MH caused alterations in intracellular Ca(2+) homeostasis different from those associated with CCD. Measurements of luminal ER/SR Ca(2+) revealed that the mutations generated leaky channels in all cases, but the leak was particularly pronounced in CCD mutants. Cytosolic and mitochondrial Ca(2+) transients induced by caffeine stimulation were drastically augmented in the MH mutant, slightly reduced in one CCD mutant (Y523S) and completely abolished in another (I4898T). The results suggest that local Ca(2+) derangements of different degrees account for the specific cellular phenotypes of the two disorders.
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PMID:Ca2+ signaling in HEK-293 and skeletal muscle cells expressing recombinant ryanodine receptors harboring malignant hyperthermia and central core disease mutations. 1568 21


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