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

Dantrolene is a skeletal muscle relaxant which acts by inhibiting intracellular Ca(2+) release from sarcoplasmic reticulum (SR). It is used primarily in the treatment of malignant hyperthermia (MH), a pharmacogenetic sensitivity to volatile anesthetics resulting in massive intracellular Ca(2+) release. Determination of the site and mechanism of action of dantrolene should contribute to the understanding of the regulation of intracellular Ca(2+) release in skeletal muscle. Photoaffinity labeling of porcine SR with [(3)H]azidodantrolene, a photoactivatable analogue of dantrolene, has identified a 160 kDa SR protein with immunologic cross-reactivity to skeletal muscle ryanodine receptor (RyR) as a possible target [Palnitkar et al. (1999) J. Med. Chem. 42, 1872-1880]. Here we demonstrate specific, AMP-PCP-enhanced, [(3)H]azidodantrolene photolabeling of both the RyR monomer and a 160 or 172 kDa protein in porcine and rabbit SR, respectively. The 160/172 kDa protein is shown to be the NH(2)-terminus of the RyR cleaved from the monomer by an endogenous protease activity consistent with that of n-calpain. MALDI-mass spectrometric analysis of the porcine 160 kDa protein identifies it as the 1400 amino acid NH(2)-terminal fragment of the skeletal muscle RyR reportedly generated by n-calpain [Shevchenko et al. (1998) J. Membr. Biol. 161, 33-34]. Immunoprecipitation of solubilized, [(3)H]azidodantrolene-photolabeled SR protein reveals that the cleaved 160/172 kDa protein remains associated with the C-terminal, 410 kDa portion of the RyR. [(3)H]Dantrolene binding to both the intact and the n-calpain-cleaved channel RyR is similarly enhanced by AMP-PCP. n-Calpain cleavage of the RyR does not affect [(3)H]dantrolene binding in the presence of AMP-PCP, but depresses drug binding in the absence of nucleotide. These results demonstrate that the NH(2)-terminus of the RyR is a molecular target for dantrolene, and suggest a regulatory role for both n-calpain activity and ATP in the interaction of dantrolene with the RyR in vivo.
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PMID:The skeletal muscle ryanodine receptor identified as a molecular target of [3H]azidodantrolene by photoaffinity labeling. 1114 48

2-[(14)C]oxoglutarate uptake in resting cells of Staphylococcus aureus 17810S occurs via two kinetically different systems: (1) a secondary, electrogenic 2-oxoglutarate:H(+) symporter (K(m)=0.105 mM), energized by an electrochemical proton potential (Delta mu H(+)) that is generated by the oxidation of endogenous amino acids and sensitive to ionophores, and (2) a Delta mu H(+)-independent facilitated diffusion system (K(m)=1.31 mM). The 2-oxoglutarate transport system of S. aureus 17810S can be classified as a new member of the MHS (metabolite:H(+) symporter) family. This transporter takes up various dicarboxylic acids in the order of affinity: succinate = malate > fumarate > 2-oxoglutarate > glutamate. Energy conservation with 2-oxoglutarate was studied in starved cells of strain 17810S. Initial transport of 2-oxoglutarate in these cells is energized by Delta mu H(+) generated via hydrolysis of residual ATP. Subsequent oxidation of the accumulated 2-oxoglutarate generates Delta mu H(+) for further, autoenergized transport of this 2-oxoacid and also for Delta mu H(+)-linked resynthesis of ATP. In the cadmium-sensitive S. aureus 17810S, Cd(2+) accumulation strongly inhibits energy conservation with 2-oxoglutarate at the level of Delta mu H(+) generation, without direct blocking of the 2-oxoglutarate transport system or ATP synthase complex. In the cadmium-resistant S. aureus 17810R, Cd(2+) does not affect energy conservation due to its extrusion by the Cd(2+) efflux system (Cd(2+)-ATPase of P-type), which prevents Cd(2+) accumulation.
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PMID:2-Oxoglutarate transport system in Staphylococcus aureus. 1147 14

Mutations G2370A, G2372A, G2373A, G2375A, Y3937A, S3938A, G3939A and K3940A were made in two potential ATP-binding motifs (amino acids 2370-2375 and 3937-3940) in the Ca(2+)-release channel of skeletal-muscle sarcoplasmic reticulum (ryanodine receptor or RyR1). Activation of [(3)H]ryanodine binding by Ca(2+), caffeine and ATP (adenosine 5'-[beta,gamma-methylene]triphosphate, AMP-PCP) was used as an assay for channel opening, since ryanodine binds only to open channels. Caffeine-sensitivity of channel opening was also assayed by caffeine-induced Ca(2+) release in HEK-293 cells expressing wild-type and mutant channels. Equilibrium [(3)H]ryanodine-binding properties and EC(50) values for Ca(2+) activation of high-affinity [(3)H]ryanodine binding were similar between wild-type RyR1 and mutants. In the presence of 1 mM AMP-PCP, Ca(2+)-activation curves were shifted to higher affinity and maximal binding was increased to a similar extent for wild-type RyR1 and mutants. ATP sensitivity of channel opening was also similar for wild-type and mutants. These observations apparently rule out sequences 2370-2375 and 3937-3940 as ATP-binding motifs. Caffeine or 4-chloro-m-cresol sensitivity, however, was decreased in mutants G2370A, G2373A and G2375A, whereas the other mutants retained normal sensitivity. Amino acids 2370-2375 lie within a sequence (amino acids 2163-2458) in which some eight RyR1 mutations have been associated with malignant hyperthermia and shown to be hypersensitive to caffeine and 4-chloro-m-cresol activation. By contrast, mutants G2370A, G2373A and G2375A are hyposensitive to caffeine and 4-chloro-m-cresol. Thus amino acids 2163-2458 form a regulatory domain (malignant hyperthermia regulatory domain 2) that regulates caffeine and 4-chloro-m-cresol sensitivity of RyR1.
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PMID:Mutations to Gly2370, Gly2373 or Gly2375 in malignant hyperthermia domain 2 decrease caffeine and cresol sensitivity of the rabbit skeletal-muscle Ca2+-release channel (ryanodine receptor isoform 1). 1169 96

Important aspects of the excitation-contraction (EC) coupling process in skeletal muscle have been revealed using mechanically-skinned fibers in which the transverse-tubular system can be depolarized by ion substitution or electrical stimulation, activating the voltage-sensors which in turn open the Ca2+ release channels in the adjacent sarcoplasmic reticulum (SR). Twitch and tetanic force responses elicited in skinned fibers closely resemble those in intact fibers, showing that the coupling mechanism is entirely functional. It was found that ATP has to be bound to the Ca2+ release channels for them to be activated by the voltage-sensors and that the coupling mechanism likely involves the voltage-sensors removing the inhibitory effects of cytoplasmic Mg2+ on the release channels; such findings are relevant to the basis of muscle fatigue and to certain diseases such as malignant hyperthermia (MH). EC coupling is evidently not mediated by upmodulation of Ca2+-induced Ca2+ release (CICR) or by an oxidation or phosphorylation reaction. The Ca2+ load in the SR of skinned fibers can be set at the endogenous level or otherwise. The normal coupling mechanism functions well in mammalian fast-twitch fibers even when the SR is only partially loaded, whereas CICR is highly dependent on SR luminal Ca2+ and caffeine is poorly effective at inducing release at the endogenous SR Ca2+ load level.
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PMID:Voltage-sensor control of Ca2+ release in skeletal muscle: insights from skinned fibers. 1189 57

Changes in intracellular Ca2+-concentration play an important role in the excitation-contraction-relaxation cycle of skeletal muscle. In this review we describe various inheritable muscle diseases to highlight the role of Ca2+-regulatory mechanisms. Upon excitation the ryanodine receptor releases Ca2+ in the cytosol. During and after contraction the sarcoplasmic reticulum (SR) Ca2+ATPase (SERCA) pumps Ca2+ back in the SR resulting in relaxation. An abnormal change in the intracellular Ca2+-concentration results in defective muscle contraction and/or relaxation, which is the cause of various muscle diseases. Malignant hyperthermia (MH) and central core disease (CCD) are both caused by mutations in the ryanodine receptor but show different clinical phenotypes. In MH an acute increase of Ca2+ results in excessive muscle contraction causing rigidity, while in CCD a chronic rise of cytosolic Ca2+ is seen, leading to mitochondrial damage, disorganization of myofibrils and muscle weakness. In Brody disease and also in mitochondrial myopathies, SERCA functions sub optimal causing a prolonged physiological Ca2+-elevation leading to slowing of relaxation. Defective actin-myosin interactions, as in nemaline myopathy and also in mitochondrial myopathies due to ATP-shortage, cause Ca2+-hyposensitivity and slowness of contraction. Information of Ca2+-kinetics in these inherited muscular diseases improves our understanding of the role of calcium in the physiology and pathophysiology of the skeletal muscle cell.
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PMID:Calcium regulation and muscle disease. 1236 86

Malignant hyperthermia (MH) is a metabolic myopathy with an abnormal release of calcium by the sarcoplasmic reticulum (SR), triggered by volatile anesthetics and succinylcholine. Similarly, caffeine enhances Ca(2+)release by the SR in vitro. In a prospective, randomized study, high-energy phosphates were studied by intramuscular 31-phosphorus magnetic resonance spectroscopy ((31)P-MRS) in 10 MH-susceptible (MHS) and 7 MH-nonsusceptible (MHN) subjects before and after injection of 0.5 ml caffeine (20 mM). Intramuscular energy balance, measured by the ratios of P(i)/PCr and P(i)/gamma-ATP, did not differ between MHS and MHN patients before and after intramuscular caffeine injection. However, within each group, P(i)/PCr and P(i)/gamma-ATP increased significantly only in the MHS group. Intramuscular caffeine injection seemed to impair the metabolic balance in MHS individuals. This may reflect a local calcium overload leading to consumption of high-energy phosphates and increase of inorganic phosphate. Intramuscular stimulation by caffeine and (31)P-MRS may provide a valuable tool to investigate MH-related metabolic disturbances.
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PMID:Caffeine impairs intramuscular energy balance in patients susceptible to malignant hyperthermia. 1292 96

Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle that presents as a hypermetabolic response to potent volatile anesthetic gases such as halothane, sevoflurane, desflurane and the depolarizing muscle relaxant succinylcholine, and rarely, in humans, to stresses such as vigorous exercise and heat. The incidence of MH reactions ranges from 1:5,000 to 1:50,000-100,000 anesthesias. However, the prevalence of the genetic abnormalities may be as great as one in 3,000 individuals. MH affects humans, certain pig breeds, dogs, horses, and probably other animals. The classic signs of MH include hyperthermia to marked degree, tachycardia, tachypnea, increased carbon dioxide production, increased oxygen consumption, acidosis, muscle rigidity, and rhabdomyolysis, all related to a hypermetabolic response. The syndrome is likely to be fatal if untreated. Early recognition of the signs of MH, specifically elevation of end-expired carbon dioxide, provides the clinical diagnostic clues. In humans the syndrome is inherited in autosomal dominant pattern, while in pigs in autosomal recessive. The pathophysiologic changes of MH are due to uncontrolled rise of myoplasmic calcium, which activates biochemical processes related to muscle activation. Due to ATP depletion, the muscle membrane integrity is compromised leading to hyperkalemia and rhabdomyolysis. In most cases, the syndrome is caused by a defect in the ryanodine receptor. Over 90 mutations have been identified in the RYR-1 gene located on chromosome 19q13.1, and at least 25 are causal for MH. Diagnostic testing relies on assessing the in vitro contracture response of biopsied muscle to halothane, caffeine, and other drugs. Elucidation of the genetic changes has led to the introduction, on a limited basis so far, of genetic testing for susceptibility to MH. As the sensitivity of genetic testing increases, molecular genetics will be used for identifying those at risk with greater frequency. Dantrolene sodium is a specific antagonist of the pathophysiologic changes of MH and should be available wherever general anesthesia is administered. Thanks to the dramatic progress in understanding the clinical manifestation and pathophysiology of the syndrome, the mortality from MH has dropped from over 80% thirty years ago to less than 5%.
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PMID:Malignant hyperthermia. 1745 35

Malignant hyperthermia (MH) susceptibility is a genetic disorder of skeletal muscle associated with mutations in the ryanodine receptor isoform 1 (RyR1) of sarcoplasmic reticulum (SR). In MH-susceptible skeletal fibers, RyR1-mediated Ca(2+) release is highly sensitive to activation by the volatile anesthetic halothane. Indeed, studies with isolated RyR1 channels (using simple Cs(+) solutions) found that halothane selectively affects mutated but not wild-type RyR1 function. However, studies in skeletal fibers indicate that halothane can also activate wild-type RyR1-mediated Ca(2+) release. We hypothesized that endogenous RyR1 agonists (ATP, lumenal Ca(2+)) may increase RyR1 sensitivity to halothane. Consequently, we studied how these agonists affect halothane action on rabbit skeletal RyR1 reconstituted into planar lipid bilayers. We found that cytosolic ATP is required for halothane-induced activation of the skeletal RyR1. Unlike RyR1, cardiac RyR2 (much less sensitive to ATP) responded to halothane even in the absence of this agonist. ATP-dependent halothane activation of RyR1 was enhanced by cytosolic Ca(2+) (channel agonist) and counteracted by Mg(2+) (channel inhibitor). Dantrolene, a muscle relaxant used to treat MH episodes, did not affect RyR1 or RyR2 basal activity and did not interfere with halothane-induced activation. Studies with skeletal SR microsomes confirmed that halothane-induced RyR1-mediated SR Ca(2+) release is enhanced by high ATP-low Mg(2+) in the cytosol and by increased SR Ca(2+) load. Thus, physiological or pathological processes that induce changes in cellular levels of these modulators could affect RyR1 sensitivity to halothane in skeletal fibers, including the outcome of halothane-induced contracture tests used to diagnose MH susceptibility.
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PMID:Halothane modulation of skeletal muscle ryanodine receptors: dependence on Ca2+, Mg2+, and ATP. 1830 28

Calcium-induced calcium release (CICR) was first discovered in skeletal muscle. CICR is defined as Ca2+ release by the action of Ca2+ alone without the simultaneous action of other activating processes. CICR is biphasically dependent on Ca2+ concentration; is inhibited by Mg2+, procaine, and tetracaine; and is potentiated by ATP, other adenine compounds, and caffeine. With depolarization of the sarcoplasmic reticulum (SR), a potential change of the SR membrane in which the luminal side becomes more negative, CICR is activated for several seconds and is then inactivated. All three types of ryanodine receptors (RyRs) show CICR activity. At least one RyR, RyR1, also shows non-CICR Ca2+ release, such as that triggered by the t-tubule voltage sensor, by clofibric acid, and by SR depolarization. Maximum rates of CICR, at the optimal Ca2+ concentration in the presence of physiological levels of ATP and Mg2+ determined in skinned fibers and fragmented SR, are much lower than the rate of physiological Ca2+ release. The primary event of physiological Ca2+ release, the Ca2+ spark, is the simultaneous opening of multiple channels, the coordinating mechanism of which does not appear to be CICR because of the low probability of CICR opening under physiological conditions. The coordination may require Ca2+, but in that case, some other stimulus or stimuli must be provided simultaneously, which is not CICR by definition. Thus CICR does not appear to contribute significantly to physiological Ca2+ release. On the other hand, CICR appears to play a key role in caffeine contracture and malignant hyperthermia. The potentiation of voltage-activated Ca2+ release by caffeine, however, does not seem to occur through secondary CICR, although the site where caffeine potentiates voltage-activated Ca2+ release might be the same site where caffeine potentiates CICR.
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PMID:Calcium-induced calcium release in skeletal muscle. 1978 79

Longissimus muscle samples from the pig genotypes Duroc (Du), Pietrain (MHS homozygote negative (PiNN), positive (PiPP)) and a Duroc-Pietrain crossbreed (DuPi) were analyzed. The PiPP samples showed a faster pH drop and higher electrical conductivity, drip loss and lightness values. Before slaughter the concentrations of the adenine nucleotides were comparable between the genotypes, but 40 min after slaughter (p.m.) the ATP concentrations decreased and IMP increased, to a higher extent in the PiPP pigs. The nucleotide values of the 12 h p.m. samples were again comparable. Activities of glycogen phosporylase (GP), phosphofructokinase (PFK) and lactate dehydrogenase (LDH) were nearly similar before slaughter. Forty minutes after slaughter the LDH activities increased in all pigs and the PFK activities in all genotypes but not in the PiPP. GP results were rather inconsistent indicating an earlier activation of this enzyme. The study showed that the reduced meat quality in the PiPP pigs is accompanied with rapid ATP degradation and accelerated enzyme activation.
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PMID:Adenine nucleotide concentrations and glycolytic enzyme activities in longissimus muscle samples of different pig genotypes collected before and after slaughter. 2159 77


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