scholarly journals [3H]ryanodine as a probe of changes in the functional state of the Ca(2+)-release channel in malignant hyperthermia.

1992 ◽  
Vol 267 (10) ◽  
pp. 6702-6709
Author(s):  
M.J. Hawkes ◽  
T.E. Nelson ◽  
S.L. Hamilton
Keyword(s):  
Malignant Hyperthermia ◽  
Functional State ◽  
Release Channel

Caffeine stimulation of malignant hyperthermia-susceptible sarcoplasmic reticulum Ca2+ release channel

1994 ◽  
Vol 267 (5) ◽  
pp. C1253-C1261 ◽  
Author(s):  
N. H. Shomer ◽  
J. R. Mickelson ◽  
C. F. Louis
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Malignant Hyperthermia ◽  
Single Channel ◽  
Release Channel ◽  
Muscle Contracture ◽  
Malignant Hyperthermia Susceptible ◽  
Open Time ◽  
Pig Muscle ◽  
Channel Mutation ◽  
The Difference

The altered caffeine sensitivity of malignant hyperthermia-susceptible (MHS) muscle contracture is one basis of the diagnostic test for this syndrome. To determine whether the Arg615-to-Cys615 mutation of the porcine sarcoplasmic reticulum (SR) Ca2+ release channel is directly responsible for this altered caffeine sensitivity, the single-channel kinetics of purified MHS and normal pig Ca2+ release channels were examined. Initial studies demonstrated that decreasing the pH of the medium in either the cis- or trans-chamber decreased the Ca2+ release channel percent open time (Po). The half-inhibitory pH of MHS channels (6.86 +/- 0.04, n = 17) was significantly different from that of normal channels (7.08 +/- 0.07, n = 14). At pH 7.4, in either 7 or 0.12 microM Ca2+, MHS channel Po was not significantly different from that of normal channels over the range 0-10 mM caffeine. Although at pH 6.8 in 7 microM Ca2+ MHS channel Po was greater than that of normal channels over the range 0-20 mM caffeine, the difference could be eliminated by dividing each mean MHS Po by a scaling factor of 3.2. Thus the MHS Ca2+ release channel mutation does not appear to be directly responsible for the altered caffeine sensitivity of MHS pig muscle contracture. Rather, this altered caffeine sensitivity may result from an altered resting myoplasmic Ca2+ concentration or the altered pH and Ca2+ sensitivity of Ca2+ release channel Po of MHS muscle.

Altered E-C coupling in triads isolated from malignant hyperthermia-susceptible porcine muscle

1995 ◽  
Vol 268 (6) ◽  
pp. C1381-C1386 ◽  
Author(s):  
R. el-Hayek ◽  
M. Yano ◽  
B. Antoniu ◽  
J. R. Mickelson ◽  
C. F. Louis ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Malignant Hyperthermia ◽  
Dihydropyridine Receptor ◽  
Normal Muscle ◽  
Direct Stimulation ◽  
Release Channel ◽  
Malignant Hyperthermia Susceptible ◽  
T Tubules ◽  
Junctional Foot Protein ◽  
Stimulation Of

Triad vesicles were isolated from normal (N) and homozygous malignant hyperthermia-susceptible (MHS) porcine skeletal muscle, and two types of sarcoplasmic reticulum Ca2+ release were investigated: 1) polylysine-induced Ca2+ release (direct stimulation of the junctional foot protein), and 2) depolarization-induced Ca2+ release (stimulation of the junctional foot protein via the dihydropyridine receptor). At submaximal concentrations of polylysine, the rates of induced Ca2+ release from the MHS triads were greater than from normal triads. The T tubules of polarized triads were depolarized by the K(+)-to-Na+ ionic replacement protocol. Higher grades of T-tubule depolarization resulted in higher rates of Ca2+ release from both MHS and normal triads but, when compared at a given grade of T-tubule depolarization, the release rate was always greater from the MHS than from normal triads. Thus the activity of the SR Ca2+ release channel is always higher in MHS than in normal muscle at a given submaximal dose of release trigger. This difference is observed when the channel is stimulated directly by polylysine or indirectly via a depolarization-induced activation of the T-tubule dihydropyridine receptor.

Results of Contracture Tests with Halothane, Caffeine, and Ryanodine Depend on Different Malignant Hyperthermia-associated Ryanodine Receptor Gene Mutations

2002 ◽  
Vol 97 (2) ◽  
pp. 345-350 ◽  
Author(s):  
Marko Fiege ◽  
Frank Wappler ◽  
Ralf Weisshorn ◽  
Mark Ulrich Gerbershagen ◽  
Markus Steinfath ◽  
...  
Keyword(s):  
Malignant Hyperthermia ◽  
Ryanodine Receptor ◽  
Time Course ◽  
Clinical Symptoms ◽  
Receptor Gene ◽  
Gene Mutations ◽  
Onset Time ◽  
Release Channel ◽  
Ryr1 Gene

Background More than 20 mutations in the gene encoding for the ryanodine receptor (RYR1), a Ca2+ release channel of the skeletal muscle sarcoplasmic reticulum, have been found to be associated with malignant hyperthermia (MH). This study was designed to investigate the effects of different mutations in the RYR1 gene on contracture development in in vitro contracture tests (IVCT) with halothane, caffeine, and ryanodine. Methods Ninety-three MH-susceptible (MHS) patients, diagnosed by the standard IVCT with halothane and caffeine, were included in this prospective study. Surplus muscle specimens were used for an IVCT with 1 microm ryanodine. The contracture course during the ryanodine IVCT was described by the attainment of different time points: onset time of contracture and times when contracture reached 2 mN or 10 mN. In addition, all patients were screened for mutations of the RYR1 gene. Results In 36 patients, four different mutations of the RYR1 gene (C487-T, G1021-A, C1840-T, G7300-A) were found. The IVCT threshold concentrations of halothane and caffeine were lower in patients with the C487-T mutation compared with patients without a detected mutation in the RYR1 gene. In the IVCT with ryanodine, contracture levels of 2 mN and 10 mN were reached earlier in muscle specimens from patients with C487-T, C1840-T, and G7300-A mutations compared with specimens from patients with the G1021-A mutation and patients without detected mutation in the RYR1 gene. Conclusions The differences between the groups in the halothane and caffeine IVCT threshold concentrations and in the time course of contracture development in the ryanodine IVCT underline the hypothesis that certain mutations in the RYR1 gene could make the ryanodine receptor more sensitive to specific ligands. This may be an explanation for varying clinical symptoms of MH crisis in humans.

scholarly journals Sever Rhabdomyolysis With Normal Renal Function Test in a 29-Year Old Who is Known to have RYR1 Mutation

2020 ◽  
Vol 5 (7) ◽  
pp. 1260-1261
Author(s):  
Roa A. Ali ◽  
Hassan Naeem
Keyword(s):  
Malignant Hyperthermia ◽  
Calcium Release ◽  
Receptor Gene ◽  
Kidney Injury ◽  
Upper Respiratory Tract ◽  
Calcium Release Channel ◽  
Rare Type ◽  
Release Channel ◽  
Function Test ◽  
Upper Respiratory

Ryanodine receptor gene (RYR-1) is a gene encode calcium release channel in skeletal muscle , mutation in this gene lead to rare type of inherited congenital myopathy which is associated with rhabdomyolysis and fatal malignant hyperthermia . We report a case of a 29 year old male known to have sporadic RYR-1 mutation who presented with myalgia and fatigue post upper respiratory tract infection symptoms during COVID19 pandemic .His Creatine Kinase was markedly elevated without evidence of acute kidney injury which is usually uncommon. We also discuss in this case importance of checking CK during COVID19 pandemic .There is no cure for RYR-1 mutation but proper genetic counselling and patient’s education about precipitating factor for malignant hyperthermia will prevent serious complication which can lead to death.

scholarly journals Increased basal metabolic rate in mice susceptible to malignant hyperthermia and heat stroke

2021 ◽  
Vol 154 (9) ◽  
Author(s):  
Matteo Serano ◽  
Laura Pietrangelo ◽  
Cecilia Paolini ◽  
Flavia A. Guarnier ◽  
Feliciano Protasi
Keyword(s):  
Malignant Hyperthermia ◽  
Heat Stroke ◽  
Gene Encoding ◽  
Release Channel ◽  
Western Blots ◽  
Ec Coupling ◽  
Mitochondrial Volume ◽  
Total Body ◽  
Old Mice

Ryanodine receptor type-1 (RYR1) and Calsequestrin-1 (CASQ1) proteins, located in the sarcoplasmic reticulum (SR), are two of the main players in skeletal excitation–contraction (EC) coupling. Mutations in the human RYR1 gene (encoding for the SR Ca2+ release channel) and ablation in mice of CASQ1 (a SR Ca2+ binding protein) cause hypersensitivity to halogenated anesthetics (malignant hyperthermia [MH] susceptibility) and to heat (heat stroke; HS). As both MH and HS are characterized by excessive cytosolic Ca2+ levels and hypermetabolic responses, we studied the metabolism of 4-mo-old mice from two different lines that are MH/HS susceptible: knock-in mice carrying a human MH mutation (RYR1YS) and CASQ1-knockout (ko) mice. RYR1YS and, to a lesser degree, CASQ1-null mice show an increased volume of oxygen consumption (VO2) and a lower respiratory quotient (RQ) compared with WT mice (indicative of a metabolism that relies more on lipids). This finding is accompanied by a reduction in total body fat mass in both Y522S and CASQ1-null mice (again, compared with WT). In addition, we found that RYR1YS and CASQ1-null mice have an increased food consumption (+26.04% and +25.58% grams/day, respectively) and higher basal core temperature (+0.57°C and +0.54°C, respectively) compared with WT mice. Finally, Western blots and electron microscopy indicated that, in hyperthermic mice, (1) SERCA (used to remove myoplasmic Ca2+) and UCP3 (responsible for a thermogenic process that dissipates mitochondrial H+ gradient) are overexpressed, and (2) mitochondrial volume and percentage of damaged mitochondria are both increased. In conclusion, the MH/HS phenotype in RYR1YS and CASQ1-null mice is associated with an intrinsically increased basal metabolism.

scholarly journals Calmodulin sensitivity of the sarcoplasmic reticulum ryanodine receptor from normal and malignant-hyperthermia-susceptible muscle

1996 ◽  
Vol 319 (2) ◽  
pp. 421-426 ◽  
Author(s):  
Sean O'DRISCOLL ◽  
Tommie V. McCARTHY ◽  
Hans M. EICHINGER ◽  
Wolf ERHARDT ◽  
Frank LEHMANN-HORN ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Malignant Hyperthermia ◽  
Ryanodine Receptor ◽  
Central Region ◽  
Dependent Manner ◽  
Release Channel ◽  
Malignant Hyperthermia Susceptible ◽  
Potential Binding ◽  
Cam Regulation

Ca2+ release from sarcoplasmic reticulum (SR) of malignant-hyperthermia-susceptible (MHS) muscle is hypersensitive to Ca2+ and caffeine. To determine if an abnormal calmodulin (CaM) regulation of the SR Ca2+-release-channel-ryanodine-receptor complex (RYR1) contributes to this hypersensitivity, we investigated the effect of CaM on high-affinity [3H]ryanodine binding to isolated SR vesicles from normal and MHS pig skeletal muscle. CaM modulated [3H]ryanodine binding in a Ca2+-dependent manner. In the presence of maximally activating Ca2+ concentrations, CaM inhibited [3H]ryanodine binding with no differences between normal and MHS vesicles. In the absence of Ca2+, however, CaM activated [3H]ryanodine binding with a 2-fold-higher potency in MHS vesicles. Significant differences between normal and MHS tissue were observed for CaM concentrations between 50 nM and 10 µM. A polyclonal antibody raised against the central region of RYR1 specifically inhibited this activating effect of CaM without affecting the inhibition by CaM. This indicates that the central region of RYR1 is a potential binding domain for CaM in the absence of Ca2+. It is suggested that in vivo an enhanced CaM sensitivity of RYR1 might contribute to the abnormal high release of Ca2+ from the SR of MHS muscle.

Malignant Hyperthermia: An Inherited Disorder of Skeletal Muscle Ca2+ Regulation

2001 ◽  
Vol 21 (2) ◽  
pp. 155-168 ◽  
Author(s):  
Charles F. Louis ◽  
Edward M. Balog ◽  
Bradley R. Fruen
Keyword(s):  
Skeletal Muscle ◽  
Malignant Hyperthermia ◽  
Muscle Relaxants ◽  
Release Channel ◽  
Major Locus ◽  
Channel Proteins ◽  
Ec Coupling ◽  
Physiologic Mechanism ◽  
Intact Muscle ◽  
Life Threatening

Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle characterized by muscle contracture and life-threatening hypermetabolic crisis following exposure to halogenated anesthetics and depolarizing muscle relaxants during surgery. Susceptibility to MH results from mutations in Ca2+ channel proteins that mediate excitation–contraction (EC) coupling, with the ryanodine receptor Ca2+ release channel (RyR1) representing the major locus. Here we review recent studies characterizing the effects of MH mutations on the sensitivity of the RyR1 to drugs and endogenous channel effectors including Ca2+ and calmodulin. In addition, we present a working model that incorporates these effects of MH mutations on the isolated RyR1 with their effects on the physiologic mechanism that activates Ca2+ release during EC coupling in intact muscle.

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