Excitation-contraction coupling in pigs heterozygous for malignant hyperthermia

Gallant, Esther M.; Lentz, Linnea

doi:10.1152/ajpcell.1992.262.2.c422

Cited by 38 publications

(34 citation statements)

References 15 publications

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“…Its distinctive properties are: 1) it is initiated by depolarization; 2) it is dependent on the presence of both RyR1 and DHPR; 3) it is independent of the DHPR L-type Ca 2ϩ current; 4) it does not depend on SR Ca 2ϩ release; and 5) it can be effectively inhibited by La 3ϩ or SKF96365 (24). Previous studies of KCl responses in MH muscle cells showed significantly larger muscle contractures and lower KCl contracture thresholds in muscle fibers dissected from MH susceptible swine compared with WT (42)(43)(44). In addition, it has been reported that the total calcium transient in MH susceptible muscle fibers was larger than control fibers when exposed to subcontracture and contracture concentrations of KCl (30,43,45,46 This is most easily detectable during the sustained phase that follows the peak of the Ca 2ϩ transient.…”

Section: Discussionmentioning

confidence: 93%

“…Previous studies of KCl responses in MH muscle cells showed significantly larger muscle contractures and lower KCl contracture thresholds in muscle fibers dissected from MH susceptible swine compared with WT (42)(43)(44). In addition, it has been reported that the total calcium transient in MH susceptible muscle fibers was larger than control fibers when exposed to subcontracture and contracture concentrations of KCl (30,43,45,46 This is most easily detectable during the sustained phase that follows the peak of the Ca 2ϩ transient. The data from our previous study on seven common MH RyR1s expressed in dyspedic myotubes gave us the first clue that the kinetics of MH-associated Ca 2ϩ transients, especially the sustained phase, is significantly different compared with WT RyR1 myotubes (30).…”

Section: Discussionmentioning

confidence: 94%

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Enhanced Excitation-coupled Calcium Entry in Myotubes Is Associated with Expression of RyR1 Malignant Hyperthermia Mutations

Yang

Allen

Pessah

et al. 2007

Journal of Biological Chemistry

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1 mM), or SKF 96365 (20 M) to Ca؉ significantly accelerated decay rates for both WT and MH, but their effect was significantly greater in MH. Nifedipine (1 M) had no effect, suggesting that the mechanism for this difference was not a reduction in L-type Ca 2؉ channel Ca 2؉ current. These data strongly suggest: 1) the decay rate in skeletal myotubes is related in part to Ca 2؉ entry through the ECCE channel; 2) the MH mutations enhance ECCE compared with wild type; and 3) the increased Ca 2؉ entry might play a significant role in the pathophysiology of MH.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 94%

Enhanced Excitation-coupled Calcium Entry in Myotubes Is Associated with Expression of RyR1 Malignant Hyperthermia Mutations

Yang

Allen

Pessah

et al. 2007

Journal of Biological Chemistry

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“…Several different preparations have been utilized for functional analysis of caffeine sensitivity of MH RyR1. These have included measurements of caffeine-induced Ca 2ϩ release from heavy SR membranes prepared from MH pig muscles (26), as well as cellular responses to caffeine utilizing either cultured primary myotubes prepared from human or pig muscle biopsies (22,27), or non-muscle cells expressing MH RyR1s (12). Collectively these diverse preparations have shown that an increased caffeine sensitivity was a common characteristic for each MH mutation.…”

Section: Heightened Efficacy Of Caffeine Toward Mh Ryr1s At Resting Imentioning

confidence: 99%

Functional Defects in Six Ryanodine Receptor Isoform-1 (RyR1) Mutations Associated with Malignant Hyperthermia and Their Impact on Skeletal Excitation-Contraction Coupling

Yang

Pessah

et al. 2003

Journal of Biological Chemistry

104

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Malignant hyperthermia (MH) is a potentially fatal pharmacogenetic disorder of skeletal muscle that segregates with >60 mutations within the MHS-1 locus on chromosome 19 coding for ryanodine receptor type 1 (RyR1). Although some MH RyR1s have been shown to enhance sensitivity to caffeine and halothane when expressed in non-muscle cells, their influence on EC coupling can only be studied in skeletal myotubes. We therefore expressed WT RyR1, six of the most common human MH RyR1s (R163C, G341R, R614C, R2163C, V2168M, and R2458H), and a newly identified C-terminal mutation (T4826I) in dyspedic myotubes to study their functional defects and how they influence EC coupling. Myotubes expressing any MH RyR1 were significantly more sensitive to stimulation by caffeine and 4-CmC than those expressing WT RyR1. ] i typical of normal myotubes at rest are key defects that contribute to the initiation of MH episodes. Malignant hyperthermia (MH)1 is a rare potentially fatal pharmacological disorder of skeletal muscle that can be triggered by commonly used volatile anesthetic agents and depolarizing muscle relaxants. It is clinically characterized by masseter spasm, tachycardia, increased end-tidal CO 2 , lactic acidosis, and hyperthermia, and if untreated progresses to death. The ryanodine receptor isoform-1 gene (ryr1) on chromosome 19q13.1 clearly represents a primary molecular locus for MH in humans, termed the MHS-1 locus, as mutations in ryr1 have been linked to more than 50% of all MH families and most central core disease (CCD) families (1). The ryr1 gene codes for a large conductance channel (RyR1) essential for release of SR Ca 2ϩ during skeletal muscle excitation contraction (EC) coupling (2, 3). Molecular genetic studies have shown that RyR1 mutations R615C and R614C co-segregate with porcine and human MH, respectively (4, 5). Functional analysis of skeletal muscle expressing either of these analogous mutations has revealed that a causative defect in MH is hypersensitive gating of the Ca 2ϩ release channel. However abnormalities in SR Ca 2ϩ release function have also been indicated even in the absence of RyR1 mutations, suggesting other loci, possibly in genes coding for RyR1 accessory proteins, may be involved in producing a common MH phenotype. To date, about 60 missense and deletion mutations (6) have been associated with an abnormal in vitro contracture test (CHCT/IVCT) and/or clinical MH or CCD. CCD is a non-progressive autosomal dominant myopathy that is characterized by hypotonia and mild proximal weakness affecting mainly the lower limbs. However the relationship between MH and CCD is not clear. Interestingly, all known MH-and CCD-related mutations found in the ryr1 gene are located in one of three "hot spots." The first hot spot is in the N-terminal region clustered between amino acid residues 35 and 614 (MH/CCD region 1); the second between amino acid residues 2163 and 2458 (MH/CCD region 2); and the third in the C-terminal transmembrane region, between amino acid residues 4643 and 4898.Functional analysis o...

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“…This difference was consistent with the previously documented higher twitch-totetanus ratio in MHS as compared with normal muscles. 7,9 In spite of this difference in tension at low frequencies, the degree of fusion at each stimulus frequency was not significantly different between the two muscle types at 36°C (see Fig. 2A).…”

Section: Resultsmentioning

confidence: 88%

“…In MHS muscles the mechanical threshold is lower, twitch-to-tetanus ratio is greater, and sensitivity to a number of drugs is enhanced 9 in comparison to normal muscles. However, other predicted alterations in contractile properties have not been observed.…”

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confidence: 98%