A Multicenter Study of 4-Chloro-m-cresol for Diagnosing Malignant Hyperthermia Susceptibility

Baur, C; Bellon, L.; Felleiter, Peter; Fiege, Marko; Fricker, Ruth; Glahn, Klaus Peter Egede; Heffron, J. J. A.; Herrmann‐Frank, Annegret; Jurkat‐Rott, Karin; Klingler, Werner; Lehane, Mary; Ørding, Helle; Tegazzin, Vincenzo; Wappler, Frank; Georgieff, Michael; Lehmann‐Horn, Frank

doi:10.1097/00000539-200001000-00040

Cited by 50 publications

(27 citation statements)

References 25 publications

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“…4-Chloro-m-cresol has been identified recently as a trigger of MH in susceptible swine [58,59] and has been recommended for use in a supplementary test for diagnosis of MH [60,61]. In the present study, mutants G2370A, G2373A and G2375A had decreased 4-chloro-m-cresol sensitivity of activation, in parallel with decreased caffeine sensitivity, suggesting that MH domain 2 is an important regulatory domain for both caffeine and 4-chlorom-cresol.…”

Section: Discussionsupporting

confidence: 56%

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)

OYAMADA

Khanna

et al. 2001

Biochemical Journal

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and K3940A were made in two potential ATPbinding motifs (amino acids 2370-2375 and 3937-3940) In the presence of 1 mM AMP-PCP, Ca# + -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 INTRODUCTIONCa# + -release channels of sarcoplasmic reticulum (ryanodine receptors, or RyRs) are large homotetrameric molecules with molecular masses of $ 2.26 MDa [1][2][3][4]. These channels are modulated by endogenous and exogenous ligands such as Ca# + , ATP, caffeine, calmodulin, Mg# + , Ruthenium Red and ryanodine, but the extent of modulation varies among RyR1, the isoform expressed in skeletal muscle, RyR2, expressed in cardiac muscle, and RyR3, expressed more ubiquitously [5][6][7]. Ca# + is a basic modulator of Ca# + -release channel function. At low concentrations, Ca# + activates both skeletal-and cardiac-muscle Ca# + -release channels ; at high concentrations, it inactivates the skeletal-muscle Ca# + -release channel. Ca# + activation and inactivation sites are localized in the C-terminal one-fifth of the RyR1 molecule region [8][9][10][11][12]. This C-terminal region of RyR also forms the Ca# + -conducting pore and contains both high-and low-affinity binding sites for ryanodine [8,[13][14][15]. The molecular mechanisms underlying the interactions of modulators with RyRs are poorly understood.Adenine nucleotides activate Ca# + -release channels with EC &! values in the millimolar range. Activation is probably through a molecular site different from, but interacting with, the Ca# + -activation or Mg# + -binding site [5][6][7]. Motifs identifying potential Abbreviations used : RyR, ryanodine receptor ; RyR1, skeletal-muscle RyR isoform ; RyR2, cardiac-muscle RyR isoform ; AMP-PCP, adenosine 5h-[β,γ-methylene]triphosphate ; MH, malignant hyperthermia ; CCD, central core disease ; pCa, klog [Ca].

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Section: Discussionsupporting

confidence: 56%

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)

OYAMADA

Khanna

et al. 2001

Biochemical Journal

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“…A recent multi-center study to evaluate the usefulness of an IVCT with 4-CmC found that the predictive value of 4-CmC for the diagnosis of MH susceptibility is as high as that of caffeine, and its use in IVCT has been proposed to refine diagnosis of MH susceptibility (30). Transient expression of R615C and WT RyR1 in COS-7 cells first revealed a significantly lower threshold for 4-CmC-induced Ca 2ϩ mobilization for MH RyR1 (56 Ϯ 3 versus 166 Ϯ 12 M respectively, Ref.…”

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

105

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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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“…4-CmC, a structural analog of phenol, activates RyR1 with an EC 50 value of ϳ50 to 200 M (Zorzato et al, 1993;Herrmann-Frank et al, 1996b). Sensitivity to activation by 4-CmC is increased for RyR1-containing mutations linked to the skeletal muscle disorder malignant hyperthermia, a finding that has led to the clinical use of 4-CmC in malignant hyperthermia diagnosis (Herrmann-Frank et al, 1996a;Baur et al, 2000). However, 4-CmC is a poor activator of the "brain" RyR isoform RyR3 , because millimolar levels of 4-CmC are required to activate this isoform (Matyash et al, 2002).…”

mentioning

confidence: 99%

Structural Determinants of 4-Chloro-m-cresol Required for Activation of Ryanodine Receptor Type 1

Jacobson¹,

Moe²,

Allen³

et al. 2006

Mol Pharmacol

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4-Chloro-m-cresol (4-CmC) is a clinically relevant activator of the intracellular Ca 2ϩ release channel, the ryanodine receptor isoform 1 (RyR1). In this study, the chemical moieties on the 4-CmC molecule required for its activation of RyR1 were determined using structure-activity relationship analysis with a set of commercially available 4-CmC analogs. Separate compounds each lacking one of the three functional groups of 4-CmC (1-hydroxyl, 3-methyl, or 4-chloro) were poor activators of RyR1. Substitution of different chemical groups for the 1-hydroxyl of 4-CmC resulted in compounds that were poor activators of RyR1, suggesting that the hydroxyl group is preferred at this position. Substitution of hydrophobic groups at the 3-position enhanced bioactivity of the compound relative to 4-CmC, whereas substitution with hydrophilic groups abolished bioactivity. Likewise, 4-CmC analogs with hydrophobic groups substituted into the 4-position enhanced bioactivity, whereas hydrophilic or charged groups diminished bioactivity. 4-CmC analogs containing a single hydrophobic group at either the 3-or 4-position as well as 3,5-disubstituted or 3,4,5-trisubstituted phenols were also effective activators of RyR1. These results indicate that the 1-hydroxyl group of 4-CmC is required for activation of RyR1 and that hydrophobic groups at the 3,4-and 5-positions are preferred. These findings suggest that the 4-CmC binding site on RyR1 most likely consists of a hydrophilic region to interact with the 1-hydroxyl as well as a hydrophobic region(s) to interact with chemical groups at the 3-and/or 4-positions of 4-CmC.

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A Multicenter Study of 4-Chloro-m-cresol for Diagnosing Malignant Hyperthermia Susceptibility

Cited by 50 publications

References 25 publications

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)

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)

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

Structural Determinants of 4-Chloro-m-cresol Required for Activation of Ryanodine Receptor Type 1

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