Pharmacologic and functional characterization of malignant hyperthermia in the R163C RyR1 knock-in mouse

Tianzhong Yang, Joyce Riehl, Eric Esteve, Klaus I. Matthaei, Samuel Goth, Paul D. Allen, Isaac N Pessah, José R. Lopez

Research output: Contribution to journalArticle

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Abstract

BACKGROUND: Malignant hyperthermia is a pharmacogenetic disorder affecting humans, dogs, pigs, and horses. In the majority of human cases and all cases in animals, malignant hyperthermia has been associated with missense mutations in the skeletal ryanodine receptor (RyR1). METHODS: The authors used a "knock-in" targeting vector to create mice carrying the RyR1 R163C malignant hyperthermia mutation. RESULTS: Validation of this new mouse model of human malignant hyperthermia susceptibility includes (1) proof of transcription of the R163C allele and expression of ryanodine receptor protein in R163C heterozygous and R163C homozygous animals; (2) fulminant malignant hyperthermia episodes in R163C heterozygous mice after exposure to 1.25-1.75% halothane or an ambient temperature of 42°C characterized by increased rectal temperature, respiratory rate, and inspiratory effort, with significant blood biochemical changes indicating metabolic acidosis, ending in death and hyperacute rigor mortis; (3) intraperitoneal pretreatment with dantrolene provided 100% protection from the halothane-triggered fulminant malignant hyperthermia episode; (4) significantly increased sensitivity (decreased effective concentration causing 50% of the maximal response) of R163C heterozygous and homozygous myotubes to caffeine, 4-chloro-m-cresol, and K-induced depolarization; (5) R163C heterozygous and homozygous myotubes have a significantly increased resting intracellular Ca concentration compared with wild type; (6) R163C heterozygous sarcoplasmic reticulum membranes have a twofold higher affinity (Kd = 35.4 nm) for [H]ryanodine binding compared with wild type (Kd = 80.1 nm) and a diminished inhibitory regulation by Mg. CONCLUSIONS: Heterozygous R163C mice represent a valid model for studying the mechanisms that cause the human malignant hyperthermia syndrome.

Original languageEnglish (US)
Pages (from-to)1164-1175
Number of pages12
JournalAnesthesiology
Volume105
Issue number6
DOIs
StatePublished - Dec 2006

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Malignant Hyperthermia
Ryanodine Receptor Calcium Release Channel
Skeletal Muscle Fibers
Halothane
Rigor Mortis
Dantrolene
Ryanodine
Temperature
Pharmacogenetics
Sarcoplasmic Reticulum
Missense Mutation
Respiratory Rate
Acidosis
Caffeine
Horses
Swine
Alleles
Dogs
Mutation
Membranes

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

Cite this

Yang, T., Riehl, J., Esteve, E., Matthaei, K. I., Goth, S., Allen, P. D., ... Lopez, J. R. (2006). Pharmacologic and functional characterization of malignant hyperthermia in the R163C RyR1 knock-in mouse. Anesthesiology, 105(6), 1164-1175. https://doi.org/10.1097/00000542-200612000-00016

Pharmacologic and functional characterization of malignant hyperthermia in the R163C RyR1 knock-in mouse. / Yang, Tianzhong; Riehl, Joyce; Esteve, Eric; Matthaei, Klaus I.; Goth, Samuel; Allen, Paul D.; Pessah, Isaac N; Lopez, José R.

In: Anesthesiology, Vol. 105, No. 6, 12.2006, p. 1164-1175.

Research output: Contribution to journalArticle

Yang, T, Riehl, J, Esteve, E, Matthaei, KI, Goth, S, Allen, PD, Pessah, IN & Lopez, JR 2006, 'Pharmacologic and functional characterization of malignant hyperthermia in the R163C RyR1 knock-in mouse', Anesthesiology, vol. 105, no. 6, pp. 1164-1175. https://doi.org/10.1097/00000542-200612000-00016
Yang, Tianzhong ; Riehl, Joyce ; Esteve, Eric ; Matthaei, Klaus I. ; Goth, Samuel ; Allen, Paul D. ; Pessah, Isaac N ; Lopez, José R. / Pharmacologic and functional characterization of malignant hyperthermia in the R163C RyR1 knock-in mouse. In: Anesthesiology. 2006 ; Vol. 105, No. 6. pp. 1164-1175.
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AU - Esteve, Eric

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AU - Goth, Samuel

AU - Allen, Paul D.

AU - Pessah, Isaac N

AU - Lopez, José R.

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N2 - BACKGROUND: Malignant hyperthermia is a pharmacogenetic disorder affecting humans, dogs, pigs, and horses. In the majority of human cases and all cases in animals, malignant hyperthermia has been associated with missense mutations in the skeletal ryanodine receptor (RyR1). METHODS: The authors used a "knock-in" targeting vector to create mice carrying the RyR1 R163C malignant hyperthermia mutation. RESULTS: Validation of this new mouse model of human malignant hyperthermia susceptibility includes (1) proof of transcription of the R163C allele and expression of ryanodine receptor protein in R163C heterozygous and R163C homozygous animals; (2) fulminant malignant hyperthermia episodes in R163C heterozygous mice after exposure to 1.25-1.75% halothane or an ambient temperature of 42°C characterized by increased rectal temperature, respiratory rate, and inspiratory effort, with significant blood biochemical changes indicating metabolic acidosis, ending in death and hyperacute rigor mortis; (3) intraperitoneal pretreatment with dantrolene provided 100% protection from the halothane-triggered fulminant malignant hyperthermia episode; (4) significantly increased sensitivity (decreased effective concentration causing 50% of the maximal response) of R163C heterozygous and homozygous myotubes to caffeine, 4-chloro-m-cresol, and K-induced depolarization; (5) R163C heterozygous and homozygous myotubes have a significantly increased resting intracellular Ca concentration compared with wild type; (6) R163C heterozygous sarcoplasmic reticulum membranes have a twofold higher affinity (Kd = 35.4 nm) for [H]ryanodine binding compared with wild type (Kd = 80.1 nm) and a diminished inhibitory regulation by Mg. CONCLUSIONS: Heterozygous R163C mice represent a valid model for studying the mechanisms that cause the human malignant hyperthermia syndrome.

AB - BACKGROUND: Malignant hyperthermia is a pharmacogenetic disorder affecting humans, dogs, pigs, and horses. In the majority of human cases and all cases in animals, malignant hyperthermia has been associated with missense mutations in the skeletal ryanodine receptor (RyR1). METHODS: The authors used a "knock-in" targeting vector to create mice carrying the RyR1 R163C malignant hyperthermia mutation. RESULTS: Validation of this new mouse model of human malignant hyperthermia susceptibility includes (1) proof of transcription of the R163C allele and expression of ryanodine receptor protein in R163C heterozygous and R163C homozygous animals; (2) fulminant malignant hyperthermia episodes in R163C heterozygous mice after exposure to 1.25-1.75% halothane or an ambient temperature of 42°C characterized by increased rectal temperature, respiratory rate, and inspiratory effort, with significant blood biochemical changes indicating metabolic acidosis, ending in death and hyperacute rigor mortis; (3) intraperitoneal pretreatment with dantrolene provided 100% protection from the halothane-triggered fulminant malignant hyperthermia episode; (4) significantly increased sensitivity (decreased effective concentration causing 50% of the maximal response) of R163C heterozygous and homozygous myotubes to caffeine, 4-chloro-m-cresol, and K-induced depolarization; (5) R163C heterozygous and homozygous myotubes have a significantly increased resting intracellular Ca concentration compared with wild type; (6) R163C heterozygous sarcoplasmic reticulum membranes have a twofold higher affinity (Kd = 35.4 nm) for [H]ryanodine binding compared with wild type (Kd = 80.1 nm) and a diminished inhibitory regulation by Mg. CONCLUSIONS: Heterozygous R163C mice represent a valid model for studying the mechanisms that cause the human malignant hyperthermia syndrome.

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