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Genet Med. 2019 Feb;21(2):441-450. doi: 10.1038/s41436-018-0066-9. Epub 2018 Jun 21.

TRPV1 variants impair intracellular Ca2+ signaling and may confer susceptibility to malignant hyperthermia.

Author information

1
Inserm U1003, Laboratory of Excellence, Ion Channels Science and Therapeutics, Equipe Labélisée par la Ligue Nationale Contre le Cancer, SIRIC ONCOLille, Université des Sciences et Technologies de Lille, Villeneuve d'Ascq, 59656, France. Fabien.vanden-abeele@inserm.fr.
2
Université de Lyon, Lyon, Cedex 07, France.
3
Univ-Lyon, CarMeN laboratory, Inserm U1060, INRA U1397, Université Claude Bernard Lyon1, INSA Lyon, Hospital Cardiology, IHU OPERA Cardioprotection, B13 Building, Lyon East, 59 Boulevard Pinel, Fr-69500, Bron, France.
4
School of Biomedical Sciences, University of Leeds, Leeds, LS2 9JT, UK.
5
Inserm U1003, Laboratory of Excellence, Ion Channels Science and Therapeutics, Equipe Labélisée par la Ligue Nationale Contre le Cancer, SIRIC ONCOLille, Université des Sciences et Technologies de Lille, Villeneuve d'Ascq, 59656, France.
6
Laboratoire de Biochimie Génétique et Moléculaire, IBP, CHU Grenoble Alpes, F-38000, Grenoble, France.
7
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas, 77030, USA.
8
Université de Lyon, UMR 5023 Ecologie des Hydrosystèmes Naturels et Anthropisés, Université Lyon 1, ENTPE, CNRS, 6 rue Raphaël Dubois, 69622, Villeurbanne, France.
9
INSERM U1216, F-38000, Grenoble, France.
10
Univ. Grenoble Alpes, Grenoble Institut des Neurosciences, GIN, F-38000, Grenoble, France.
11
Université de Lyon, Lyon, Cedex 07, France. Fabien.Van-Coppenolle@univ-lyon1.fr.
12
Univ-Lyon, CarMeN laboratory, Inserm U1060, INRA U1397, Université Claude Bernard Lyon1, INSA Lyon, Hospital Cardiology, IHU OPERA Cardioprotection, B13 Building, Lyon East, 59 Boulevard Pinel, Fr-69500, Bron, France. Fabien.Van-Coppenolle@univ-lyon1.fr.

Abstract

PURPOSE:

Malignant hyperthermia (MH) is a pharmacogenetic disorder arising from uncontrolled muscle calcium release due to an abnormality in the sarcoplasmic reticulum (SR) calcium-release mechanism triggered by halogenated inhalational anesthetics. However, the molecular mechanisms involved are still incomplete.

METHODS:

We aimed to identify transient receptor potential vanilloid 1 (TRPV1) variants within the entire coding sequence in patients who developed sensitivity to MH of unknown etiology. In vitro and in vivo functional studies were performed in heterologous expression system, trpv1-/- mice, and a murine model of human MH.

RESULTS:

We identified TRPV1 variants in two patients and their heterologous expression in muscles of trpv1-/- mice strongly enhanced calcium release from SR upon halogenated anesthetic stimulation, suggesting they could be responsible for the MH phenotype. We confirmed the in vivo significance by using mice with a knock-in mutation (Y524S) in the type I ryanodine receptor (Ryr1), a mutation analogous to the Y522S mutation associated with MH in humans. We showed that the TRPV1 antagonist capsazepine slows the heat-induced hypermetabolic response in this model.

CONCLUSION:

We propose that TRPV1 contributes to MH and could represent an actionable therapeutic target for prevention of the pathology and also be responsible for MH sensitivity when mutated.

KEYWORDS:

Calcium; Hereditary disease; Malignant hyperthermia; TRP channel; TRPV1

PMID:
29930394
PMCID:
PMC6752298
DOI:
10.1038/s41436-018-0066-9
[Indexed for MEDLINE]
Free PMC Article

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