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

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.
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Soumis le : mardi 11 février 2020 - 20:10:00
Dernière modification le : mardi 26 mai 2020 - 12:23:12
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Fabien Vanden Abeele, Sabine Lotteau, Sylvie Ducreux, Charlotte Dubois, Nicole Monnier, et al.. TRPV1 variants impair intracellular Ca2+ signaling and may confer susceptibility to malignant hyperthermia. Genetics in Medicine, Nature Publishing Group, 2019, 21 (2), pp.441-450. ⟨10.1038/s41436-018-0066-9⟩. ⟨hal-02475163⟩



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