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

Fabien Vanden Abeele (1, 2) , Sabine Lotteau (3, 4, 5, 6, 7, 8) , Sylvie Ducreux (8, 6) , Charlotte Dubois (1) , Nicole Monnier (9) , Amy Hanna (10) , Dimitra Gkika (1, 2) , Caroline Romestaing (11, 12, 13, 5) , Lucile Noyer (1, 2) , Matthieu Flourakis (1) , Nolwenn Tessier (3, 4, 5, 8) , Ribal Al-Mawla (8) , Christophe Chouabe (8) , Etienne Lefai (8) , Joël Lunardi (9) , Susan Hamilton (10) , Julien Fauré (9, 14, 3) , Fabien van Coppenolle (3, 4, 5, 8) , Natalia Prevarskaya (1, 2)

1 LabEx ICST, Laboratoire d'excellence Canaux Ioniques d'Intérêt Thérapeutique, Equipe Labélisée par la Ligue Nationale Contre le Cancer, SIRIC ONCOLille
2 PHYCELL - Laboratoire de Physiologie Cellulaire : Canaux ioniques, inflammation et cancer - U 1003
3 INSERM - Institut National de la Santé et de la Recherche Médicale
4 INSA Lyon - Institut National des Sciences Appliquées de Lyon
5 UCBL - Université Claude Bernard Lyon 1
6 Université de Lyon
7 School of Biomedical Sciences
8 CarMeN - Cardiovasculaire, métabolisme, diabétologie et nutrition
9 IBP, Laboratoire de Biochimie Génétique et Moléculaire
10 Department of Molecular Physiology and Biophysics
11 LEHNA - Laboratoire d'Ecologie des Hydrosystèmes Naturels et Anthropisés
12 CNRS - Centre National de la Recherche Scientifique
13 ENTPE - École Nationale des Travaux Publics de l'État
14 GIN - [GIN] Grenoble Institut des Neurosciences

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.

Mots clés: mice; hereditary diseases; malignant hyperthermia; hereditary disease; TRP channel; calcium; TRPV1

Mots clés: souris; maladie héréditaire; hyperthermie maligne

Domaines: Sciences du Vivant [q-bio]

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, 2019, 21 (2), pp.441-450. ⟨10.1038/s41436-018-0066-9⟩. ⟨hal-02475163⟩