The work of Fabien Van Coppenolle and Sylvie Ducreux,  from CarMeN team 5  in collaboration with other team 5 and 2 members, have just identify and characterize human variants of the TRPV1 channel that confer muscle sensitivity to anesthetics exposure, suggesting suggest that TRPV1 plays a critical role in the aberrant Ca2+ homeostasis observed in Malignant hyperthermia (MH).

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 poorly understood.

In the study published at June 21, 2018 in the journal “Genetics in Medicine”, we aimed to identify 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. We identified TRPV1 variants in 2 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, 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.

We propose that TRPV1 contributes to MH and could represent a putative therapeutic target for prevention of the pathology.

 

 

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

Fabien Vanden Abeele , Sabine Lotteau , Sylvie Ducreux , Charlotte Dubois , Nicole Monnier , Amy Hanna , Dimitra Gkika , Caroline Romestaing , Lucile Noyer , Matthieu Flourakis ,Nolwenn Tessier , Ribal Al-Mawla , Christophe Chouabe , Etienne Lefai , Joël Lunardi , Susan Hamilton , Julien Fauré , Fabien Van Coppenolle  & Natalia Prevarskaya

Genetics in Medicine (2018)

DOI: 10.1038/s41436-018-0066-9

https://www.nature.com/articles/s41436-018-0066-9

Contacts:

Fabien Van Coppenolle

Equipe 5 – Laboratoire CarMeN

Mail :fabien.van-coppenolle@univ-lyon1.fr

 

 

Illustration du profil de Sylvie BIDAULT-DUCREUXSylvie Ducreux

Equipe 5 – Laboratoire CarMeN

Mail :sylvie.ducreux@univ-lyon1.fr