TRPV1 variants impair intracellular Ca 2+ signaling and may confer susceptibility to malignant hyperthermia

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anesthetics / pharmacology
  • Animals
  • Calcium
  • Calcium Signaling*
  • Disease Models, Animal
  • Female
  • Gene Expression / drug effects
  • Gene Knock-In Techniques
  • Genetic Predisposition to Disease*
  • HEK293 Cells
  • Homeostasis
  • Humans
  • Male
  • Malignant Hyperthermia / genetics*
  • Malignant Hyperthermia / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Muscle, Skeletal / metabolism
  • TRPV Cation Channels / genetics*
  • TRPV Cation Channels / metabolism

Substances

  • Anesthetics
  • TRPV Cation Channels
  • TRPV1 protein, human
  • TRPV1 protein, mouse
  • Calcium