Striving toward hyperthermia-free analgesia: lessons from loss-of-function mutations of human TRPV1
Tingting Li, Man-Kyo Chung
Tingting Li, Man-Kyo Chung
Published February 1, 2023
Citation Information: J Clin Invest. 2023;133(3):e167338. https://doi.org/10.1172/JCI167338.
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Commentary

Striving toward hyperthermia-free analgesia: lessons from loss-of-function mutations of human TRPV1

Abstract

Transient receptor potential vanilloid 1 (TRPV1), a receptor for capsaicin and noxious heat, has been one of the most compelling targets for analgesics. However, systemic inhibition of TRPV1 is an impractical approach as a pain killer, since systemic antagonism induces hyperthermia. Two articles in this issue of the JCI report phenotypes from separate, rare missense mutations of human TRPV1. He, Zambelli, and colleagues investigated TRPV1K710N, which showed reduced functionality, while Katz, Zaguri, and co-authors reported on TRPV1N331K, which led to a complete functional knockout. The findings provide insights that will improve our understanding of the endogenous functions of TRPV1 in humans and may facilitate a rational TRPV1-targeting approach to achieve hyperthermia-free analgesia.

Authors

Tingting Li, Man-Kyo Chung

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Figure 1

Phenotypes of two rare loss-of-function missense mutations of human TRPV1.

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Phenotypes of two rare loss-of-function missense mutations of human TRPV...
Katz, Zaguri, and co-authors (9) reported phenotypes of two individuals carrying TRPV1N331K/N331K, which is located in the ankyrin repeat domain at the N-terminal domain. He, Zambelli, and co-authors (7) reported phenotypes of knockin mice carrying Trpv1K710N/K710N, a loss-of-function missense mutation rarely observed in humans. TRPV1K710N is located in the TRP domain of the C-terminal domain. TRPV1N331K/N331K shows a complete deficit in activation, whereas TRPV1K710N shows a partial loss of function.