Retinoids activate the irritant receptor TRPV1 and produce sensory hypersensitivity
Shijin Yin, … , Susan M. Carlton, Hongzhen Hu
Shijin Yin, … , Susan M. Carlton, Hongzhen Hu
Published August 8, 2013
Citation Information: J Clin Invest. 2013;123(9):3941-3951. https://doi.org/10.1172/JCI66413.
View: Text | PDF
Research Article Dermatology

Retinoids activate the irritant receptor TRPV1 and produce sensory hypersensitivity

Abstract

Retinoids are structurally related derivatives of vitamin A and are required for normal vision as well as cell proliferation and differentiation. Clinically, retinoids are effective in treating many skin disorders and cancers. Application of retinoids evokes substantial irritating side effects, including pain and inflammation; however, the precise mechanisms accounting for the sensory hypersensitivity are not understood. Here we show that both naturally occurring and synthetic retinoids activate recombinant or native transient receptor potential channel vanilloid subtype 1 (TRPV1), an irritant receptor for capsaicin, the pungent ingredient of chili peppers. In vivo, retinoids produced pain-related behaviors that were either eliminated or significantly reduced by genetic or pharmacological inhibition of TRPV1 function. These findings identify TRPV1 as an ionotropic receptor for retinoids and provide cellular and molecular insights into retinoid-evoked hypersensitivity. These findings also suggest that selective TRPV1 antagonists are potential therapeutic drugs for treating retinoid-induced sensory hypersensitivity.

Authors

Shijin Yin, Jialie Luo, Aihua Qian, Junhui Du, Qing Yang, Shentai Zhou, Weihua Yu, Guangwei Du, Richard B. Clark, Edgar T. Walters, Susan M. Carlton, Hongzhen Hu

×

Figure 1

Activation of recombinant TRPV1 by both synthetic and naturally occurring retinoids.

Options: View larger image (or click on image) Download as PowerPoint
Activation of recombinant TRPV1 by both synthetic and naturally occurrin...
(A) AM580 (100 μM) and 4-HPR (100 μM) specifically evoked [Ca2+]i responses in HEK293T cells transfected with recombinant TRPV1. Neither retinoid had an effect on HEK293T cells transfected with TRPA1, TRPV3, or TRPM8. The y axis refers to a net increase of relative fluorescence units (RFU) induced by AM580 and 4-HPR after subtraction of the baseline response to vehicle alone. (B) Left: representative traces showing that AM580-activated TRPV1-mediated current in a concentration-dependent manner. Right: representative current–voltage (I–V) curves taken at specified time points from the traces on the left illustrate that an outwardly rectifying whole-cell current was evoked by AM580 at 1 μM (b), whereas 10 μM (c) AM580 activated a current with a linear I-V relationship in a TRPV1-expressing HEK293T cell (a refers to the baseline response). (C) An endogenous retinoid, 9-cis-RA, also activated TRPV1 current in a concentration-dependent manner similar to that activated by AM580 (a refers to the baseline response; b and c indicate responses activated by 10 and 30 μM 9-cis-RA, respectively). (D) Both AM580 (10 μM, n = 5) and 9-cis-RA (10 μM, n = 4) increased single channel open probability (nPo) in inside-out patches excised from TRPV1-expressing HEK293T cells (*P < 0.05). (E) Synthetic retinoids activate TRPV1 in a concentration-dependent manner. (F) Summary of effects of selected endogenous retinoids on TRPV1-expressing cells. Currents were recorded at a membrane potential of –60 mV. n = 5–10 per concentration for all retinoids examined.