2020.07.17 Journal club

Transient receptor potential vanilloid 4 (TRPV4) channel as a target of crotamiton and its bimodal effects

Hiroki Kittaka1 & Yu Yamanoi1,2,3 & Makoto Tominaga1,2,4

Received: 21 January 2017 / Revised: 2 May 2017 / Accepted: 12 May 2017 / Published online: 13 June 2017 # Springer-Verlag Berlin Heidelberg 2017

Abstract The sensation of itching can be defined as Ban un- pleasant cutaneous sensation that provokes a desire to scratch.^ The perception of itching is not critical for the main- tenance of life, but persistent itching can be extremely irritat- ing and decreases the quality of life. Crotamiton (N-ethyl-o- crotonotoluidide) has been used as an anti-itch agent for humans for around 70 years. In spite of the long use of crotamiton, its mechanism of action remains unknown. We hypothesized that crotamiton might have effects on transient receptor potential (TRP) channels expressed in the peripheral nervous system and the skin. We first examined the effects of crotamiton on TRP channels by whole-cell patch-clamp re- cordings. We found that crotamiton strongly inhibited TRPV (vanilloid) 4 channels followed by large currents after crotamiton washout. In mice, crotamiton inhibited itch- related behaviors induced by a TRPV4-selective agonist (GSK1016790A). We biophysically investigated the large TRPV4 currents after crotamiton washout. Comparing single-channel open probabilities and current amplitudes of TRPV4, increases in both parameters were found to contribute to the large washout currents of TRPV4. Because the change in current amplitudes suggested pore dilation of TRPV4, we examined this possibility with cation replacement experiments and by measuring changes in reversal potentials. Greater cat- ion influxes and changes in reversal potentials upon crotamiton washout were observed, suggesting that the TRPV4 pore dilated in its uninhibited state. From these re- sults, we identified the molecular target of crotamiton as TRPV4 and demonstrated pore dilation of TRPV4 upon crotamiton washout.

Keywords Crotamiton . TRPV4 . Pore dilation . Itch