# TRPV1 and TRPA1 channels exhibit bifurcated sensing of singlet oxygen and hydrogen peroxide

## TL;DR

TRPV1 and TRPA1 channels react differently to singlet oxygen and hydrogen peroxide, showing unique patterns of activation and inhibition.

## Contribution

The study reveals distinct and bifurcated sensing mechanisms of TRPV1 and TRPA1 to two reactive oxygen species.

## Key findings

- TRPV1 is enhanced by singlet oxygen through faster opening and increased current.
- TRPA1 is initially activated but then permanently inhibited by singlet oxygen.
- TRPA1 is more sensitive to hydrogen peroxide than TRPV1, involving intracellular cysteine residues.

## Abstract

By responding to stimuli of diverse physics and chemical nature, transient receptor potential (TRP) channels fulfill important physiological functions in both excitable and non-excitable cells. Capsaicin (CAP) from chili peppers and allyl isothiocyanate (AITC) from mustard are natural and potent agonists for TRPV1 and TRPA1, respectively. Upon exposure to hydrogen peroxide (H2O2), the central molecule in redox signaling pathways, TRPA1 shows robust activation and much higher sensitivity than TRPV1. Singlet oxygen (1O2), the molecular oxygen in electrically excited states, is the least studied reactive oxygen species (ROS). Here we report that both TRPV1 and TRPA1 are sensitive to the modification by 1O2, but they exhibit drastically different responses. 1O2 generated by excited photosensitizers enhances the function of TRPV1 by accelerating its opening kinetics, increasing the current amplitude, and left-shifting the voltage-dependent activation curve towards physiological membrane potentials. A histidine residue located in the N-terminal ankyrin repeat domain of TRPV1 is identified to be important in 1O2 modification process. In contrast, as reported by imaging of cytosolic calcium, 1O2 modification of TRPA1 leads to a transient increase and then permanent inhibition of channel activity, and eventually obliterates TRPA1's response to AITC but not carvacrol – electrophilic and non-electrophilic agonists for TRPA1, respectively. Conversely, hTRPA1 is much more sensitive to H2O2, with the EC50 for channel activation about five times lower than that of hTRPV1, and the responses by two channels to H2O2 mainly involves intracellular cysteine residues. The physiological significance of the distinct responses of TRPV1 and TRPA1 to two representative ROS, 1O2 and H2O2, warrants further investigation.