Journal Article

Photochemical activation of TRPA1 channels in neurons and animals

Mills, Robert, Zylka, Mark J, Roth, Bryan L, Cheung, Chung Yan J, Bruni, Giancarlo, Jin, Youngnam N, Coutinho-Budd, Jaeda, Milan, David J, Kokel, David, Sprague, Jared, Setola, Vincent, Huang, Xi-Ping, Jin, Shan, Hamblin, Michael R, Peterson, Randall T, Huang, Liyi, Woolf, Clifford J

2013

Overview

Optovin is a small molecule that renders zebrafish embryos responsive to light through generation of singlet oxygen and activation of the TrpA1b channel, providing a new tool for optogenetics. Optogenetics is a powerful research tool because it enables high-resolution optical control of neuronal activity. However, current optogenetic approaches are limited to transgenic systems expressing microbial opsins and other exogenous photoreceptors. Here, we identify optovin, a small molecule that enables repeated photoactivation of motor behaviors in wild-type zebrafish and mice. To our surprise, optovin's behavioral effects are not visually mediated. Rather, photodetection is performed by sensory neurons expressing the cation channel TRPA1. TRPA1 is both necessary and sufficient for the optovin response. Optovin activates human TRPA1 via structure-dependent photochemical reactions with redox-sensitive cysteine residues. In animals with severed spinal cords, optovin treatment enables control of motor activity in the paralyzed extremities by localized illumination. These studies identify a light-based strategy for controlling endogenous TRPA1 receptors in vivo , with potential clinical and research applications in nontransgenic animals, including humans.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/378 / 631/92 / 631/92/613 / 639/638/439/944 / Animals / Behavior, Animal - drug effects / Behavior, Animal - radiation effects / Biochemical Engineering / Biochemistry / Bioorganic Chemistry / Cell Biology / Chemistry / Chemistry/Food Science / Cysteine - chemistry / Cysteine - metabolism / Danio rerio / Electron Transport - drug effects / Electron Transport - radiation effects / Embryo, Nonmammalian / Extremities / Gene expression / Genetics / Humans / Ion Channels - agonists / Ion Channels - genetics / Ion Channels - metabolism / Lasers / Light / Light Signal Transduction - drug effects / Light Signal Transduction - radiation effects / Mice / Motor Activity - drug effects / Motor Activity - physiology / Motor Activity - radiation effects / Mutation / Neurons / Oxidation-Reduction / Photoactivation / Photochemical Processes - drug effects / Photochemical Processes - radiation effects / Photochemical reactions / Photochemicals / Photoreception / Piperazines - pharmacology / Protein Isoforms - agonists / Protein Isoforms - genetics / Protein Isoforms - metabolism / Sensory Receptor Cells - drug effects / Sensory Receptor Cells - physiology / Sensory Receptor Cells - radiation effects / Small Molecule Libraries - pharmacology / Structure-Activity Relationship / Transient Receptor Potential Channels / TRPA1 Cation Channel / Zebrafish / Zebrafish Proteins - agonists / Zebrafish Proteins - genetics / Zebrafish Proteins - metabolism