Kokel, D., Cheung, C.Y., Mills, R., Coutinho-Budd, J., Huang, L., Setola, V., Sprague, J., Jin, S., Jin, Y.N., Huang, X.P., Bruni, G., Woolf, C.J., Roth, B.L., Hamblin, M.R., Zylka, M.J., Milan, D.J., and Peterson, R.T. (2013) Photochemical activation of TRPA1 channels in neurons and animals. Nature Chemical Biology. 9(4):257-263.
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.
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