Abstract
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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Acknowledgements
We thank K. Kwan and D. Corey (Harvard Medical School), T. Miyamoto and A. Patapoutian (Scripps Research Institute), and T. Numata and Y. Mori (Kyoto University) for human TrpA1 constructs. A. Schier, D. Prober and D. Robson (Harvard University) generously provided TrpA1 mutant zebrafish. We thank R. Gaudet, A. Vakkasglu, B. Shoichet, T. Dunn, M. Ahrens, F. Engert, R. Mazitschek and members of our research groups for helpful advice. This work was supported by US National Institutes of Health (NIH) grants K01MH091449 (D.K.), MH086867 and MH085205 (R.T.P.), P01 NS072040 (C.J.W.), R01 AI050875 (L.H. and M.R.H.); the Charles and Ann Sanders Massachusetts General Hospital Research Scholar award (R.T.P.); and the Michael Hooker Chair and the NIMH PDSP (B.L.R.). M.J.Z. was supported by grants from National Institute of Neurological Disorders and Stroke (NINDS; R01NS060725, R01NS067688), J.C.-B. was supported by a National Research Service Award training grant from NINDS (F31NS068038) and D.J.M. was supported by NIH grants HL109004 and DA026982.
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D.K. designed and performed the research, analyzed the data and wrote the manuscript with R.T.P. C.Y.J.C., R.M., J.C.-B., L.H., V.S., J.S., S.J., Y.N.J., G.B. and X.-P.H. designed and performed the experiments and interpreted data. C.J.W., B.L.R., M.R.H., M.J.Z. and D.J.M. analyzed and interpreted the data. All authors contributed to data interpretation and commented on the manuscript.
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Kokel, D., Cheung, C., Mills, R. et al. Photochemical activation of TRPA1 channels in neurons and animals. Nat Chem Biol 9, 257–263 (2013). https://doi.org/10.1038/nchembio.1183
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DOI: https://doi.org/10.1038/nchembio.1183
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