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Kokel, David

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Kokel

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Kokel, David
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    Photochemical activation of TRPA1 channels in neurons and animals
    (2013) Kokel, David; Cheung, Chung Yan J.; Mills, Robert; Coutinho-Budd, Jaeda; Huang, Liyi; Setola, Vincent; Sprague, Jared; Jin, Shan; Jin, Youngnam N.; Huang, Xi-Ping; Bruni, Giancarlo; Woolf, Clifford; Roth, Bryan L.; Hamblin, Michael; Zylka, Mark J.; Milan, David; Peterson, Randall
    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 animals. Surprisingly, 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 non-transgenic animals, including humans.
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    Discovering novel neuroactive drugs through high-throughput behavior-based chemical screening in the zebrafish
    (Frontiers Media S.A., 2014) Bruni, Giancarlo; Lakhani, Parth; Kokel, David
    Most neuroactive drugs were discovered through unexpected behavioral observations. Systematic behavioral screening is inefficient in most model organisms. But, automated technologies are enabling a new phase of discovery-based research in central nervous system (CNS) pharmacology. Researchers are using large-scale behavior-based chemical screens in zebrafish to discover compounds with new structures, targets, and functions. These compounds are powerful tools for understanding CNS signaling pathways. Substantial differences between human and zebrafish biology will make it difficult to translate these discoveries to clinical medicine. However, given the molecular genetic similarities between humans and zebrafish, it is likely that some of these compounds will have translational utility. We predict that the greatest new successes in CNS drug discovery will leverage many model systems, including in vitro assays, cells, rodents, and zebrafish.