Identification of compounds producing non-visual photosensation via TRPA1 in zebrafish

Abstract

TRPA1 receptors sense chemical irritants, but they do not normally respond to light. Previous studies have identified compounds that confer photosensitivity onto vertebrate TRPA1. However, the pharmacology of TRPA1-mediated non-visual photosensation remains poorly understood. To identify novel compounds that affect this process, we screened a large chemical library for compounds that increased light-elicited motor activity in larval zebrafish. We found structurally diverse hit compounds that were photoreactive and produced specific behavioral phenotypes. A subset of these compounds required functional TRPA1 to produce behavioral phenotypes in vivo. These findings provide novel prototype compounds for controlling TRPA1 with light and improve our understanding of non-visual TRPA1-mediated photosensation.

Deep phenotypic profiling of neuroactive drugs in larval zebrafish

“…The mechanism of action of central nervous system (CNS) drugs remains poorly understood, even for those used for decades (e.g., ketamine 1 ). The complex nature of G-Protein Coupled Receptor (GPCR) and ion channel-mediated pathways of the vertebrate nervous system [2][3][4][5][6][7][8][9][10][11] exacerbate the problem. Because of the prevalence of polypharmacology in neuroactive drugs 12 , a "magic bullet" single-target approach to drug discovery 13 falls short 14 .…”

“…Despite historically limited throughput, rapid phenotypic profiling of thousands of compounds in vivo is now possible using larval zebrafish [17][18][19][20][21] . These vertebrates have high levels of shared genetics 22,23 and CNS anatomy 24 (with humans) and scale to high-throughput testing of complex behavioral readouts [2][3][4][5][6][7][8][9][10][11] . Phenotypic screening in larval zebrafish, combined with human-target-based cheminformatic methods such as the Similarity Ensemble Approach (SEA 25,26 ), and enrichment factor (EF) calculations 27,10,28,29 , have enabled novel drug discovery and target deconvolution for neuroactive phenotypes in mammals.…”

Simultaneous analysis of neuroactive compounds in zebrafish

“…Previous screens identified new neuroactive compounds and predicted their targets, later supported by in vitro assays (23,(30)(31)(32)(33). Diverse compounds have been identified, including photoactivatable transient receptor potential channel A1 (TRPA1) ligands (34), antiepileptics (35), antipsychotics (36), appetite modulators (37), and anesthetic-like compounds (38,39).…”