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Identification of novel light-activated chemical tools for the study of TRPA1-mediated non-visual photosensation


Over the past decade, the transient receptor potential ankyrin 1 (TRPA1) receptor has been extensively studied because of its wide distribution across the human body and its roles in many aspects of sensation, some of which are physiological and others of which are pathophysiological. A member of the TRP channel family, TRPA1 is most commonly found in somatosensory neurons present in nociceptors, especially the dorsal root ganglia and trigeminal ganglia, but its expression has been reported in tissues as disparate as the cells of the inner ear, non-neuronal cells in the small and large intestines and lungs, and in the beta islet cells of the pancreas. Physiologically, TRPA1’s primary role is as a nociceptive chemosensor detecting exogenous agonists that are irritants, such as AITC from wasabi, and endogenous agonists that are indicators of oxidative stress, such as H2O2. However, when TRPA1 becomes dysregulated, its physiological roles can become distorted. Research has demonstrated that TRPA1 is involved in many pathologies including chronic pain and inflammation, neuropathic pain, itch, and respiratory diseases, but to date, few TRPA1-targeting therapeutics have been successful, and it is evident that greater understanding of the receptor is required to address this need. Recently, the discovery of optovin revealed that a synthetic photoreactive compound could confer photosensitivity onto vertebrate TRPA1, but much is still unknown about photo-dependent TRPA1 activation. One way to approach this question is through identification of additional chemotypes that act similarly to optovin. In this dissertation, I describe the process of identifying such compounds and the characterization of their properties. Analysis of data from a large-scale, behavior-based chemical screen conducted in larval zebrafish established a small subset of compounds that induced a strong behavioral response to light. Structural analysis showed that the hit compounds were in fact structurally diverse, and photochemical, behavioral, and toxicity studies uncovered characteristics unique to each compound. Experiments using TRPA1 mutant zebrafish confirmed that a subset of these hits are TRPA1-dependent. Together, these structurally, photochemically, and pharmacologically diverse compounds form a tool set that can be used to modulate the TRPA1 receptor, allowing future researchers to gain a better understanding of the receptor’s characteristics and mechanisms, research its roles in sensation and photo-behaviors, and identify therapeutics to address pathologies caused by its dysregulation.

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