TRPswitch—A Step-Function Chemo-optogenetic Ligand for the Vertebrate TRPA1 Channel
- 5 October 2020
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of the American Chemical Society
- Vol. 142 (41), 17457-17468
- https://doi.org/10.1021/jacs.0c06811
Abstract
Chemo-optogenetics has produced powerful tools for optical control of cell activity, but current tools suffer from a variety of limitations including low unitary conductance, the need to modify the target channel, or the inability to control both on and off switching. Using a zebrafish behavior-based screening strategy, we discovered “TRPswitch”, a photoswitchable non-electrophilic ligand scaffold for the transient receptor potential ankyrin 1 (TRPA1) channel. TRPA1 exhibits high unitary channel conductance, making it an ideal target for chemo-optogenetic tool development. Key molecular determinants for the activity of TRPswitch were elucidated and allowed for replacement of the TRPswitch azobenzene with a next-generation azoheteroarene. The TRPswitch compounds enable reversible, repeatable, and nearly quantitative light-induced activation and deactivation of the vertebrate TRPA1 channel with violet and green light, respectively. The utility of TRPswitch compounds was demonstrated in larval zebrafish hearts exogenously expressing zebrafish Trpa1b, where heartbeat could be controlled using TRPswitch and light. Therefore, TRPA1/TRPswitch represents a novel step-function chemo-optogenetic system with a unique combination of high conductance, high efficiency, activity against an unmodified vertebrate channel, and capacity for bidirectional optical switching. This chemo-optogenetic system will be particularly applicable in systems where a large depolarization current is needed or sustained channel activation is desirable.Funding Information
- Engineering and Physical Sciences Research Council (EP/R00188X/1)
- National Institute of Neurological Disorders and Stroke (K99NS112599)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK082971)
- National Heart, Lung, and Blood Institute (R00HL124070, R01HL141353)
- American Heart Association (16POST29680003)
- L. J. Skaggs and Mary C. Skaggs Foundation
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