Photochemical activation of TRPA1 channels in neurons and animals

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 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.

Transient Receptor Potential Ankyrin 1 Activation within the Cardiac Myocyte Limits Ischemia–reperfusion Injury in Rodents

“…We previously showed that aspirin, unlike ibuprofen, can block the ability for opioids to reduce myocardial reperfusion injury. 30 Although more studies are needed, potentially other myocardial salvaging techniques (such as using volatile anesthetics 31 or implementing remote conditioning 31 ) may also have a reduced efficacy for limiting myocardial ischemia-reperfusion injury when TRPA1 is inhibited.…”

“…32 For our study, the binding site for optovin is identified to be within a region of critical cysteines present on TRPA1 that is also essential for reactive aldehyde-induced TRPA1 activation. 12, 31 Although further studies will be needed, the TRPA1 activators we used may reduce injury during a heart attack by occupying critical cysteines of TRPA1; limiting the amount of irreversible reactions which occur by reactive aldehydes during the initial minutes of reperfusion.…”

Optogenetic pharmacology for control of native neuronal signaling proteins

“…Very recently, a small molecule known as optovin was shown to serve as a photochromic activator of TRPA1 channels, enabling optical control of behavior in zebrafish 23 (Table 1). …”

Automated high-throughput measurement of body movements and cardiac activity of Xenopus tropicalis tadpoles

“…However, thus far vertebrate in vivo screenings for neuroactive or cardiotoxic molecules have been performed with zebrafish embryos. In these studies, compound treated animals were explored by using fully automated systems and/or specialized software for alterations of behavioral patterns [15][16][17] or cardiac activity [18,19]. One of the major obstacles performing such investigations with Xenopus tadpoles is the lack of simple and effective high-throughput screening methodologies.…”