Optical research tools give investigators a powerful way to study sensory physiology, including pain signaling, and a new light-activated molecule has just expanded the toolbox. The compound, dubbed optovin by its discoverers, binds the sensory transient receptor potential A1 (TRPA1) channel in a light-sensitive manner, giving tight temporal and spatial control over TRPA1 activation. And unlike optogenetic tools that require transgenic animals (see PRF related news story), optovin can be used in wild-type, non-transgenic animals.
“TRPA1 is a really important channel for pain, inflammation, and itch,” said Diana Bautista, a researcher who studies sensory transduction at the University of California, Berkeley, and who was not involved in the new work. “So it’s exciting to have a new tool that will allow for temporal and spatial control of its activity.” The study was published online February 10 in Nature Chemical Biology.
The research team, led by Randall Peterson at Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, US, identified optovin in a screen for light-responsive behavior in zebrafish embryos. A flash of violet light to a dish containing optovin evoked fin and tail movements in the tiny fish. The movement was independent of vision—which had not yet developed in the embryos—and was involuntary, resulting from a spinal reflex arc.
The scientists, including first author David Kokel, next found that the movement depended on sensory neurons, and specifically on the presence of TRPA1, because fish genetically manipulated to lack the channel did not respond to optovin. Experiments with mouse and human cells further suggested a key role for TRPA1 in mediating optovin activity. Among dissociated, wild-type mouse dorsal root ganglia (DRG) neurons, all optovin-sensitive neurons were also activated by the TRPA1 agonist mustard oil. And non-excitable human embryonic kidney (HEK) cells transfected with the human TRPA1 channel responded to light-activated optovin.
Bautista also expressed enthusiasm for the in-vivo work the investigators performed. Rather than simply describe the molecule, she said, “They’ve shown in several models that optovin works well to activate the channel under control of light.” For instance, in adult wild-type mice, a swab of optovin to the ear followed by exposure to laser light elicited a head-shaking response, indicating that the optovin-light combination had activated sensory neurons.
The fact that the compound works on human TRPA1 channels indicates that it might hold some potential as a therapeutic agent, although Peterson called that “pure science fiction at this point.” Nevertheless, Bautista called TRPA1 “a really attractive target” for analgesic or anti-itch therapies, “especially given its accessibility.” TRPA1 channels are expressed in sensory nerve endings of the skin, which opens the way for topical application of optovin-like compounds and manipulation by an external light source. “It’s much easier to translate topical agents,” Bautista said, from animal models to potential human therapies, because they need not be delivered systemically. One could imagine such agents working like topical capsaicin, which inactivates pain-sensing neurons by activating TRPV1.
Peterson says the work has more immediate promise in terms of finding—or synthesizing—other agents that might activate other TRP channels or even more distantly related molecules. TRPA1 channels may be “primed” to detect a molecule like optovin because “those channels are built to be chemosensors, and they respond to electrophiles,” a class of reactive chemicals that includes optovin and other TRPA1 activators, said Peterson. But if, as Peterson believes, other agents could be engineered to work similarly at other channel types, it would broaden the novel tool’s utility even further.
Stephani Sutherland, PhD, is a freelance neuroscience writer based in Southern California.
