Current optogenetics and chemo-optogenetics suffer from a variety of limitations including low unitary conductance (which requires oversaturation and can result in off-site effects, including cytotoxicity), the need to covalently modify the target channel, and/or the inability to control both on and off switching. These limitations produce uncertainty when trying to dissect complex biological systems.

This work identifies “TRPswitch” as a photoswitchable, nonelectrophilic ligand scaffold for the transient receptor potential ankyrin 1 (TRPA1) channel. TRPswitch A and B are two photoswitchable small molecules that enable optical control of currents in Trpa1b expressing cells in vivo. The TRPswitches specifically enable repeatable optical control of both neuronal and non-neuronal cells. Importantly, the TRPswitches allow for sustained channel activation after only a brief pulse of violet light illumination, but the channel can also be rapidly deactivated with green light illumination. As only short pulses of light are required to control the activity of the TRPA1 channel, cells subjected to the TRPA1/TRPswitch chemo-optogenetic system are less prone to photo-toxicity. Specifically, this new tool will also be beneficial in applications where a large depolarization current is needed, such as in large primary motor neurons, or when sustained channel activation is desirable.