Photoswitchable, non-electrophilic ligand for on/off TRPA1 channel control.

Current optogenetics and chemo-optogenetics requires oversaturation that can result in off-site effects, including cytotoxicity to overcome low unitary conductance, 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 sustained channel activation with a brief pulse of violet light, and can also be rapidly deactivated with green light. With only short pulses of light required to control activity, cells subjected to the TRPA1/TRPswitch chemo-optogenetic system are less prone to photo-toxicity. 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.

Proof of Concept

• Robust and easy to use in cultured mammalian cells and in zebrafish.
• Reversible and repeatable activation of TRPswitch.
• Rapid receptor response with violet or green light.

Lam, P.-Y., Mendu, S. K., Mills, R. W., Zheng, B., Padilla, H., Milan, D. J., … Peterson, R. T. (2017). A high-conductance chemo-optogenetic system based on the vertebrate channel Trpa1b. Scientific Reports, 7(1). doi: 10.1038/s41598-017-11791-z

Aaron Duffy
(801) 585-1377
aaron.duffy@utah.edu