Two-photon properties of pharmacogenetic tools

Carroll, E.C. et al. Proc. Natl. Acad. Sci. USA. 112, E776–E785 (2015).

Photoswitchable tethered ligands (PTLs) in conjunction with their engineered receptors can activate neurons in response to optical stimulation. Typically, these PTLs are switched by UV or blue light, which is not efficient in highly scattering tissue such as the brain. Carroll et al. characterized the two-photon properties of the glutamate analogs L-MAG0 and L-MAG0₄₆₀ in solution and when bound to their cognate receptor LiGluR. L-MAG0 deactivates upon illumination with near-infrared light, whereas L-MAG0₄₆₀ can be efficiently and quickly activated under the same conditions. Using two-photon digital holography to switch L-MAG0₄₆₀, the researchers could achieve currents almost as high as with one-photon illumination in cultured hippocampal neurons expressing LiGluR. Furthermore, two-photon activation of these tools is compatible with calcium imaging using red calcium sensors such as R-GECO1.0.