Optical Control of Dopamine D2-like Receptors with Cell-Specific Fast-Relaxing Photoswitches

Dopamine D2-likereceptors (D2R, D3R, and D4R) control diversephysiological and behavioral functions and are important targets forthe treatment of a variety of neuropsychiatric disorders. Their complexdistribution and activation kinetics in the brain make it difficultto target specific receptor populations with sufficient precision.We describe a new toolkit of light-activatable, fast-relaxing, covalentlytaggable chemical photoswitches that fully activate, partially activate,or block D2-like receptors. This technology combines the spatiotemporalprecision of a photoswitchable ligand (P) with cell type and spatialspecificity of a genetically encoded membrane anchoring protein (M)to which the P tethers. These tools set the stage for targeting endogenousD2-like receptor signaling with molecular, cellular, and spatiotemporalprecision using only one wavelength of light.

Automated summary

Dopamine D2-like receptors (D2R, D3R, and D4R) play important roles in controlling various physiological and behavioral functions and are targeted for the treatment of neuropsychiatric disorders. Researchers have developed a new toolkit of light-activatable chemical photoswitches that can fully activate, partially activate, or block D2-like receptors. This technology combines the spatiotemporal precision of a photoswitchable ligand with the cell type and spatial specificity of a genetically encoded membrane anchoring protein. These tools enable precise targeting of endogenous D2-like receptor signaling using only one wavelength of light.