G protein-coupled receptors (GPCRs) coupling to Gi/o signaling pathways are involved in the control of important physiological functions, which are difficult to investigate because of the limitation of tools to control the signaling pathway with precise kinetics and specificity. We established two vertebrate cone opsins, short- and long-wavelength opsin, for long-lasting and repetitive activation of Gi/o signaling pathways in vitro and in vivo. We demonstrate for both opsins the repetitive fast, membrane-delimited, ultra light-sensitive, and wavelength-dependent activation of the Gi/o pathway in HEK cells. We also show repetitive control of Gi/o pathway activation in 5-HT1A receptor domains in the dorsal raphe nucleus (DRN) in brain slices and in vivo, which is sufficient to modulate anxiety behavior in mice. Thus, vertebrate cone opsins represent a class of tools for understanding the role of Gi/o-coupled GPCRs in health and disease.
G-protein-coupled receptors (GPCRs) integrate extracellular cues into intracellular signals to modulate the cellular state. Owing to their diverse modulatory functions, GPCRs represent one of the major drug targets of the pharmaceutical industry. Until now, the characterization and control of GPCRs and their intracellular signalling cascades have mainly relied on chemical compounds, which either activate or inhibit GPCR pathways, albeit with limited receptor and cell-type specificity. Recently, new approaches have been developed to control signalling cascades in cell- and receptor-type-specific ways. The chemical approach focuses on GPCR design and activation by an inert chemical compound, whereas the physical approach uses designer GPCRs and activation by physical stimuli, such as light.
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