Lamprey Parapinopsin (“UVLamP”): a Bistable UV‐Sensitive Optogenetic Switch for Ultrafast Control of GPCR Pathways

Optogenetics uses light‐sensitive proteins, so‐called optogenetic tools, for highly precise spatiotemporal control of cellular states and signals. The major limitations of such tools include the overlap of excitation spectra, phototoxicity, and lack of sensitivity. The protein characterized in this study, the Japanese lamprey parapinopsin, which we named UVLamP, is a promising optogenetic tool to overcome these limitations. Using a hybrid strategy combining molecular, cellular, electrophysiological, and computational methods we elucidated a structural model of the dark state and probed the optogenetic potential of UVLamP. Interestingly, it is the first described bistable vertebrate opsin that has a charged amino acid interacting with the Schiff base in the dark state, that has no relevance for its photoreaction. UVLamP is a bistable UV‐sensitive opsin that allows for precise and sustained optogenetic control of G protein‐coupled receptor (GPCR) pathways and can be switched on, but more importantly also off within milliseconds via lowintensity short light pulses. UVLamP exhibits an extremely narrow excitation spectrum in the UV range allowing for sustained activation of the G(i/o) pathway with a millisecond UV light pulse. Its sustained pathway activation can be switched off, surprisingly also with a millisecond blue light pulse, minimizing phototoxicity. Thus, UVLamP serves as a minimally invasive, narrow‐bandwidth probe for controlling the G(i/o) pathway, allowing for combinatorial use with multiple optogenetic tools or sensors. Because UVLamP activated G(i/o) signals are generally inhibitory and decrease cellular activity, it has tremendous potential for health‐related applications such as relieving pain, blocking seizures, and delaying neurodegeneration.