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bioRxiv · 10.64898/2026.03.11.711017

Development of a genetically encoded fluorescent indicator for facilitating deorphanization of GPR52

Lan, G.·Wang, H.·Qian, T.·Xie, S.·Qian, C.·Ursu, D.·Bornemann, K. D.·Hengerer, B.·Li, Y.
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Abstract

GPR52 is an orphan G protein-coupled receptor implicated in psychiatric and neurodegenerative disorders, but its endogenous ligand remains unidentified, limiting the exploration of its physiological functions and therapeutic potential. We pioneered a novel methodology for orphan GPCR ligand discovery utilizing the GPCR-activation-based (GRAB) strategy by developing GPR52-1.0, a genetically encoded fluorescent sensor. GPR52-1.0 exhibits excellent membrane trafficking and high sensitivity in HEK293T cells, cultured neurons, and acute mouse brain slices. Notably, it detects neuronal activity-dependent endogenous ligand release in the striatum, with responses abolished by a specific antagonist. This sensor provides a powerful tool for identifying GPR52s endogenous ligand(s) and enables real-time monitoring of its activation. Our work lays the foundation for uncovering GPR52s physiological roles and supports future efforts to develop GPR52-targeted therapeutics.

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Lan, G., Wang, H., Qian, T., Xie, S., Qian, C., Ursu, D., Bornemann, K. D., Hengerer, B., Li, Y.. 2026-03-13. Development of a genetically encoded fluorescent indicator for facilitating deorphanization of GPR52. https://doi.org/10.64898/2026.03.11.711017

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