Optical functionalization of human Class A orphan G-protein-coupled receptors

Nature Communications
Maurizio MorriHarald Janovjak

Abstract

G-protein-coupled receptors (GPCRs) form the largest receptor family, relay environmental stimuli to changes in cell behavior and represent prime drug targets. Many GPCRs are classified as orphan receptors because of the limited knowledge on their ligands and coupling to cellular signaling machineries. Here, we engineer a library of 63 chimeric receptors that contain the signaling domains of human orphan and understudied GPCRs functionally linked to the light-sensing domain of rhodopsin. Upon stimulation with visible light, we identify activation of canonical cell signaling pathways, including cAMP-, Ca2+-, MAPK/ERK-, and Rho-dependent pathways, downstream of the engineered receptors. For the human pseudogene GPR33, we resurrect a signaling function that supports its hypothesized role as a pathogen entry site. These results demonstrate that substituting unknown chemical activators with a light switch can reveal information about protein function and provide an optically controlled protein library for exploring the physiology and therapeutic potential of understudied GPCRs.

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Citations

Nov 6, 2018·Current Drug Targets·Surovi SaikiaRajeev Sarmah
Jul 11, 2019·Nature Reviews. Neuroscience·Pierre PaolettiAlexandre Mourot
Oct 10, 2018·Frontiers in Cellular Neuroscience·Cameron K Baker, John G Flannery
Nov 22, 2020·Pharmacological Reviews·Torsten Schöneberg, Ines Liebscher
Jun 11, 2021·Molecular Therapy : the Journal of the American Society of Gene Therapy·Yingying JiangJianjun Zhang
Jul 11, 2021·Brain : a Journal of Neurology·Li-Ping XiaZhen-Zhong Xu

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PCR

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