Nanomolar range of FAM237B can activate receptor GPR83

Secretory myeloid-derived growth factor (MYDGF) exerts beneficial effects on organ repair, probably via a plasma membrane receptor; however, the identity of the expected receptor has remained elusive. In a recent study, MYDGF was reported as an agonist of the sphingosine-1-phosphate receptor 2 (S1PR2), an A-class G protein-coupled receptor that mediates the functions of the signaling lipid, sphingosine-1-phosphate (S1P). In the present study, we conducted living cell-based functional assays to test whether S1PR2 is a receptor for MYDGF. In the NanoLuc Binary Technology (NanoBiT)-based β-arrestin recruitment assay and the cAMP-response element (CRE)-controlled NanoLuc reporter assay, S1P could efficiently activate human S1PR2 overexpressed in human embryonic kidney (HEK) 293T cells; however, recombinant human MYDGF, overexpressed either fromEscherichia colior HEK293 cells, had no detectable effect. Thus, the results demonstrated that human MYDGF is not a ligand of human S1PR2. Considering the high conservation of MYDGF and S1PR2 in evolution, MYDGF is also probably not a ligand of S1PR2 in other vertebrates.

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Identification of the orphan GPR25 as a receptor of the chemokine CXCL17

Hu,

Yu,

Wang

et al. 2024

Preprint

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C-X-C motif chemokine ligand 17 (CXCL17) is a small secretory protein primarily expressed in mucosal tissues and likely functions as a chemoattractant, but its receptor is still controversial. In the present study, we identified the rarely studied orphan G protein-coupled receptor 25 (GPR25) as a receptor of CXCL17 via prediction by the newly developed AlphaFold 3 algorithm and validation by the NanoBiT-based beta-arrestin recruitment assay. In the beta-arrestin recruitment assay, recombinant human CXCL17 could activate human GPR25 in transfected human embryonic kidney (HEK) 293T cells with an EC50 value around 100 nM, but it had no activation effect on 17 other tested G protein-coupled receptors (GPCRs). Deletion of three conserved C-terminal residues of human CXCL17 almost abolished its activity, and alanine replacement of W95 or R178 of human GPR25, two conserved residues in the predicted orthosteric ligand binding pocket, almost abolished its response towards CXCL17. These results are consistent with the AlphaFold 3-predicted binding model in which the highly conserved C-terminal fragment of CXCL17 inserts into the orthosteric ligand binding pocket of the receptor GPR25. According to the expression pattern of CXCL17 and GPR25 shown at the Human Protein Atlas, CXCL17 might be an endogenous agonist of GPR25 in human and other mammals, but this hypothesis needs to be tested in future studies via more assays. The present deorphanization paves the way for further functional characterization of the orphan receptor GPR25 and the orphan ligand CXCL17.

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Nanomolar range of FAM237B can activate receptor GPR83

Cited by 3 publications

References 26 publications

Is myeloid-derived growth factor a ligand of the sphingosine-1-phosphate receptor 2?

Is myeloid-derived growth factor a ligand of the sphingosine-1-phosphate receptor 2?

Is myeloid-derived growth factor a ligand of the sphingosine-1-phosphate receptor 2?

Identification of the orphan GPR25 as a receptor of the chemokine CXCL17

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