Class A (rhodopsin-like) G protein-coupled receptor of the plasma membrane, 540 residues with a seven-transmembrane fold, expressed most highly in brain and spinal cord and also in retinal pigment epithelium, hypothalamus, adipose tissue, pancreatic islets, liver, kidney and vasculature. Cryo-EM structures of the human receptor in apo and Gq-coupled states show that it engages heterotrimeric Gq, and that it adopts an active-like conformation without a bound ligand: the canonical DRY motif is replaced by HRL so the ionic lock is absent, and the extracellular domain is collapsed so that no conventional orthosteric pocket exists. GPR75 remains formally an orphan receptor in the IUPHAR classification. Two endogenous agonists have been proposed - the chemokine CCL5/RANTES and the cytochrome P450 eicosanoid 20-hydroxyeicosatetraenoic acid - and both assignments are disputed, the CCL5 claim resting on heterologous-expression pharmacology in a small number of studies and the structural work raising doubt about orthosteric ligand binding in general. Independently of the ligand question, human loss-of-function variants in GPR75 are associated with protection from obesity and type 2 diabetes, and Gpr75-null rodents are lean, hypophagic and resistant to diet-induced insulin resistance, which has made the receptor a prominent anti-obesity drug target. Its evolutionary relatives by transmembrane sequence are peptide receptors such as galanin and growth hormone secretagogue receptors rather than chemokine receptors.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic assertion that GPR75 is active in the plasma membrane, shared with a broad set of class A receptor descendants. Reason: Correct and uncontroversial. GPR75 is a multi-pass plasma membrane protein; the cryo-EM work purified it as a membrane receptor in complex with Gq, and the Human Protein Atlas IDA agrees. |
| GO:0007186 G protein-coupled receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic assertion that GPR75 participates in G protein-coupled receptor signalling. Reason: Core biological process, and supported directly by the human structure, which was solved in a Gq-coupled state. This is the level at which GPR75 can be annotated with confidence given that its agonist is unsettled. Supporting Evidence: PMID:41545757 Here we present the cryo-EM structures of human GPR75 in apo and Gq-coupled states |
| GO:0016493 C-C chemokine receptor activity | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Phylogenetic transfer of C-C chemokine receptor activity to human GPR75. The PAINT tree was inspected. The annotation's WITH/FROM is MGI:MGI:2441843 (mouse Gpr75) plus node PANTHER:PTN002796002, and mouse Gpr75 does carry GO:0016493 with IDA from PMID:17001303, so the IBD is experimentally grounded - in exactly one descendant, the direct orthologue of the target. Reason: Not removed, because the donor annotation is a genuine experimental annotation whose full text was not read here, and because CCL5-dependent, GPR75-dependent responses have been reported by more than one group (PMID:17001303 in transfected cells, PMID:29772059 in SH-SY5Y cells that lack CCR1/CCR3/CCR5). But it is an over-annotation of human GPR75 for four reasons. First, there is no experimental support on the human protein at all: the IBA, the Ensembl IEA and the ISS all reduce to the same mouse orthologue (UniProtKB:Q6X632 / MGI:2441843), so what looks like three independent lines of evidence is one. Second, IUPHAR still classifies GPR75 as an orphan receptor and 2025-2026 reviews state that the agonist status of both CCL5 and 20-HETE remains controversial. Third, the 2026 cryo-EM structures show a completely collapsed extracellular domain with no conventional orthosteric pocket and a receptor that is constitutively active without ligand - a particularly hard architecture to reconcile with chemokine binding, which normally requires an extended N-terminal and extracellular-loop recognition surface. Fourth, GPR75 is not a chemokine receptor by descent; its nearest relatives by transmembrane sequence are peptide receptors of other families. The defensible molecular function for this gene remains the generic GO:0004930. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: SOURCE EVIDENCE WEAK Sources checked: MGI:MGI:2441843 Β· Gpr75 (mouse) SOURCE WEAK OR INFERRED The sole experimental descendant cited. Its C-C chemokine receptor activity IDA comes from a heterologous-overexpression pharmacology study whose RANTES/CCL5 agonism IUPHAR has not accepted and which current reviews describe as controversial. PANTHER:PTN002796002 Β· PTN002796002 SOURCE WEAK OR INFERRED The IBD node for this term. Because the only experimental descendant listed for it is mouse Gpr75, the direct orthologue of the target, the IBA adds no phylogenetic breadth over the mouse-to-human ISS and Ensembl Compara IEA rows that this gene already carries for the same term. Supporting Evidence: PMID:40362321 however, its definitive endogenous ligand remains unidentified, and GPR75 is currently classified as an orphan receptor by International Union of Basic and Clinical Pharmacology (IUPHAR) PMID:41545757 a completely collapsed extracellular domain eliminates the traditional orthosteric binding pocket, raising critical questions about previously reported small molecule ligands PMID:40757922 Recent studies have suggested several potential endogenous ligands for GPR75, including 20-HETE and RANTES/CCL5, but their status as true receptor agonists remains controversial. |
| GO:0004930 G protein-coupled receptor activity | IEA GO_REF:0000120 | ACCEPT | Summary: Generic G protein-coupled receptor activity from combined automated methods (InterPro signature plus mouse orthologue). Reason: Core molecular function and the right level of claim for this gene. GPR75 has the class A seven-transmembrane fold and has been captured in a Gq-coupled complex, but its endogenous agonist is unsettled, so no ligand-specific receptor term can be justified. Supporting Evidence: PMID:41545757 Here we present the cryo-EM structures of human GPR75 in apo and Gq-coupled states PMID:40362321 More recent studies have classified GPR75 as a GΞ±q protein-coupled receptor within the Class A rhodopsin-like family |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Plasma membrane localisation from the UniProt subcellular-location vocabulary. Reason: Core location for a seven-transmembrane receptor that couples Gq at the cell surface. |
| GO:0007186 G protein-coupled receptor signaling pathway | IEA GO_REF:0000120 | ACCEPT | Summary: G protein-coupled receptor signalling from combined automated methods. Reason: Core biological process, confirmed by the Gq-coupled structure. |
| GO:0016020 membrane | IEA GO_REF:0000002 | ACCEPT | Summary: Generic membrane localisation from the InterPro GPCR signatures. Reason: Correct, though the plasma membrane annotations carried by this gene are more informative. |
| GO:0016493 C-C chemokine receptor activity | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Automatic transfer of the mouse Gpr75 chemokine-receptor annotation to the human orthologue via Ensembl Compara. Reason: Same underlying claim, and the same single source, as the IBA and ISS rows for this term. The mouse experimental annotation is real, and CCL5-dependent GPR75-dependent responses have been reported in more than one system, so this is not scored as wrong; but human GPR75 has no experimental support for chemokine binding, IUPHAR still lists it as an orphan, the agonist status of CCL5 is described as controversial in current reviews, and the 2026 cryo-EM structures show a collapsed extracellular domain with no conventional orthosteric pocket, which is difficult to reconcile with chemokine recognition. The generic GO:0004930 is the claim this gene can support. Supporting Evidence: PMID:40757922 Recent studies have suggested several potential endogenous ligands for GPR75, including 20-HETE and RANTES/CCL5, but their status as true receptor agonists remains controversial. PMID:41545757 a completely collapsed extracellular domain eliminates the traditional orthosteric binding pocket, raising critical questions about previously reported small molecule ligands |
| GO:0070098 chemokine-mediated signaling pathway | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Process counterpart of the chemokine-receptor claim, transferred from mouse Gpr75. Reason: Stands or falls with the C-C chemokine receptor activity annotation and is over-annotated for the same reasons - no human experimental support, IUPHAR orphan status, and a receptor architecture that argues against orthosteric chemokine binding. Retained rather than removed because the mouse IDA behind it is a genuine experimental annotation. Supporting Evidence: PMID:40362321 However, debate continues regarding GPR75βs endogenous ligands. |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | ACCEPT | Summary: Human Protein Atlas immunolocalisation to the plasma membrane. Reason: Core location, consistent with every other line of evidence. |
| GO:0005886 plasma membrane | IC PMID:29772059 The orphan G-protein-coupled receptor 75 signaling is activa... | ACCEPT | Summary: Curator inference that GPR75 acts at the plasma membrane, from the CCL5-response and receptor-internalisation experiments in SH-SY5Y cells. Reason: The location is correct regardless of how the CCL5 agonism question is resolved; the study shows surface expression by flow cytometry and ligand-induced internalisation. Supporting Evidence: PMID:29772059 Both qPCR and flow cytometry show that these cells express GPR75 but do not express CCR5, CCR3 or CCR1 receptors. |
| GO:0004930 G protein-coupled receptor activity | ISS GO_REF:0000024 | ACCEPT | Summary: Curator-judged sequence-similarity transfer of generic receptor activity from mouse Gpr75. Reason: Core molecular function; the generic term is the appropriate level of claim for a receptor whose agonist is unsettled. |
| GO:0007186 G protein-coupled receptor signaling pathway | ISS GO_REF:0000024 | ACCEPT | Summary: Curator-judged sequence-similarity transfer from mouse Gpr75. Reason: Core biological process. |
| GO:0016493 C-C chemokine receptor activity | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Curator-judged sequence-similarity transfer of the chemokine-receptor claim from mouse Gpr75 (UniProtKB Q6X632). Reason: This is the same mouse-to-human transfer that also appears as an Ensembl IEA and, through a node whose only experimental descendant is mouse Gpr75, as an IBA. Three rows, one source study. The claim is not wrong in kind - CCL5-evoked, GPR75-dependent signalling has been reported in transfected cells and in SH-SY5Y neuroblastoma cells lacking CCR1/CCR3/CCR5 - but it overstates what is known about the human protein, which IUPHAR still lists as an orphan and whose 2026 structures show no conventional orthosteric pocket. Supporting Evidence: PMID:29772059 Therefore, we propose that GPR75 is a novel receptor for CCL5 that could explain some of the pharmacological action of this chemokine. PMID:40362321 At present, the endogenous ligands, agonists, and antagonists for GPR75 have not been conclusively identified, and some controversy persists in this area. |
| GO:0070098 chemokine-mediated signaling pathway | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Process counterpart of the chemokine-receptor ISS, transferred from mouse Gpr75. Reason: Stands or falls with the C-C chemokine receptor activity annotation and is over-annotated for the same reasons - no human experimental support, IUPHAR orphan status, and a receptor architecture that argues against orthosteric chemokine binding. |
| GO:0005886 plasma membrane | TAS PMID:10381362 Cloning and characterization of a novel orphan G-protein-cou... | ACCEPT | Summary: Author statement in the original cloning paper that the predicted seven-transmembrane protein is a cell-surface receptor. Reason: Correct location, though asserted from sequence prediction rather than measured in that paper; it is corroborated by the later IDA and structural work. Supporting Evidence: PMID:10381362 Protein sequence analysis predicts the presence of seven transmembrane domains, a characteristic feature of GPRs. |
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Download this section (compressed HTML)Q: Does CCL5/RANTES bind human GPR75 directly, or do the reported GPR75-dependent CCL5 responses reflect a co-receptor, a heteromer, or transactivation? No direct binding measurement has been published, and the 2026 structures show a collapsed extracellular domain that offers neither of the two recognition surfaces chemokine receptors normally use.
Suggested experts: Italo Mocchetti, Simona Dedoni
Q: If GPR75 is constitutively active with no orthosteric pocket, what actually regulates it in vivo - an allosteric lipid, a protein partner, receptor trafficking, or expression level alone?
Suggested experts: H Eric Xu, Can-Rong Wu
Q: Should GO retain C-C chemokine receptor activity on the mouse Gpr75 experimental annotation that seeds all the human propagations, given that IUPHAR does not recognise the deorphanization? This is a source-annotation question for MGI and GO_Central rather than a human-gene question.
Q: Is the lean, insulin-sensitive phenotype of GPR75 loss mediated by constitutive receptor activity rather than by loss of agonist-evoked signalling? If so, a useful antagonist would need inverse-agonist properties.
Suggested experts: Michal Laniado Schwartzman
Experiment: Measure direct binding of fluorescently or radiolabelled CCL5 to purified human GPR75 reconstituted in nanodiscs, by saturation and competition binding and by mass photometry, alongside a validated chemokine receptor such as CCR5 as a positive control and surface mutants of the apo GPR75 structure as specificity controls. A negative result with adequate power would settle the annotation question.
Hypothesis: CCL5 binds human GPR75 directly with an affinity consistent with the reported functional potencies.
Type: Direct ligand binding to purified receptor
Experiment: In SH-SY5Y cells with GPR75 knocked out, reconstitute with wild-type GPR75 versus receptors carrying mutations in the residual extracellular surface and test CCL5-evoked ERK and AKT phosphorylation; in parallel run proximity labelling on CCL5-stimulated cells to identify any co-receptor present in the GPR75 vicinity.
Hypothesis: The GPR75-dependent effects of CCL5 in neuronal cells require a partner receptor or an indirect route rather than direct chemokine binding.
Type: Genetic reconstitution plus proximity proteomics
Experiment: Compare basal and agonist-stimulated Gq activation and beta-arrestin recruitment for wild-type GPR75 versus the HRL-motif and Lys134-Asp210 salt-bridge mutants predicted to destabilise the ligand-free active state, and screen a lipid and small-molecule library for modulators that act on the basal signal rather than on a stimulated one.
Hypothesis: GPR75 signals constitutively in cells and is modulated allosterically rather than orthosterically.
Type: Pharmacological profiling of constitutive activity
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