Affinage

GPR176

G-protein coupled receptor 176 · UniProt Q14439

Length
515 aa
Mass
57.0 kDa
Annotated
2026-06-10
18 papers in source corpus 10 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GPR176 is a constitutively active, SCN-enriched orphan class-A GPCR that suppresses cAMP signalling in an agonist-independent manner by coupling to the atypical Gz G-protein subclass, thereby setting the pace of circadian behaviour (PMID:26882873). This Gz–cAMP activity operates in parallel to the Vipr2 pathway in the SCN (PMID:26882873) and is also embedded in a regulatory circuit with the neuropeptides Nmu/Nms that tunes light-induced phase shifts (PMID:35908898). Efficient cell-surface expression of functional GPR176 depends on N-linked glycosylation at four conserved N-terminal asparagine residues, loss of which lowers protein levels and indirectly attenuates its cAMP-repressive output (PMID:32157140). Beyond the clock, GPR176 functions as a pro-fibrotic and pro-tumorigenic effector: it drives fibroblast-to-myofibroblast transition through Smad2 phosphorylation and induction of αSMA, fibronectin, and collagen, and promotes fibrosis across multiple organs (PMID:38694958, PMID:39047914). In cancer it physically engages the G-protein GNAS via its transmembrane helix 3–intracellular loop 2 region to activate cAMP/PKA signalling and repress mitophagy through the BNIP3L axis, promoting colorectal cancer progression (PMID:36905238), a process antagonized by exosomal miR-382-5p that downregulates GPR176 and disrupts the GPR176–GNAS interaction (PMID:40578589). GPR176 is transcriptionally activated by E2F4 and confers ferroptosis resistance by suppressing mitophagy in esophageal cancer (PMID:42253509). In the prefrontal cortex it is expressed in parvalbumin-positive interneurons where it constrains their firing output (PMID:41188983).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2016 High

    Established GPR176's core molecular identity: an orphan GPCR that represses cAMP constitutively through the unusual Gz subclass to set circadian period, answering how this SCN-enriched receptor controls the clock without a known ligand.

    Evidence Knockout mice, heterologous expression, cAMP measurement and G-protein coupling analysis

    PMID:26882873

    Open questions at the time
    • No endogenous ligand identified
    • Mechanism of constitutive activity at structural level unresolved
  2. 2016 Medium

    Showed GPR176 acts in a pathway genetically separate from Vipr2, clarifying that it is a non-redundant input to SCN timekeeping.

    Evidence Genetic epistasis with Gpr176 and Vipr2 mutant mice

    PMID:26882873

    Open questions at the time
    • Molecular basis of pathway independence not defined
    • Single-lab readout limited to period phenotype
  3. 2020 High

    Identified N-glycosylation as a prerequisite for functional GPR176, answering how the receptor reaches the cell surface and why glycan loss diminishes its activity.

    Evidence PNGase F deglycosylation of mouse hypothalamus, site-directed mutagenesis, heterologous cAMP assay

    PMID:32157140

    Open questions at the time
    • Does not address ligand binding or signalling kinetics
    • Effect shown only on total expression, not trafficking dynamics directly
  4. 2022 Medium

    Placed GPR176 within an Nmu/Nms neuropeptide circuit that modulates light-induced phase shifts, extending its role from period-setting to photic entrainment.

    Evidence Microarray, triple Nmu/Nms/Gpr176 knockout mice with behavioural and SCN gene-expression phenotyping

    PMID:35908898

    Open questions at the time
    • Direct molecular link between GPR176 and Nmu/Nms signalling unresolved
    • Single lab
  5. 2023 Medium

    Defined a cancer-promoting mechanism: GPR176 binds GNAS via its TM3-ICL2 domain to activate cAMP/PKA and repress mitophagy, connecting the receptor's signalling to colorectal cancer progression.

    Evidence Co-IP, homology modelling, Gpr176-deficient mouse cancer models, cAMP/PKA and mitophagy assays

    PMID:36905238

    Open questions at the time
    • Domain mapping relies on homology model only
    • No reciprocal structural validation of the interaction interface
  6. 2024 Medium

    Established GPR176 as a pro-fibrotic effector in hepatic stellate cells across in vitro and in vivo models, broadening its role beyond the brain.

    Evidence siRNA knockdown in primary mouse HSCs and PCLS, Gpr176 knockout in CCl4 and BDL fibrosis models, human tissue IHC

    PMID:38694958

    Open questions at the time
    • Downstream signalling in HSCs not fully mapped
    • Single lab
  7. 2024 Medium

    Linked GPR176 mechanistically to fibroblast-to-myofibroblast transition via Smad2 phosphorylation, identifying a TGFβ1-adjacent node it controls without being TGFβ1-regulated itself.

    Evidence siRNA knockdown in NRK-49F renal fibroblasts, Western blot for αSMA/fibronectin/collagen and phospho-Smad2

    PMID:39047914

    Open questions at the time
    • How GPR176 modulates Smad2 phosphorylation is undefined
    • G-protein coupling in fibroblasts not tested
  8. 2025 Medium

    Identified an upstream regulatory mechanism whereby exosomal miR-382-5p suppresses GPR176 and disrupts its GNAS interaction to limit angiogenesis in liver metastasis.

    Evidence RNA pull-down, RIP, Co-IP, in vivo/in vitro angiogenesis and vascular permeability assays, exosome characterization

    PMID:40578589

    Open questions at the time
    • Direct connection between GPR176-GNAS and CXCR1/CXCR2 levels mechanistically incomplete
    • Single lab
  9. 2025 Medium

    Revealed a neuronal excitability role: GPR176 in PV+ prefrontal interneurons constrains firing by acting on action-potential repolarization, distinct from synaptic effects.

    Evidence In situ expression, shRNA knockdown, whole-cell electrophysiology in PV+ interneurons, behaviour

    PMID:41188983

    Open questions at the time
    • Effector channels/G-protein pathway mediating the effect unidentified
    • Link to cAMP signalling not established here
  10. 2026 Medium

    Placed GPR176 downstream of E2F4 transcriptional control and showed it confers ferroptosis resistance via mitophagy suppression, integrating its mitophagy role into a transcriptional-to-cell-death axis in esophageal cancer.

    Evidence ChIP/promoter binding, E2F4 and GPR176 over/knockdown, mitophagy and ferroptosis markers, rescue experiments

    PMID:42253509

    Open questions at the time
    • Whether GNAS/cAMP-PKA mediates the ferroptosis effect not tested
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • The identity of the endogenous activating ligand(s) for GPR176 and the structural basis of its constitutive Gz coupling remain unresolved.
  • No ligand identity established
  • Detection in a single preprint cell-based assay
  • No structure of receptor or receptor-G protein complex

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 1
Pathway
R-HSA-1643685 Disease 3 R-HSA-162582 Signal Transduction 2 R-HSA-9909396 Circadian clock 2
Partners
GNAS

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 GPR176 is an SCN-enriched orphan GPCR that represses cAMP signalling in an agonist-independent (constitutively active) manner, and couples to the unique G-protein subclass Gz (not canonical Gi) to reduce cAMP production and set the pace of circadian behaviour. Genetic knockout mice, heterologous expression assays, cAMP measurement, G-protein coupling analysis Nature Communications High 26882873
2016 GPR176 acts independently of and in parallel to the Vipr2 GPCR pathway in the SCN, as established by genetic epistasis in knockout animals. Genetic epistasis analysis using Gpr176 and Vipr2 mutant mice Nature Communications Medium 26882873
2020 GPR176 undergoes N-linked glycosylation at four conserved asparagine residues in its N-terminal region; mutation of these residues reduces protein expression and attenuates cAMP-repressive activity in cells, establishing N-glycosylation as a prerequisite for efficient expression of functional GPR176. Peptide-N-glycosidase F treatment of mouse hypothalamus extracts, site-directed mutagenesis of N-glycosylation sites, heterologous expression, cAMP assay Scientific Reports High 32157140
2020 N-glycosylation of GPR176 is required for proper cell-surface expression; deficient N-glycosylation does not directly compromise the intrinsic agonist-independent cAMP-repressive activity but reduces it indirectly by lowering total protein levels. Site-directed mutagenesis of N-glycosylation sites, heterologous expression, cAMP assay Scientific Reports Medium 32157140
2023 GPR176 physically interacts with G protein GNAS intracellularly via its transmembrane helix 3–intracellular loop 2 domain; this GPR176/GNAS complex activates the cAMP/PKA signalling pathway and inhibits mitophagy via the cAMP/PKA/BNIP3L axis to promote colorectal cancer progression. Co-immunoprecipitation, homology modelling, in vitro and in vivo cancer models with Gpr176-deficient mice, cAMP/PKA assay, mitophagy assays Advanced Science Medium 36905238
2022 Gpr176 knockout in mice leads to upregulation of Nmu and Nms mRNA in the SCN; triple knockout of Nmu/Nms/Gpr176 results in enhanced light-induced phase shifts and reduced Per1 and cFos induction by light, indicating a functional interaction among Nmu, Nms, and Gpr176 in modulating light-induced circadian phase shifts. Microarray analysis, triple knockout mouse generation and behavioural phenotyping, SCN gene expression analysis Biological & Pharmaceutical Bulletin Medium 35908898
2024 GPR176 is induced in activated hepatic stellate cells (HSCs) and plays a profibrotic role: siRNA-mediated knockdown reduces fibrogenic characteristics in primary mouse HSCs and precision-cut liver slices; Gpr176 knockout mice develop less severe fibrosis in CCl4 and bile duct ligation models. siRNA knockdown in primary mouse HSCs and PCLS, GPR176 knockout mouse fibrosis models (CCl4 and BDL), immunohistochemistry of human CLD tissue JHEP Reports Medium 38694958
2024 GPR176 promotes fibroblast-to-myofibroblast transition in fibrosis: Gpr176 expression is increased in fibrotic lungs, kidneys, liver, and heart; siRNA knockdown of Gpr176 in rat renal fibroblasts reduces TGFβ1-induced expression of αSMA, fibronectin, and collagen, and attenuates Smad2 phosphorylation, without being itself regulated by TGFβ1. Gene expression analysis in fibrosis mouse models, siRNA knockdown in NRK-49F cells, Western blot for αSMA/fibronectin/collagen and phospho-Smad2 Biochimica et Biophysica Acta – Molecular Cell Research Medium 39047914
2025 Exosomal miR-382-5p downregulates GPR176 expression and disrupts its interaction with GNAS in the liver, thereby reducing CXCR1/CXCR2 levels and suppressing angiogenesis and vascular permeability in colorectal cancer liver metastasis models. RNA pull-down, RNA immunoprecipitation (RIP), Co-IP, in vivo and in vitro angiogenesis/vascular permeability assays, exosome isolation and characterization Cellular Signalling Medium 40578589
2024 A cell-based assay (GzESTY) detected the presence of endogenous ligands for GPR176 in brain extracts, providing functional evidence that endogenous activating ligands for GPR176 exist in brain tissue. Cell-based Gz-coupled signal transduction assay (GzESTY) with brain extract fractions bioRxiv (preprint)preprint Low bio_10.1101_2024.07.26.605282
2025 Gpr176 is expressed predominantly in parvalbumin-positive (PV+) interneurons of the prefrontal cortex; knockdown of Gpr176 increases firing output of PV+ interneurons by altering membrane potential changes during the repolarizing phase of action potentials, without affecting synaptic activity. In situ expression analysis, shRNA-mediated knockdown, whole-cell electrophysiology in PV+ interneurons, behavioural assays Molecular Brain Medium 41188983
2026 E2F4 directly binds the GPR176 promoter and transcriptionally activates GPR176 expression; elevated GPR176 suppresses mitophagy and confers resistance to ferroptosis in esophageal cancer cells, and GPR176 overexpression abrogates the enhanced mitophagy and ferroptosis induced by E2F4 depletion. ChIP/promoter binding assay, overexpression and knockdown of E2F4 and GPR176, mitophagy markers (MMP, ROS, autophagy proteins), ferroptosis markers (MDA, Fe2+, lipid ROS), rescue experiments Human Mutation Medium 42253509

Source papers

Stage 0 corpus · 18 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 Gpr176 is a Gz-linked orphan G-protein-coupled receptor that sets the pace of circadian behaviour. Nature communications 68 26882873
2023 GPR176 Promotes Cancer Progression by Interacting with G Protein GNAS to Restrain Cell Mitophagy in Colorectal Cancer. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 54 36905238
2020 Identification and functional characterisation of N-linked glycosylation of the orphan G protein-coupled receptor Gpr176. Scientific reports 30 32157140
2020 Time-Restricted G-Protein Signaling Pathways via GPR176, Gz, and RGS16 Set the Pace of the Master Circadian Clock in the Suprachiasmatic Nucleus. International journal of molecular sciences 16 32709014
2017 G-protein-coupled receptor signaling through Gpr176, Gz, and RGS16 tunes time in the center of the circadian clock [Review]. Endocrine journal 12 28502923
2022 Nmu/Nms/Gpr176 Triple-Deficient Mice Show Enhanced Light-Resetting of Circadian Locomotor Activity. Biological & pharmaceutical bulletin 11 35908898
2023 Oncogenic roles of GPR176 in breast cancer: a potential marker of aggressiveness and a potential target of gene therapy. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 8 37079213
2024 The oncogenic roles of GPR176 in ovarian cancer: a molecular target for aggressiveness and gene therapy. Journal of obstetrics and gynaecology : the journal of the Institute of Obstetrics and Gynaecology 6 38835234
2023 Exploring the Correlation Between GPR176, a Potential Target Gene of Gastric Cancer, and Immune Cell Infiltration. Pharmacogenomics and personalized medicine 6 37284492
2023 The promoting effects of GPR176 expression on proliferation, chemoresistance, lipogenesis and invasion of oesophageal cancer. Journal of cancer research and clinical oncology 6 37584712
2024 Orphan receptor GPR176 in hepatic stellate cells exerts a profibrotic role in chronic liver disease. JHEP reports : innovation in hepatology 4 38694958
2025 Exosomal miR-382-5p prevents pre-metastatic niche formation by inhibiting GPR176/GNAS-CXCR1/CXCR2 axis in colorectal cancer liver metastasis. Cellular signalling 3 40578589
2024 GPR176 promotes fibroblast-to-myofibroblast transition in organ fibrosis progression. Biochimica et biophysica acta. Molecular cell research 3 39047914
2026 Establishing FDA-approved oncology drugs as GPR176 inhibitor through homology modelling, molecular docking, MMGBSA, DFT, and molecular dynamics simulation. Scientific reports 0 41484214
2026 GPR176 enhances the epithelial‑mesenchymal transition in gastric cancer cells by activating the PI3K/AKT/mTOR signaling pathway. Oncology reports 0 41574720
2026 GPR176 represses mitophagy to promote the progression of osteosarcoma by facilitating mTORC1 activity via PI3K-AKT pathway. Translational cancer research 0 41969458
2026 E2F4 Mediates Mitophagy to Inhibit Ferroptosis in Esophageal Cancer Cells by Activating GPR176. Human mutation 0 42253509
2025 Gpr176 modulates the firing pattern of parvalbumin-positive interneurons in the orbitofrontal cortex of mouse. Molecular brain 0 41188983

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