Affinage

GPR83

G-protein coupled receptor 83 · UniProt Q9NYM4

Length
423 aa
Mass
48.3 kDa
Annotated
2026-04-28
24 papers in source corpus 15 papers cited in narrative 19 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GPR83 is a class A orphan GPCR that functions as a neuromodulatory receptor integrating energy homeostasis, nociception, dopamine signaling, and reward behavior in the central and peripheral nervous systems. The receptor signals constitutively through Gαq/11 and contains a zinc(II)-binding site (His145, His204, Cys207, Glu217) that activates signaling; candidate endogenous ligands include the neuropeptide-like proteins FAM237A and FAM237B, which activate GPR83 at nanomolar concentrations and induce β-arrestin recruitment and receptor internalization, while shorter PEN and proCCK-derived peptides elicit biased agonism across Gαi, Gαs, and β-arrestin pathways (PMID:23335960, PMID:36853120, PMID:35605991, PMID:32713278). GPR83 heterodimerizes with GHSR1a in hypothalamic neurons to attenuate ghrelin-driven orexigenic signaling, and its expression on nucleus accumbens cholinergic interneurons and DRG nociceptors modulates dopamine release dynamics, morphine reward, and nociceptive sensitivity (PMID:23744028, PMID:31199956, PMID:36352334, PMID:41406857). A specific isoform (isoform-4) carrying a 20-amino-acid insertion in the second intracellular loop induces Foxp3 expression in CD4+ T cells under inflammatory conditions, although GPR83 is dispensable for baseline regulatory T cell development (PMID:20200545, PMID:18479351).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2008 Medium

    Whether GPR83 is functionally required for regulatory T cell biology was tested: despite being a TGF-β-induced marker of Foxp3+ cells, Gpr83 knockout mice showed normal Treg development and suppressive function, establishing that GPR83 is not essential for core Treg identity.

    Evidence Gpr83 KO mice assessed by flow cytometry and T-cell transfer colitis model

    PMID:18479351

    Open questions at the time
    • Whether GPR83 contributes to Treg function under specific inflammatory contexts beyond colitis
    • Endogenous ligand in immune compartment unknown
  2. 2010 Medium

    How GPR83 isoforms differ functionally was resolved: isoform-4, containing a 20-amino-acid insertion in the second intracellular loop, uniquely suppresses inflammation and induces Foxp3, whereas isoform-1 does not, establishing that this loop insertion determines immunomodulatory signaling capacity.

    Evidence Retroviral transduction of CD4+ T cells with isoform-1 vs. isoform-4, in vivo inflammation model

    PMID:20200545

    Open questions at the time
    • Downstream signaling pathway engaged by isoform-4 not identified
    • Whether isoform-4 is expressed endogenously at functional levels in T cells
  3. 2012 Medium

    A role for GPR83 in central thermoregulation was established: knockdown in the hypothalamic preoptic area reduced active-cycle core body temperature and increased circulating adiponectin, linking hypothalamic GPR83 to metabolic and thermoregulatory control.

    Evidence Lentiviral shRNA knockdown in mouse POA with telemetric temperature monitoring and adiponectin ELISA

    PMID:22560055

    Open questions at the time
    • Mechanism connecting GPR83 signaling to thermoregulatory circuits not defined
    • Ligand driving POA GPR83 function unknown
  4. 2013 High

    Two foundational properties of GPR83 signaling were defined: constitutive Gαq/11 coupling and a zinc(II)-specific activation mechanism mediated by a defined metal-binding site (His145, His204, Cys207, Glu217), while heterodimerization with GHSR1a was shown to dampen ghrelin signaling in energy homeostasis.

    Evidence Second messenger assays with site-directed mutagenesis for zinc binding; in vitro heterodimerization assays combined with Gpr83 KO mouse ghrelin challenge phenotyping

    PMID:23335960 PMID:23744028

    Open questions at the time
    • Physiological relevance of zinc activation in vivo not tested
    • Structural basis of GHSR1a heterodimer interface unknown
    • Whether homodimerization (also observed) has functional consequence
  5. 2016 Medium

    PEN, a proSAAS-derived neuropeptide, was proposed as an endogenous GPR83 ligand and GPR83 was shown to interact functionally with GPR171 in brain regions, suggesting coordinated neuropeptide signaling — though the PEN–GPR83 pairing was subsequently disputed.

    Evidence Radioligand binding, receptor knockdown in Neuro2A cells and mouse brain, co-expression signaling assays

    PMID:27117253

    Open questions at the time
    • PEN as GPR83 ligand not replicated by independent group (disputed by PMID:36853120)
    • Molecular basis of GPR83–GPR171 interaction not characterized
    • Functional consequence of GPR83–GPR171 co-expression in vivo unknown
  6. 2019 High

    GPR83's role in mesolimbic dopamine signaling and reward was established: expression on NAc cholinergic interneurons and VTA dopamine neurons was mapped, GPR83 KO enhanced baseline dopamine release and disrupted tonic/phasic balance, and NAc-specific knockdown attenuated morphine conditioned place preference.

    Evidence GPR83/eGFP reporter mice, fast-scan cyclic voltammetry, global KO and regional shRNA knockdown with behavioral assay

    PMID:31199956

    Open questions at the time
    • Ligand activating GPR83 on cholinergic interneurons not identified
    • Downstream signaling pathway in NAc neurons not dissected
  7. 2020 Medium

    FAM237A (neurosecretory protein GL) was identified as a specific GPR83 agonist that requires C-terminal amidation for activity, resolving the question of endogenous ligand identity through a functional screen using cells competent for neuropeptide processing.

    Evidence Functional GPCR screening using endocrine host cell lines, cell-based activation assay

    PMID:32713278

    Open questions at the time
    • In vivo confirmation that FAM237A activates GPR83 in brain not yet shown
    • Whether FAM237A and GPR83 co-localize in relevant circuits not mapped
  8. 2021 Medium

    GPR83 was linked to anxiety-related behavior in a sex- and region-dependent manner: global KO reduced anxiety in males, while BLA-specific knockdown increased anxiety in females, and glucocorticoid treatment downregulated GPR83 in amygdala and NAc.

    Evidence Global KO behavioral assays, stereotaxic lentiviral shRNA knockdown in BLA and NAc, dexamethasone with RT-qPCR

    PMID:34512237

    Open questions at the time
    • Mechanism underlying sex-specific effects not identified
    • Whether glucocorticoid regulation is direct or indirect unknown
  9. 2022 Medium

    Biased agonism at GPR83 was defined: PEN variants preferentially couple to Gαi while proCCK-derived peptides engage Gαs at low concentrations and switch to Gαi at high concentrations, and GPR83 on DRG nociceptors was shown to tune nociceptive signaling with knockdown reducing pain behavior.

    Evidence cAMP/Gαs, Gαi, and β-arrestin recruitment assays; DRG immunohistochemistry, siRNA knockdown, calcium imaging, behavioral pain models

    PMID:35605991 PMID:36352334

    Open questions at the time
    • PEN binding to GPR83 disputed by PMID:36853120
    • Biased agonism not validated with purified receptor reconstitution
    • Which G protein couples GPR83 in DRG nociceptors in vivo unknown
  10. 2023 Medium

    Independent confirmation established FAM237A as a nanomolar-affinity GPR83 ligand inducing β-arrestin recruitment and internalization, while PEN and proCCK56-63 showed no detectable activity, challenging the earlier ligand assignments.

    Evidence NanoBiT-based ligand-binding and β-arrestin recruitment assays in HEK293T cells

    PMID:36853120 PMID:37689599

    Open questions at the time
    • Discrepancy with PEN/proCCK studies not mechanistically resolved
    • In vivo demonstration of FAM237A–GPR83 axis still lacking
    • FAM237B potency and selectivity less characterized
  11. 2025 High

    Pharmacological tool compounds validated the GPR83 binding site and confirmed in vivo relevance to opioid reward: virtual screening yielded agonists and an antagonist whose binding was abolished by mutagenesis of predicted contact residues, and peripheral antagonist administration blocked morphine CPP in WT but not KO mice.

    Evidence Homology modeling, virtual screening, cell-based assays, site-directed mutagenesis, GPR83 KO mouse conditioned place preference and antinociception assays

    PMID:41406857

    Open questions at the time
    • Crystal or cryo-EM structure of GPR83 not yet available
    • Whether small molecule antagonist acts centrally after peripheral dosing not clarified
    • Selectivity profile of tool compounds across related GPCRs not fully characterized

Open questions

Synthesis pass · forward-looking unresolved questions
  • The definitive endogenous ligand for GPR83 remains contested — FAM237A is the strongest current candidate but in vivo validation of an FAM237A–GPR83 signaling axis in brain circuits is lacking, and no high-resolution structure of GPR83 has been determined.
  • No in vivo demonstration of FAM237A activating GPR83 in defined neural circuits
  • No solved structure of GPR83 alone or in complex with ligand/G protein
  • Mechanism by which GPR83 modulates cholinergic interneuron function in NAc undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 5 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 3 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-112316 Neuronal System 3
Partners
ARRB1FAM237AFAM237BGHSR1AGNA11GNAQGPR171
Complex memberships
GPR83–GHSR1a heterodimerGPR83–GPR171 heteromer

Evidence

Reading pass · 19 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 PEN (a proSAAS-derived neuropeptide) binds to and activates GPR83; reduction of GPR83 expression in mouse brain and Neuro2A cells reduced PEN binding and signaling, establishing GPR83 as the major receptor for PEN. Radioligand binding, receptor knockdown in Neuro2A cells and mouse brain, second messenger assays Science signaling Medium 27117253
2016 GPR83 co-localizes with GPR171 in some brain regions, and co-expression of these two receptors in cell lines altered the signaling properties of each receptor, indicating a functional receptor-receptor interaction. Immunohistochemistry co-localization, co-expression signaling assays in cell lines Science signaling Medium 27117253
2013 GPR83 heterodimerizes with the ghrelin receptor (GHSR1a), and this heterodimerization diminishes activation of GHSR1a by acyl-ghrelin; Gpr83-deficient mice show potentiated orexigenic and adipogenic effects of ghrelin. In vitro heterodimerization assays, Gpr83 knockout mouse phenotyping (ghrelin challenge) Nature communications High 23744028
2013 GPR83 hypothalamic expression is regulated by nutrient availability and is decreased in obese mice; in the arcuate nucleus it co-localizes with GHSR1a and agouti-related protein. qPCR expression analysis in diet-manipulated and obese mice; immunohistochemistry co-localization Nature communications Medium 23744028
2013 Mouse GPR83 signals constitutively through Gq/11 without affecting Gi or Gs pathways; zinc(II) (but not calcium(II) or magnesium(II)) potently activates mGPR83, and key ion-binding residues His145, His204, Cys207, and Glu217 mediate this activation. Second messenger assays (Gq/11, Gi, Gs), site-directed mutagenesis, zinc challenge in transfected cells PloS one High 23335960
2013 mGPR83 forms homodimers, as demonstrated in transfected cells. Dimerization assay in transfected cells PloS one Low 23335960
2012 Knockdown of GPR83 in the hypothalamic preoptic area reduces core body temperature during the active cycle and increases circulating adiponectin levels, establishing GPR83's role in central thermoregulation and adiponectin control. Lentiviral shRNA knockdown in mouse POA, telemetric core body temperature monitoring, ELISA for adiponectin Metabolism: clinical and experimental Medium 22560055
2022 PEN22 and PEN20 facilitate GPR83 coupling to Gαi, whereas shorter PEN peptides (PEN18, PEN19) and proCCK56-62/proCCK56-63 facilitate coupling to Gαs; at higher concentrations proCCK peptides switch to Gαi coupling, demonstrating biased agonism and Gα subtype selectivity dependent on peptide identity and concentration. Second messenger assays (cAMP/Gαs, Gαi), β-arrestin recruitment assay, radioligand binding, receptor endocytosis assay in transfected cells Molecular pharmacology Medium 35605991
2022 ProCCK56-62 and proCCK56-63, derived from procholecystokinin, bind GPR83 with high affinity, activate second messenger pathways, and induce ligand-mediated receptor endocytosis. Radioligand binding, second messenger assays, receptor endocytosis assay in transfected cells Molecular pharmacology Medium 35605991
2023 Mature human FAM237A binds GPR83 with nanomolar affinity and activates the receptor, inducing β-arrestin recruitment and receptor internalization in HEK293T cells; PEN and proCCK56-63 showed no detectable interaction with GPR83 in these assays. NanoBiT-based ligand-binding assay, fluorescent ligand visualization, NanoBiT-based β-arrestin recruitment assay in HEK293T cells The FEBS journal Medium 36853120
2023 Mature human FAM237B activates GPR83 at nanomolar concentrations (1–10 nM) in a β-arrestin recruitment assay, identifying FAM237B as another endogenous agonist for GPR83. NanoBiT-based β-arrestin recruitment assay with recombinant FAM237B produced via intein-fusion approach Amino acids Low 37689599
2020 FAM237A (neurosecretory protein GL) is identified as a specific activator of GPR83; its active form is a C-terminally cleaved, amidated ~9 kDa secreted protein processed via the regulated secretory pathway; the related FAM237B activates GPR83 with reduced potency. Functional GPCR screening using endocrine host cell lines competent for post-translational processing, cell-based activation assay SLAS discovery : advancing life sciences R & D Medium 32713278
2020 In endometrial Ishikawa cells, GPR83 mediates PEN-induced ERK phosphorylation via a Gαq/11-dependent pathway; in HEK293 cells lacking β-arrestin, GPR83 also signals via a β-arrestin-dependent pathway; both pathways together are required for full responsiveness to PEN. ERK phosphorylation assay, pharmacological inhibition of Gαq/11, β-arrestin-deficient HEK293 cells, PEN peptide treatment F&S science Medium 35559741
2019 GPR83 is expressed on cholinergic interneurons in the nucleus accumbens and on ventral tegmental area dopamine neurons; GPR83 knockout leads to enhanced baseline dopamine release in the nucleus accumbens and disrupts tonic vs. phasic dopamine release ratio; shRNA-mediated knockdown of GPR83 in the nucleus accumbens attenuates morphine conditioned place preference. GPR83/eGFP reporter mice (fluorescence localization), fast-scan cyclic voltammetry (dopamine release), GPR83 KO mice, shRNA knockdown with conditioned place preference behavioral assay Neuropharmacology High 31199956
2021 Global GPR83 knockout reduces anxiety-related behaviors in male mice; local GPR83 knockdown in the basolateral amygdala increases anxiety-like behaviors in female mice; dexamethasone decreases GPR83 expression in the amygdala and nucleus accumbens of female mice, linking glucocorticoid regulation to GPR83 levels in specific brain regions. Global KO behavioral assays, stereotaxic lentiviral shRNA knockdown in specific amygdala subregions and NAc, dexamethasone treatment with RT-qPCR Frontiers in neuroscience Medium 34512237
2022 GPR83 expression in dorsal root ganglion nociceptors tunes nociceptive signaling; siRNA-mediated silencing of Gpr83 in DRG reduces neuronal and behavioral nociception, as well as pathologic pain in hind paw inflammation and chemotherapy-induced peripheral neuropathy; PEN application differentially modulates nociceptor responses depending on exposure time, likely via Gq/11-mediated receptor downregulation. Immunohistochemistry of DRG, siRNA knockdown in DRG, calcium imaging, behavioral pain assays (von Frey, CFA inflammation, CIPN model), in vivo PEN administration Neurotherapeutics Medium 36352334
2010 GPR83 isoform-4, which contains 20 additional amino acids in the second cytoplasmic loop compared to isoform-1, but not isoform-1, suppresses inflammatory responses in vivo and induces Foxp3 expression in retrovirally transduced CD4+ T cells under inflammatory conditions, demonstrating that this intracellular loop insertion determines isoform-specific immunomodulatory signaling. Retroviral transduction of T cells with isoform-1 vs. isoform-4, in vivo inflammation model, Foxp3 expression analysis Genes and immunity Medium 20200545
2008 Naïve CD4+ T cell activation induces Gpr83 expression in a TGF-β-dependent manner, and Gpr83 expression is restricted to Foxp3-expressing cells; however, Gpr83-deficient mice have normal thymic and peripheral regulatory T cell development and suppressive function in a T-cell transfer colitis model. Flow cytometry, Gpr83 KO mice, T-cell transfer colitis model, TGF-β blockade Immunology Medium 18479351
2025 Virtual screening against a GPR83 homology model identified two small molecule agonists (CPD1, CPD27) and one antagonist (CPD25); site-directed mutagenesis of predicted binding residues disrupted ligand binding, validating the model; peripheral CPD25 administration blocked morphine conditioned place preference in wild-type but not GPR83 KO mice; GPR83 agonism blunted and antagonism enhanced morphine antinociception. Homology modeling, virtual screening, cell-based activation assay, site-directed mutagenesis, shRNA knockdown validation, GPR83 KO mouse conditioned place preference, antinociception assay Molecular pharmacology High 41406857

Source papers

Stage 0 corpus · 24 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 Identification of GPR83 as the receptor for the neuroendocrine peptide PEN. Science signaling 67 27117253
2013 The orphan receptor Gpr83 regulates systemic energy metabolism via ghrelin-dependent and ghrelin-independent mechanisms. Nature communications 66 23744028
2000 Y-receptor-like genes GPR72 and GPR73: molecular cloning, genomic organisation and assignment to human chromosome 11q21.1 and 2p14 and mouse chromosome 9 and 6. Biochimica et biophysica acta 32 10760605
2013 G-protein coupled receptor 83 (GPR83) signaling determined by constitutive and zinc(II)-induced activity. PloS one 22 23335960
2012 Downregulation of GPR83 in the hypothalamic preoptic area reduces core body temperature and elevates circulating levels of adiponectin. Metabolism: clinical and experimental 19 22560055
2022 GPR83 engages endogenous peptides from two distinct precursors to elicit differential signaling. Molecular pharmacology 17 35605991
2000 Cloning and chromosomal mapping of the mouse and human genes encoding the orphan glucocorticoid-induced receptor (GPR83). Cytogenetics and cell genetics 17 11060465
2010 Inflammation in vivo is modulated by GPR83 isoform-4 but not GPR83 isoform-1 expression in regulatory T cells. Genes and immunity 16 20200545
2018 Targeting the Recently Deorphanized Receptor GPR83 for the Treatment of Immunological, Neuroendocrine and Neuropsychiatric Disorders. Progress in molecular biology and translational science 15 30340784
2019 Neuropeptide PEN and Its Receptor GPR83: Distribution, Signaling, and Regulation. ACS chemical neuroscience 13 30726666
2008 Gpr83 expression is not required for the maintenance of intestinal immune homeostasis and regulation of T-cell-dependent colitis. Immunology 11 18479351
2023 FAM237A, rather than peptide PEN and proCCK56-63, binds to and activates the orphan receptor GPR83. The FEBS journal 10 36853120
2019 The role of the neuropeptide PEN receptor, GPR83, in the reward pathway: Relationship to sex-differences. Neuropharmacology 10 31199956
2021 PEN Receptor GPR83 in Anxiety-Like Behaviors: Differential Regulation in Global vs Amygdalar Knockdown. Frontiers in neuroscience 9 34512237
2020 A Pilot Screen of a Novel Peptide Hormone Library Identified Candidate GPR83 Ligands. SLAS discovery : advancing life sciences R & D 9 32713278
2020 Uterine Gpr83 mRNA is highly expressed during early pregnancy and GPR83 mediates the actions of PEN in endometrial and non-endometrial cells. F&S science 8 35559741
2022 Gpr83 Tunes Nociceptor Function, Controlling Pain. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 7 36352334
2023 Nanomolar range of FAM237B can activate receptor GPR83. Amino acids 3 37689599
2025 Expression of Tacr1 and Gpr83 by spinal projection neurons. Molecular pain 2 40331673
2023 Is the Neuropeptide PEN a Ligand of GPR83? International journal of molecular sciences 2 37894796
2025 GPR83 protects cochlear hair cells against ibrutinib-induced hearing loss through AKT signaling pathways. Frontiers in medicine 0 40248074
2025 ProSAAS neuropeptides and receptors GPR171 and GPR83: Potential therapeutic applications for pain, anxiety, and body weight regulation. The Journal of pharmacology and experimental therapeutics 0 40450835
2025 Identification of small molecule ligands for GPR83 that modulate morphine antinociception and reward. Molecular pharmacology 0 41406857
2019 Two Proximally Close Priority Candidate Genes for diplopodia-1, an Autosomal Inherited Craniofacial-Limb Syndrome in the Chicken: MRE11 and GPR83. The Journal of heredity 0 30597046