{"gene":"GPR83","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":2016,"finding":"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.","method":"Radioligand binding, receptor knockdown in Neuro2A cells and mouse brain, second messenger assays","journal":"Science signaling","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods in single lab; disputed by later studies","pmids":["27117253"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Immunohistochemistry co-localization, co-expression signaling assays in cell lines","journal":"Science signaling","confidence":"Medium","confidence_rationale":"Tier 3 — co-expression functional assay in single lab","pmids":["27117253"],"is_preprint":false},{"year":2013,"finding":"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.","method":"In vitro heterodimerization assays, Gpr83 knockout mouse phenotyping (ghrelin challenge)","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — in vitro interaction assay corroborated by KO mouse phenotype showing potentiated ghrelin response","pmids":["23744028"],"is_preprint":false},{"year":2013,"finding":"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.","method":"qPCR expression analysis in diet-manipulated and obese mice; immunohistochemistry co-localization","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization tied to functional context (energy regulation), single lab","pmids":["23744028"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Second messenger assays (Gq/11, Gi, Gs), site-directed mutagenesis, zinc challenge in transfected cells","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 — functional assay with mutagenesis identifying specific residues","pmids":["23335960"],"is_preprint":false},{"year":2013,"finding":"mGPR83 forms homodimers, as demonstrated in transfected cells.","method":"Dimerization assay in transfected cells","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 — single assay, single lab, no functional follow-up","pmids":["23335960"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Lentiviral shRNA knockdown in mouse POA, telemetric core body temperature monitoring, ELISA for adiponectin","journal":"Metabolism: clinical and experimental","confidence":"Medium","confidence_rationale":"Tier 2 — direct in vivo KD with specific physiological readouts, single lab","pmids":["22560055"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Second messenger assays (cAMP/Gαs, Gαi), β-arrestin recruitment assay, radioligand binding, receptor endocytosis assay in transfected cells","journal":"Molecular pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal functional assays, single lab","pmids":["35605991"],"is_preprint":false},{"year":2022,"finding":"ProCCK56-62 and proCCK56-63, derived from procholecystokinin, bind GPR83 with high affinity, activate second messenger pathways, and induce ligand-mediated receptor endocytosis.","method":"Radioligand binding, second messenger assays, receptor endocytosis assay in transfected cells","journal":"Molecular pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal binding and functional assays, single lab; disputed by PMID 36853120","pmids":["35605991"],"is_preprint":false},{"year":2023,"finding":"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.","method":"NanoBiT-based ligand-binding assay, fluorescent ligand visualization, NanoBiT-based β-arrestin recruitment assay in HEK293T cells","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal assays in single lab; contradicts earlier PEN/proCCK findings","pmids":["36853120"],"is_preprint":false},{"year":2023,"finding":"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.","method":"NanoBiT-based β-arrestin recruitment assay with recombinant FAM237B produced via intein-fusion approach","journal":"Amino acids","confidence":"Low","confidence_rationale":"Tier 3 — single assay, single lab","pmids":["37689599"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Functional GPCR screening using endocrine host cell lines competent for post-translational processing, cell-based activation assay","journal":"SLAS discovery : advancing life sciences R & D","confidence":"Medium","confidence_rationale":"Tier 2 — functional screening with processing characterization, single lab","pmids":["32713278"],"is_preprint":false},{"year":2020,"finding":"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.","method":"ERK phosphorylation assay, pharmacological inhibition of Gαq/11, β-arrestin-deficient HEK293 cells, PEN peptide treatment","journal":"F&S science","confidence":"Medium","confidence_rationale":"Tier 2 — two orthogonal signaling pathway dissections, single lab","pmids":["35559741"],"is_preprint":false},{"year":2019,"finding":"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.","method":"GPR83/eGFP reporter mice (fluorescence localization), fast-scan cyclic voltammetry (dopamine release), GPR83 KO mice, shRNA knockdown with conditioned place preference behavioral assay","journal":"Neuropharmacology","confidence":"High","confidence_rationale":"Tier 2 — direct localization with functional consequence, multiple orthogonal methods including KO and regional KD","pmids":["31199956"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Global KO behavioral assays, stereotaxic lentiviral shRNA knockdown in specific amygdala subregions and NAc, dexamethasone treatment with RT-qPCR","journal":"Frontiers in neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — region-specific KD with defined behavioral phenotype, single lab","pmids":["34512237"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Immunohistochemistry of DRG, siRNA knockdown in DRG, calcium imaging, behavioral pain assays (von Frey, CFA inflammation, CIPN model), in vivo PEN administration","journal":"Neurotherapeutics","confidence":"Medium","confidence_rationale":"Tier 2 — direct KD with multiple pain readouts, single lab","pmids":["36352334"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Retroviral transduction of T cells with isoform-1 vs. isoform-4, in vivo inflammation model, Foxp3 expression analysis","journal":"Genes and immunity","confidence":"Medium","confidence_rationale":"Tier 2 — direct isoform comparison with defined in vivo and molecular readouts, single lab","pmids":["20200545"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Flow cytometry, Gpr83 KO mice, T-cell transfer colitis model, TGF-β blockade","journal":"Immunology","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse with defined cellular assay, multiple readouts, single lab","pmids":["18479351"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Homology modeling, virtual screening, cell-based activation assay, site-directed mutagenesis, shRNA knockdown validation, GPR83 KO mouse conditioned place preference, antinociception assay","journal":"Molecular pharmacology","confidence":"High","confidence_rationale":"Tier 1–2 — mutagenesis validating binding site + KO mouse in vivo pharmacology, multiple methods","pmids":["41406857"],"is_preprint":false}],"current_model":"GPR83 is a class A GPCR that signals constitutively through Gq/11 and can be activated by neuropeptides (PEN from proSAAS, and FAM237A/FAM237B), signaling via Gαq/11, Gαi, Gαs, and β-arrestin pathways in a ligand- and context-dependent (biased agonism) manner; it heterodimerizes with GHSR1a to dampen ghrelin signaling and with GPR171 to modulate feeding-related signaling, is expressed on cholinergic interneurons in the nucleus accumbens and DRG nociceptors to regulate dopamine release, morphine reward, and pain sensitivity, and contains a zinc(II)-binding site involving His145, His204, Cys207, and Glu217 that can activate the receptor."},"narrative":{"teleology":[{"year":2008,"claim":"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","pmids":["18479351"],"confidence":"Medium","gaps":["Whether GPR83 contributes to Treg function under specific inflammatory contexts beyond colitis","Endogenous ligand in immune compartment unknown"]},{"year":2010,"claim":"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","pmids":["20200545"],"confidence":"Medium","gaps":["Downstream signaling pathway engaged by isoform-4 not identified","Whether isoform-4 is expressed endogenously at functional levels in T cells"]},{"year":2012,"claim":"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","pmids":["22560055"],"confidence":"Medium","gaps":["Mechanism connecting GPR83 signaling to thermoregulatory circuits not defined","Ligand driving POA GPR83 function unknown"]},{"year":2013,"claim":"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","pmids":["23335960","23744028"],"confidence":"High","gaps":["Physiological relevance of zinc activation in vivo not tested","Structural basis of GHSR1a heterodimer interface unknown","Whether homodimerization (also observed) has functional consequence"]},{"year":2016,"claim":"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","pmids":["27117253"],"confidence":"Medium","gaps":["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"]},{"year":2019,"claim":"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","pmids":["31199956"],"confidence":"High","gaps":["Ligand activating GPR83 on cholinergic interneurons not identified","Downstream signaling pathway in NAc neurons not dissected"]},{"year":2020,"claim":"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","pmids":["32713278"],"confidence":"Medium","gaps":["In vivo confirmation that FAM237A activates GPR83 in brain not yet shown","Whether FAM237A and GPR83 co-localize in relevant circuits not mapped"]},{"year":2021,"claim":"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","pmids":["34512237"],"confidence":"Medium","gaps":["Mechanism underlying sex-specific effects not identified","Whether glucocorticoid regulation is direct or indirect unknown"]},{"year":2022,"claim":"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","pmids":["35605991","36352334"],"confidence":"Medium","gaps":["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"]},{"year":2023,"claim":"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","pmids":["36853120","37689599"],"confidence":"Medium","gaps":["Discrepancy with PEN/proCCK studies not mechanistically resolved","In vivo demonstration of FAM237A–GPR83 axis still lacking","FAM237B potency and selectivity less characterized"]},{"year":2025,"claim":"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","pmids":["41406857"],"confidence":"High","gaps":["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"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[4,7,9,11,12]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,1]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4,9,2]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[16]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,7,12,9,2]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[13,15,14]}],"complexes":["GPR83–GHSR1a heterodimer","GPR83–GPR171 heteromer"],"partners":["GHSR1A","GPR171","FAM237A","FAM237B","ARRB1","GNAQ","GNA11"],"other_free_text":[]},"mechanistic_narrative":"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]."},"prefetch_data":{"uniprot":{"accession":"Q9NYM4","full_name":"G-protein coupled receptor 83","aliases":["G-protein coupled receptor 72"],"length_aa":423,"mass_kda":48.3,"function":"G-protein coupled receptor for PEN, a neuropeptide produced from the precursor protein, proSAAS (encoded by PCSK1N). Acts through a G(i)- and G(q)-alpha-mediated pathway in response to PEN (PubMed:27117253). Plays a role in food intake and body weight regulation. May contribute to the regulation of anxiety-related behaviors (By similarity)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9NYM4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GPR83","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/GPR83","total_profiled":1310},"omim":[{"mim_id":"605569","title":"G PROTEIN-COUPLED RECEPTOR 83; GPR83","url":"https://www.omim.org/entry/605569"},{"mim_id":"164031","title":"NUCLEOLAR PROTEIN NOP2; NOP2","url":"https://www.omim.org/entry/164031"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":15.0}],"url":"https://www.proteinatlas.org/search/GPR83"},"hgnc":{"alias_symbol":[],"prev_symbol":["GPR72"]},"alphafold":{"accession":"Q9NYM4","domains":[{"cath_id":"1.20.1070.10","chopping":"67-271_280-362","consensus_level":"high","plddt":92.2451,"start":67,"end":362}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NYM4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NYM4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NYM4-F1-predicted_aligned_error_v6.png","plddt_mean":76.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GPR83","jax_strain_url":"https://www.jax.org/strain/search?query=GPR83"},"sequence":{"accession":"Q9NYM4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NYM4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NYM4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NYM4"}},"corpus_meta":[{"pmid":"27117253","id":"PMC_27117253","title":"Identification of GPR83 as the receptor for the neuroendocrine peptide PEN.","date":"2016","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/27117253","citation_count":67,"is_preprint":false},{"pmid":"23744028","id":"PMC_23744028","title":"The orphan receptor Gpr83 regulates systemic energy metabolism via ghrelin-dependent and ghrelin-independent mechanisms.","date":"2013","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/23744028","citation_count":66,"is_preprint":false},{"pmid":"10760605","id":"PMC_10760605","title":"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.","date":"2000","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/10760605","citation_count":32,"is_preprint":false},{"pmid":"23335960","id":"PMC_23335960","title":"G-protein coupled receptor 83 (GPR83) signaling determined by constitutive and zinc(II)-induced activity.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23335960","citation_count":22,"is_preprint":false},{"pmid":"22560055","id":"PMC_22560055","title":"Downregulation of GPR83 in the hypothalamic preoptic area reduces core body temperature and elevates circulating levels of adiponectin.","date":"2012","source":"Metabolism: clinical and experimental","url":"https://pubmed.ncbi.nlm.nih.gov/22560055","citation_count":19,"is_preprint":false},{"pmid":"35605991","id":"PMC_35605991","title":"GPR83 engages endogenous peptides from two distinct precursors to elicit differential signaling.","date":"2022","source":"Molecular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/35605991","citation_count":17,"is_preprint":false},{"pmid":"11060465","id":"PMC_11060465","title":"Cloning and chromosomal mapping of the mouse and human genes encoding the orphan glucocorticoid-induced receptor (GPR83).","date":"2000","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11060465","citation_count":17,"is_preprint":false},{"pmid":"20200545","id":"PMC_20200545","title":"Inflammation in vivo is modulated by GPR83 isoform-4 but not GPR83 isoform-1 expression in regulatory T cells.","date":"2010","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/20200545","citation_count":16,"is_preprint":false},{"pmid":"30340784","id":"PMC_30340784","title":"Targeting the Recently Deorphanized Receptor GPR83 for the Treatment of Immunological, Neuroendocrine and Neuropsychiatric Disorders.","date":"2018","source":"Progress in molecular biology and translational science","url":"https://pubmed.ncbi.nlm.nih.gov/30340784","citation_count":15,"is_preprint":false},{"pmid":"30726666","id":"PMC_30726666","title":"Neuropeptide PEN and Its Receptor GPR83: Distribution, Signaling, and Regulation.","date":"2019","source":"ACS chemical neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/30726666","citation_count":13,"is_preprint":false},{"pmid":"18479351","id":"PMC_18479351","title":"Gpr83 expression is not required for the maintenance of intestinal immune homeostasis and regulation of T-cell-dependent colitis.","date":"2008","source":"Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/18479351","citation_count":11,"is_preprint":false},{"pmid":"31199956","id":"PMC_31199956","title":"The role of the neuropeptide PEN receptor, GPR83, in the reward pathway: Relationship to sex-differences.","date":"2019","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/31199956","citation_count":10,"is_preprint":false},{"pmid":"36853120","id":"PMC_36853120","title":"FAM237A, rather than peptide PEN and proCCK56-63, binds to and activates the orphan receptor GPR83.","date":"2023","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/36853120","citation_count":10,"is_preprint":false},{"pmid":"34512237","id":"PMC_34512237","title":"PEN Receptor GPR83 in Anxiety-Like Behaviors: Differential Regulation in Global vs Amygdalar Knockdown.","date":"2021","source":"Frontiers in neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/34512237","citation_count":9,"is_preprint":false},{"pmid":"32713278","id":"PMC_32713278","title":"A Pilot Screen of a Novel Peptide Hormone Library Identified Candidate GPR83 Ligands.","date":"2020","source":"SLAS discovery : advancing life sciences R & D","url":"https://pubmed.ncbi.nlm.nih.gov/32713278","citation_count":9,"is_preprint":false},{"pmid":"35559741","id":"PMC_35559741","title":"Uterine Gpr83 mRNA is highly expressed during early pregnancy and GPR83 mediates the actions of PEN in endometrial and non-endometrial cells.","date":"2020","source":"F&S science","url":"https://pubmed.ncbi.nlm.nih.gov/35559741","citation_count":8,"is_preprint":false},{"pmid":"36352334","id":"PMC_36352334","title":"Gpr83 Tunes Nociceptor Function, Controlling Pain.","date":"2022","source":"Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/36352334","citation_count":7,"is_preprint":false},{"pmid":"37689599","id":"PMC_37689599","title":"Nanomolar range of FAM237B can activate receptor GPR83.","date":"2023","source":"Amino acids","url":"https://pubmed.ncbi.nlm.nih.gov/37689599","citation_count":3,"is_preprint":false},{"pmid":"40331673","id":"PMC_40331673","title":"Expression of Tacr1 and Gpr83 by spinal projection neurons.","date":"2025","source":"Molecular pain","url":"https://pubmed.ncbi.nlm.nih.gov/40331673","citation_count":2,"is_preprint":false},{"pmid":"37894796","id":"PMC_37894796","title":"Is the Neuropeptide PEN a Ligand of GPR83?","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37894796","citation_count":2,"is_preprint":false},{"pmid":"40450835","id":"PMC_40450835","title":"ProSAAS neuropeptides and receptors GPR171 and GPR83: Potential therapeutic applications for pain, anxiety, and body weight regulation.","date":"2025","source":"The Journal of pharmacology and experimental therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/40450835","citation_count":0,"is_preprint":false},{"pmid":"30597046","id":"PMC_30597046","title":"Two Proximally Close Priority Candidate Genes for diplopodia-1, an Autosomal Inherited Craniofacial-Limb Syndrome in the Chicken: MRE11 and GPR83.","date":"2019","source":"The Journal of heredity","url":"https://pubmed.ncbi.nlm.nih.gov/30597046","citation_count":0,"is_preprint":false},{"pmid":"41406857","id":"PMC_41406857","title":"Identification of small molecule ligands for GPR83 that modulate morphine antinociception and reward.","date":"2025","source":"Molecular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41406857","citation_count":0,"is_preprint":false},{"pmid":"40248074","id":"PMC_40248074","title":"GPR83 protects cochlear hair cells against ibrutinib-induced hearing loss through AKT signaling pathways.","date":"2025","source":"Frontiers in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40248074","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12257,"output_tokens":4113,"usd":0.049233},"stage2":{"model":"claude-opus-4-6","input_tokens":7666,"output_tokens":3184,"usd":0.176895},"total_usd":0.226128,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Radioligand binding, receptor knockdown in Neuro2A cells and mouse brain, second messenger assays\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in single lab; disputed by later studies\",\n      \"pmids\": [\"27117253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Immunohistochemistry co-localization, co-expression signaling assays in cell lines\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — co-expression functional assay in single lab\",\n      \"pmids\": [\"27117253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro heterodimerization assays, Gpr83 knockout mouse phenotyping (ghrelin challenge)\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vitro interaction assay corroborated by KO mouse phenotype showing potentiated ghrelin response\",\n      \"pmids\": [\"23744028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"qPCR expression analysis in diet-manipulated and obese mice; immunohistochemistry co-localization\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization tied to functional context (energy regulation), single lab\",\n      \"pmids\": [\"23744028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Second messenger assays (Gq/11, Gi, Gs), site-directed mutagenesis, zinc challenge in transfected cells\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — functional assay with mutagenesis identifying specific residues\",\n      \"pmids\": [\"23335960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"mGPR83 forms homodimers, as demonstrated in transfected cells.\",\n      \"method\": \"Dimerization assay in transfected cells\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single assay, single lab, no functional follow-up\",\n      \"pmids\": [\"23335960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Lentiviral shRNA knockdown in mouse POA, telemetric core body temperature monitoring, ELISA for adiponectin\",\n      \"journal\": \"Metabolism: clinical and experimental\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct in vivo KD with specific physiological readouts, single lab\",\n      \"pmids\": [\"22560055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Second messenger assays (cAMP/Gαs, Gαi), β-arrestin recruitment assay, radioligand binding, receptor endocytosis assay in transfected cells\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal functional assays, single lab\",\n      \"pmids\": [\"35605991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ProCCK56-62 and proCCK56-63, derived from procholecystokinin, bind GPR83 with high affinity, activate second messenger pathways, and induce ligand-mediated receptor endocytosis.\",\n      \"method\": \"Radioligand binding, second messenger assays, receptor endocytosis assay in transfected cells\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal binding and functional assays, single lab; disputed by PMID 36853120\",\n      \"pmids\": [\"35605991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"NanoBiT-based ligand-binding assay, fluorescent ligand visualization, NanoBiT-based β-arrestin recruitment assay in HEK293T cells\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal assays in single lab; contradicts earlier PEN/proCCK findings\",\n      \"pmids\": [\"36853120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"NanoBiT-based β-arrestin recruitment assay with recombinant FAM237B produced via intein-fusion approach\",\n      \"journal\": \"Amino acids\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single assay, single lab\",\n      \"pmids\": [\"37689599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Functional GPCR screening using endocrine host cell lines competent for post-translational processing, cell-based activation assay\",\n      \"journal\": \"SLAS discovery : advancing life sciences R & D\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional screening with processing characterization, single lab\",\n      \"pmids\": [\"32713278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"ERK phosphorylation assay, pharmacological inhibition of Gαq/11, β-arrestin-deficient HEK293 cells, PEN peptide treatment\",\n      \"journal\": \"F&S science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — two orthogonal signaling pathway dissections, single lab\",\n      \"pmids\": [\"35559741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"GPR83/eGFP reporter mice (fluorescence localization), fast-scan cyclic voltammetry (dopamine release), GPR83 KO mice, shRNA knockdown with conditioned place preference behavioral assay\",\n      \"journal\": \"Neuropharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization with functional consequence, multiple orthogonal methods including KO and regional KD\",\n      \"pmids\": [\"31199956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Global KO behavioral assays, stereotaxic lentiviral shRNA knockdown in specific amygdala subregions and NAc, dexamethasone treatment with RT-qPCR\",\n      \"journal\": \"Frontiers in neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — region-specific KD with defined behavioral phenotype, single lab\",\n      \"pmids\": [\"34512237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Immunohistochemistry of DRG, siRNA knockdown in DRG, calcium imaging, behavioral pain assays (von Frey, CFA inflammation, CIPN model), in vivo PEN administration\",\n      \"journal\": \"Neurotherapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct KD with multiple pain readouts, single lab\",\n      \"pmids\": [\"36352334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Retroviral transduction of T cells with isoform-1 vs. isoform-4, in vivo inflammation model, Foxp3 expression analysis\",\n      \"journal\": \"Genes and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct isoform comparison with defined in vivo and molecular readouts, single lab\",\n      \"pmids\": [\"20200545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Flow cytometry, Gpr83 KO mice, T-cell transfer colitis model, TGF-β blockade\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with defined cellular assay, multiple readouts, single lab\",\n      \"pmids\": [\"18479351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Homology modeling, virtual screening, cell-based activation assay, site-directed mutagenesis, shRNA knockdown validation, GPR83 KO mouse conditioned place preference, antinociception assay\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mutagenesis validating binding site + KO mouse in vivo pharmacology, multiple methods\",\n      \"pmids\": [\"41406857\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GPR83 is a class A GPCR that signals constitutively through Gq/11 and can be activated by neuropeptides (PEN from proSAAS, and FAM237A/FAM237B), signaling via Gαq/11, Gαi, Gαs, and β-arrestin pathways in a ligand- and context-dependent (biased agonism) manner; it heterodimerizes with GHSR1a to dampen ghrelin signaling and with GPR171 to modulate feeding-related signaling, is expressed on cholinergic interneurons in the nucleus accumbens and DRG nociceptors to regulate dopamine release, morphine reward, and pain sensitivity, and contains a zinc(II)-binding site involving His145, His204, Cys207, and Glu217 that can activate the receptor.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"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].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"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.\",\n      \"evidence\": \"Gpr83 KO mice assessed by flow cytometry and T-cell transfer colitis model\",\n      \"pmids\": [\"18479351\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether GPR83 contributes to Treg function under specific inflammatory contexts beyond colitis\", \"Endogenous ligand in immune compartment unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"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.\",\n      \"evidence\": \"Retroviral transduction of CD4+ T cells with isoform-1 vs. isoform-4, in vivo inflammation model\",\n      \"pmids\": [\"20200545\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream signaling pathway engaged by isoform-4 not identified\", \"Whether isoform-4 is expressed endogenously at functional levels in T cells\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"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.\",\n      \"evidence\": \"Lentiviral shRNA knockdown in mouse POA with telemetric temperature monitoring and adiponectin ELISA\",\n      \"pmids\": [\"22560055\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting GPR83 signaling to thermoregulatory circuits not defined\", \"Ligand driving POA GPR83 function unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"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.\",\n      \"evidence\": \"Second messenger assays with site-directed mutagenesis for zinc binding; in vitro heterodimerization assays combined with Gpr83 KO mouse ghrelin challenge phenotyping\",\n      \"pmids\": [\"23335960\", \"23744028\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological relevance of zinc activation in vivo not tested\", \"Structural basis of GHSR1a heterodimer interface unknown\", \"Whether homodimerization (also observed) has functional consequence\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"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.\",\n      \"evidence\": \"Radioligand binding, receptor knockdown in Neuro2A cells and mouse brain, co-expression signaling assays\",\n      \"pmids\": [\"27117253\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"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.\",\n      \"evidence\": \"GPR83/eGFP reporter mice, fast-scan cyclic voltammetry, global KO and regional shRNA knockdown with behavioral assay\",\n      \"pmids\": [\"31199956\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ligand activating GPR83 on cholinergic interneurons not identified\", \"Downstream signaling pathway in NAc neurons not dissected\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"Functional GPCR screening using endocrine host cell lines, cell-based activation assay\",\n      \"pmids\": [\"32713278\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo confirmation that FAM237A activates GPR83 in brain not yet shown\", \"Whether FAM237A and GPR83 co-localize in relevant circuits not mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"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.\",\n      \"evidence\": \"Global KO behavioral assays, stereotaxic lentiviral shRNA knockdown in BLA and NAc, dexamethasone with RT-qPCR\",\n      \"pmids\": [\"34512237\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism underlying sex-specific effects not identified\", \"Whether glucocorticoid regulation is direct or indirect unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"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.\",\n      \"evidence\": \"cAMP/Gαs, Gαi, and β-arrestin recruitment assays; DRG immunohistochemistry, siRNA knockdown, calcium imaging, behavioral pain models\",\n      \"pmids\": [\"35605991\", \"36352334\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"NanoBiT-based ligand-binding and β-arrestin recruitment assays in HEK293T cells\",\n      \"pmids\": [\"36853120\", \"37689599\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Discrepancy with PEN/proCCK studies not mechanistically resolved\", \"In vivo demonstration of FAM237A–GPR83 axis still lacking\", \"FAM237B potency and selectivity less characterized\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"evidence\": \"Homology modeling, virtual screening, cell-based assays, site-directed mutagenesis, GPR83 KO mouse conditioned place preference and antinociception assays\",\n      \"pmids\": [\"41406857\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [4, 7, 9, 11, 12]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4, 9, 2]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 7, 12, 9, 2]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [13, 15, 14]}\n    ],\n    \"complexes\": [\n      \"GPR83–GHSR1a heterodimer\",\n      \"GPR83–GPR171 heteromer\"\n    ],\n    \"partners\": [\n      \"GHSR1A\",\n      \"GPR171\",\n      \"FAM237A\",\n      \"FAM237B\",\n      \"ARRB1\",\n      \"GNAQ\",\n      \"GNA11\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}