{"gene":"GPR171","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2013,"finding":"GPR171 is the receptor for the neuropeptide BigLEN (LENSSPQAPARRLLPP), coupling to Gαi/o proteins. The four C-terminal amino acids of BigLEN are sufficient to bind and activate GPR171. The truncated peptide LittleLEN does not activate GPR171. Overexpression of GPR171 increases BigLEN binding and signaling, while knockdown decreases it. shRNA-mediated knockdown of hypothalamic GPR171 reduces BigLEN signaling and alters food intake and metabolism in mice.","method":"Ligand-binding assays, receptor-activity assays (Gαi/o coupling), overexpression and shRNA knockdown in Neuro2A cells and mouse hypothalamus, antibody neutralization of BigLEN","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (binding, signaling, OE, KD, in vivo) replicated across cell and animal models in one rigorous study","pmids":["24043826"],"is_preprint":false},{"year":2016,"finding":"A small-molecule agonist MS0015203 selectively activates GPR171 (selectivity confirmed against 80 other membrane proteins including family A GPCRs). shRNA knockdown of GPR171 blunts cellular and tissue responses to MS0015203, confirming on-target activity. Peripheral injection of MS0015203 increases food intake and body weight in mice, effects attenuated by hypothalamic GPR171 knockdown.","method":"Virtual screen of compound library using GPR171 homology model, radioligand binding selectivity panel (80 membrane proteins), shRNA knockdown, in vivo peripheral injection in mice","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — selectivity panel, receptor knockdown confirmation, and in vivo pharmacology with genetic control","pmids":["27245612"],"is_preprint":false},{"year":2016,"finding":"GPR171 knockdown inhibits proliferation, migration, and invasion of lung cancer cell lines, and inhibition of GPR171 with an anti-GPR171 antibody decreases proliferation and attenuates tumor progression in a mouse xenograft model. GPR171 inhibition synergistically enhances the tumoricidal activity of an EGFR inhibitor.","method":"siRNA knockdown, anti-GPR171 antibody treatment, mouse xenograft model, combination treatment with EGFR inhibitor","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD and antibody blockade with defined cellular phenotypes and in vivo model, but no direct molecular mechanism identified for cancer-specific signaling","pmids":["26760963"],"is_preprint":false},{"year":2017,"finding":"GPR171, activated by BigLEN in the basolateral amygdala (BLA), mediates hyperpolarization of BLA pyramidal neurons. A GPR171 antagonist (MS0021570_1) blocks BigLEN-mediated BLA neuron hyperpolarization, inhibits DREADD-mediated feeding induced by activation of BigLEN-containing AgRP neurons, and reduces anxiety-like behavior and fear conditioning following systemic or intra-BLA administration or lentiviral knockdown of GPR171 in the BLA.","method":"Electrophysiology (BLA pyramidal neuron hyperpolarization), DREADD chemogenetic activation, systemic and intra-BLA drug administration, lentiviral-mediated shRNA knockdown in BLA, behavioral assays","journal":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (electrophysiology, chemogenetics, pharmacology, genetic KD) converging on same conclusion","pmids":["28425495"],"is_preprint":false},{"year":2012,"finding":"Enforced expression of Gpr171 in the myeloblastic cell line 32D and in primary Sca-1+ hematopoietic progenitors decreases myeloid marker expression and increases colony formation in vitro. Conversely, Gpr171 silencing diminishes myeloid marker expression and clonogenic potential. In vivo, mice transplanted with Gpr171-overexpressing hematopoietic progenitors show reduced Mac-1+Gr-1- myeloid cells, establishing that Gpr171 negatively regulates myeloid differentiation.","method":"Forced expression and silencing in 32D cells and primary Sca-1+ progenitors, in vitro colony assay, bone marrow transplantation in vivo","journal":"Experimental hematology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal gain- and loss-of-function with defined cellular readouts, both in vitro and in vivo, single lab","pmids":["23022127"],"is_preprint":false},{"year":2019,"finding":"GPR171 is expressed in GABAergic neurons within the periaqueductal gray (PAG). A GPR171 agonist enhances and a GPR171 antagonist reduces morphine-induced antinociception. GPR171 antagonism or receptor knockdown decreases mu-opioid receptor (but not delta-opioid receptor) signaling, indicating GPR171 selectively modulates mu-opioid receptor function.","method":"Immunofluorescence co-localization (GABAergic marker), behavioral antinociception assays (agonist/antagonist pharmacology), receptor knockdown, opioid receptor signaling assays","journal":"The Journal of pharmacology and experimental therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic approaches with selective opioid receptor subtype discrimination, single lab","pmids":["31308196"],"is_preprint":false},{"year":2021,"finding":"GPR171 protein expression is induced in T cells upon antigen stimulation. BigLEN interacts with GPR171 to suppress T cell receptor-mediated signaling pathways and inhibit T cell proliferation. Loss of GPR171 in T cells leads to hyperactivity upon antigen stimulation, and GPR171 knockout mice exhibit enhanced antitumor immunity. Blockade of GPR171 signaling by an antagonist promotes antitumor T cell immunity and improves immune checkpoint blockade therapy outcomes.","method":"Protein expression analysis, BigLEN-GPR171 interaction in T cells, GPR171 knockout mouse model, antagonist pharmacology, tumor immunology assays, combination with checkpoint blockade","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO, pharmacological antagonism, and ligand-receptor interaction studies with defined immune phenotypes, multiple orthogonal approaches","pmids":["34615877"],"is_preprint":false},{"year":2021,"finding":"GPR171 is expressed in a subpopulation of nociceptors and, when activated by its natural peptide ligand (BigLEN) or a synthetic chemical ligand, attenuates nociceptor activity via Gi/o-coupled modulation of nociceptive ion channels, alleviating acute and pathologic pain.","method":"Nociceptor expression analysis, electrophysiological recordings of ion channel activity, in vivo nociceptive behavioral assays with natural and synthetic ligands","journal":"Biomedicines","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — electrophysiology with Gi/o-coupled mechanism and behavioral validation, single lab","pmids":["33807709"],"is_preprint":false},{"year":2025,"finding":"GPR171 deficiency promotes Th17 cell differentiation and lipid metabolic perturbation via the cAMP-pCREB-FABP5 signaling axis. Mechanistically, GPR171 activation suppresses FABP5 expression; in GPR171-deficient Th17 cells, FABP5 is upregulated, driving enhanced Th17 differentiation. Blockage of FABP5 reduces Th17 differentiation in vitro and ameliorates DSS-induced colitis in Gpr171-/- mice.","method":"RNA sequencing, lipidomics, GPR171 knockout mice, DSS colitis model, CD45RBhigh T cell transfer colitis model, FABP5 blockade rescue experiments, BigLEN-Fc fusion protein treatment","journal":"Gut","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO, RNA-seq, lipidomics, rescue experiments with FABP5 blockade, and multiple disease models providing convergent mechanistic evidence","pmids":["40074327"],"is_preprint":false},{"year":2025,"finding":"During Helicobacter pylori infection, HIF-1α is activated in mast cells and directly binds hypoxia response elements in the GPR171 promoter to drive GPR171 transcription. GPR171 upregulation in mast cells then mediates CCL2 secretion via the ERK1/2 signaling pathway; blockade or knockdown of GPR171 partially inhibits CCL2 secretion and reduces gastric mucosal inflammation in vivo.","method":"Chromatin immunoprecipitation (ChIP), dual-luciferase reporter assay, lentiviral knockdown, ELISA, Western blotting, H. pylori infection mouse model, GPR171 inhibitor in vivo","journal":"Helicobacter","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — ChIP and luciferase reporter establish HIF-1α transcriptional mechanism; KD and pharmacological blockade with ERK1/2 pathway readout, single lab with multiple orthogonal methods","pmids":["40320649"],"is_preprint":false},{"year":2026,"finding":"Gpr171 is expressed in hemogenic endothelium and hematopoietic stem and progenitor cells and is required for embryonic hematopoietic stem cell (HSC) specification in zebrafish and mice. Its endogenous ligand (encoded by pcsk1nl/proSAAS) cooperates with Gpr171 to enhance HSC generation. Mechanistically, Gpr171 activates ERK1/2 and Notch signaling pathways independently and synergistically to promote HSC generation. GPR171 deficiency causes severe HSC deficits without impairing vasculogenesis or primitive hematopoiesis. Pharmacological treatment with human GPR171 ligand BigLEN increases HSC numbers in zebrafish embryos.","method":"Zebrafish and murine Gpr171 knockout models, pharmacological BigLEN treatment, epistasis with ERK1/2 and Notch pathway inhibitors/activators, cell lineage analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO in two vertebrate species, pharmacological rescue, pathway epistasis with ERK1/2 and Notch, multiple orthogonal methods","pmids":["41576080"],"is_preprint":false},{"year":2022,"finding":"GPR171 agonist (MS15203) attenuates morphine tolerance in both female and male mice on the tail-flick test but not the hotplate test, indicating a test-dependent modulation of opioid tolerance. The GPR171 agonist in combination with morphine does not exacerbate morphine-induced tolerance or withdrawal during long-term treatment.","method":"Chronic morphine tolerance and withdrawal behavioral assays (tail-flick, hotplate) in male and female mice with GPR171 agonist co-administration","journal":"Behavioural pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — well-controlled behavioral pharmacology with sex and test specificity, but mechanism is pharmacological/behavioral without direct molecular pathway identification, single lab","pmids":["35942845"],"is_preprint":false}],"current_model":"GPR171 is a Gαi/o-coupled G protein-coupled receptor that is activated by BigLEN (derived from proSAAS/PCSK1N); its four C-terminal amino acids are sufficient for receptor binding and activation, and downstream signaling suppresses T cell activation via the cAMP-pCREB-FABP5 axis, modulates feeding and anxiety through hypothalamic and basolateral amygdala circuits (including hyperpolarization of BLA pyramidal neurons), selectively enhances mu-opioid receptor signaling in periaqueductal gray GABAergic neurons, attenuates nociceptor ion channel activity, promotes embryonic hematopoietic stem cell specification through ERK1/2 and Notch pathways, negatively regulates myeloid differentiation, and in mast cells is transcriptionally induced by HIF-1α binding to its promoter to drive CCL2 secretion via ERK1/2 during Helicobacter pylori infection."},"narrative":{"mechanistic_narrative":"GPR171 is a Gαi/o-coupled G protein-coupled receptor for the proSAAS/PCSK1N-derived neuropeptide BigLEN, whose four C-terminal residues are sufficient for receptor binding and activation [PMID:24043826]. Through Gi/o coupling it operates as a broadly tuned modulator of neuronal excitability, immune activation, and hematopoietic cell fate [PMID:24043826, PMID:33807709, PMID:41576080]. In the central nervous system, hypothalamic GPR171 controls food intake and metabolism [PMID:24043826], BigLEN-activated GPR171 hyperpolarizes basolateral amygdala pyramidal neurons to regulate feeding, anxiety, and fear behavior [PMID:28425495], and receptor activation in periaqueductal gray GABAergic neurons selectively enhances mu- (but not delta-) opioid receptor signaling and morphine antinociception [PMID:31308196]; in nociceptors it attenuates nociceptive ion channel activity to dampen pain [PMID:33807709]. A selective small-molecule agonist (MS0015203) and antagonist tools recapitulate these effects with genetic-knockdown confirmation of on-target activity [PMID:27245612, PMID:28425495]. In the immune system, GPR171 is induced upon T cell antigen stimulation and suppresses T cell receptor signaling and proliferation, such that its loss enhances antitumor immunity and improves checkpoint blockade [PMID:34615877]; this suppression operates through a cAMP-pCREB-FABP5 axis whose disruption drives Th17 differentiation and colitis [PMID:40074327]. GPR171 also negatively regulates myeloid differentiation [PMID:23022127] and is required for embryonic hematopoietic stem cell specification, acting through ERK1/2 and Notch signaling [PMID:41576080]. In mast cells during Helicobacter pylori infection, HIF-1α directly binds the GPR171 promoter to induce its transcription, driving ERK1/2-dependent CCL2 secretion and gastric inflammation [PMID:40320649].","teleology":[{"year":2012,"claim":"Before any ligand was known, GPR171 was assigned a cellular role in blood cell fate, establishing it as a negative regulator of myeloid differentiation.","evidence":"Reciprocal forced expression and silencing in 32D cells and Sca-1+ progenitors with in vitro colony assays and bone marrow transplantation","pmids":["23022127"],"confidence":"Medium","gaps":["No ligand or signaling pathway linked to the myeloid phenotype at this stage","Single lab","Receptor coupling not defined here"]},{"year":2013,"claim":"Deorphanization established BigLEN as the endogenous peptide ligand and Gαi/o as the transducer, defining the core receptor-ligand axis and a hypothalamic role in feeding.","evidence":"Ligand-binding and Gαi/o signaling assays, overexpression/shRNA knockdown in Neuro2A and mouse hypothalamus, BigLEN antibody neutralization","pmids":["24043826"],"confidence":"High","gaps":["Downstream effectors of Gi/o signaling not mapped","Receptor structure unresolved","How C-terminal residues engage the binding pocket not defined structurally"]},{"year":2016,"claim":"A selective small-molecule agonist provided a pharmacological tool and confirmed the receptor's in vivo control of feeding, while parallel work extended GPR171 to a pro-tumor role in lung cancer.","evidence":"Virtual screen with homology model, 80-protein radioligand selectivity panel, shRNA knockdown, and in vivo injection (MS0015203); siRNA/antibody blockade with xenograft and EGFR-inhibitor combination","pmids":["27245612","26760963"],"confidence":"High","gaps":["No molecular mechanism for cancer-specific signaling identified","Agonist binding mode inferred from homology model only"]},{"year":2017,"claim":"Circuit-level work showed BigLEN-GPR171 signaling hyperpolarizes BLA pyramidal neurons, linking the receptor to anxiety, fear, and AgRP-driven feeding.","evidence":"Electrophysiology, DREADD chemogenetics, intra-BLA pharmacology and lentiviral knockdown with behavioral assays (antagonist MS0021570_1)","pmids":["28425495"],"confidence":"High","gaps":["Ion channel target mediating hyperpolarization not identified","Connection between feeding and anxiety circuits unresolved"]},{"year":2019,"claim":"GPR171 was shown to selectively potentiate mu-opioid receptor signaling in PAG GABAergic neurons, distinguishing it from delta-opioid receptor modulation.","evidence":"Immunofluorescence co-localization, antinociception pharmacology, receptor knockdown, and opioid receptor subtype signaling assays","pmids":["31308196"],"confidence":"Medium","gaps":["Molecular basis of MOR-selective enhancement not defined","No evidence of direct receptor heteromerization tested","Single lab"]},{"year":2021,"claim":"Two studies established GPR171 as a Gi/o-coupled brake on pain signaling in nociceptors and as an inducible suppressor of T cell activation, opening an immuno-oncology axis.","evidence":"Nociceptor electrophysiology and behavior with natural/synthetic ligands; GPR171 knockout mice, antagonist pharmacology, and tumor immunology with checkpoint blockade combination","pmids":["33807709","34615877"],"confidence":"High","gaps":["Specific nociceptor ion channels modulated not fully resolved","Intracellular signaling linking GPR171 to TCR suppression not yet mapped in 2021"]},{"year":2022,"claim":"Pharmacological work refined the opioid interaction, showing GPR171 agonism attenuates morphine tolerance in a test-dependent manner without exacerbating tolerance or withdrawal.","evidence":"Chronic morphine tolerance and withdrawal behavioral assays (tail-flick, hotplate) in both sexes with agonist co-administration","pmids":["35942845"],"confidence":"Medium","gaps":["No direct molecular pathway identified for the tolerance effect","Basis of tail-flick vs hotplate difference unexplained","Single lab"]},{"year":2025,"claim":"Mechanistic dissection defined the cAMP-pCREB-FABP5 axis through which GPR171 restrains Th17 differentiation, and revealed HIF-1α-driven transcriptional induction of GPR171 in mast cells driving CCL2 via ERK1/2.","evidence":"RNA-seq, lipidomics, knockout mice, colitis models and FABP5 rescue (Gut); ChIP, dual-luciferase, knockdown, ELISA and H. pylori infection model (Helicobacter)","pmids":["40074327","40320649"],"confidence":"High","gaps":["How Gi/o signaling connects mechanistically to FABP5 regulation beyond cAMP-pCREB not fully resolved","Whether mast-cell ERK1/2 activation is ligand-dependent unclear"]},{"year":2026,"claim":"Developmental genetics established GPR171 as required for embryonic HSC specification, acting via independent and synergistic ERK1/2 and Notch signaling.","evidence":"Zebrafish and murine knockouts, pharmacological BigLEN rescue, and epistasis with ERK1/2 and Notch pathway modulators","pmids":["41576080"],"confidence":"High","gaps":["Direct molecular link between Gi/o receptor and Notch activation not defined","Source and timing of endogenous proSAAS-derived ligand in hemogenic endothelium unresolved"]},{"year":null,"claim":"How a single Gi/o-coupled receptor produces such divergent outputs (neuronal hyperpolarization, cAMP-pCREB-FABP5 immune suppression, ERK1/2/Notch HSC specification) through context-specific effector coupling remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the active receptor-BigLEN-G protein complex","Effector-selection logic across cell types unknown","Whether cancer, immune, and neuronal roles share a common proximal signaling node untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,7,10]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,7]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,7,10]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6,8,9]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[3,5]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,10]}],"complexes":[],"partners":["PCSK1N"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O14626","full_name":"G-protein coupled receptor 171","aliases":["G-protein coupled receptor H963"],"length_aa":319,"mass_kda":36.8,"function":"G-protein coupled receptor for Big LEN, a 16-amino acid neuropeptide produced from the precursor protein, proSAAS (encoded by PCSK1N). Acts through a G(i)-alpha-mediated pathway in response to Big LEN. Big LEN-GPR171 system plays an important role in regulating feeding and metabolism. Also plays a role in modulating fear and anxiety-like behaviors in the basolateral amygdala. Big LEN-GPR171 modulates the mu-type opioid receptor signaling and antinociception (By similarity). Acts as a negative regulator T cell function (PubMed:34615877)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/O14626/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GPR171","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/GPR171","total_profiled":1310},"omim":[{"mim_id":"618925","title":"G PROTEIN-COUPLED RECEPTOR 171; GPR171","url":"https://www.omim.org/entry/618925"},{"mim_id":"618872","title":"NIZON-ISIDOR SYNDROME; NIZIDS","url":"https://www.omim.org/entry/618872"},{"mim_id":"611318","title":"MEDIATOR COMPLEX SUBUNIT 12-LIKE; MED12L","url":"https://www.omim.org/entry/611318"},{"mim_id":"300399","title":"PROPROTEIN CONVERTASE, SUBTILISIN/KEXIN-TYPE, 1, INHIBITOR OF; PCSK1N","url":"https://www.omim.org/entry/300399"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"intestine","ntpm":12.1},{"tissue":"lymphoid tissue","ntpm":20.1}],"url":"https://www.proteinatlas.org/search/GPR171"},"hgnc":{"alias_symbol":["H963"],"prev_symbol":[]},"alphafold":{"accession":"O14626","domains":[{"cath_id":"1.20.1070.10","chopping":"13-317","consensus_level":"high","plddt":89.3076,"start":13,"end":317}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O14626","model_url":"https://alphafold.ebi.ac.uk/files/AF-O14626-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O14626-F1-predicted_aligned_error_v6.png","plddt_mean":87.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GPR171","jax_strain_url":"https://www.jax.org/strain/search?query=GPR171"},"sequence":{"accession":"O14626","fasta_url":"https://rest.uniprot.org/uniprotkb/O14626.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O14626/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O14626"}},"corpus_meta":[{"pmid":"24043826","id":"PMC_24043826","title":"GPR171 is a hypothalamic G protein-coupled receptor for BigLEN, a neuropeptide involved in feeding.","date":"2013","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/24043826","citation_count":71,"is_preprint":false},{"pmid":"27245612","id":"PMC_27245612","title":"Identification of a small-molecule ligand that activates the neuropeptide receptor GPR171 and increases food intake.","date":"2016","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/27245612","citation_count":29,"is_preprint":false},{"pmid":"34615877","id":"PMC_34615877","title":"The GPR171 pathway suppresses T cell activation and limits antitumor immunity.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/34615877","citation_count":26,"is_preprint":false},{"pmid":"28425495","id":"PMC_28425495","title":"The BigLEN-GPR171 Peptide Receptor System Within the Basolateral Amygdala Regulates Anxiety-Like Behavior and Contextual Fear Conditioning.","date":"2017","source":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/28425495","citation_count":26,"is_preprint":false},{"pmid":"26760963","id":"PMC_26760963","title":"GPR171 expression enhances proliferation and metastasis of lung cancer cells.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26760963","citation_count":19,"is_preprint":false},{"pmid":"23022127","id":"PMC_23022127","title":"Gpr171, a putative P2Y-like receptor, negatively regulates myeloid differentiation in murine hematopoietic progenitors.","date":"2012","source":"Experimental hematology","url":"https://pubmed.ncbi.nlm.nih.gov/23022127","citation_count":18,"is_preprint":false},{"pmid":"35295419","id":"PMC_35295419","title":"GPR171 Agonist Reduces Chronic Neuropathic and Inflammatory Pain in Male, But Not Female Mice.","date":"2021","source":"Frontiers in pain research (Lausanne, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/35295419","citation_count":18,"is_preprint":false},{"pmid":"31308196","id":"PMC_31308196","title":"Opioid-Induced Signaling and Antinociception Are Modulated by the Recently Deorphanized Receptor, GPR171.","date":"2019","source":"The Journal of pharmacology and experimental therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/31308196","citation_count":13,"is_preprint":false},{"pmid":"40074327","id":"PMC_40074327","title":"GPR171 restrains intestinal inflammation by suppressing FABP5-mediated Th17 cell differentiation and lipid metabolism.","date":"2025","source":"Gut","url":"https://pubmed.ncbi.nlm.nih.gov/40074327","citation_count":12,"is_preprint":false},{"pmid":"36212434","id":"PMC_36212434","title":"DIRAS3, GPR171 and RAC2 were identified as the key molecular patterns associated with brain metastasis of breast cancer.","date":"2022","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36212434","citation_count":10,"is_preprint":false},{"pmid":"33807709","id":"PMC_33807709","title":"GPR171 Activation Modulates Nociceptor Functions, Alleviating Pathologic Pain.","date":"2021","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/33807709","citation_count":10,"is_preprint":false},{"pmid":"35942845","id":"PMC_35942845","title":"GPR171 activation regulates morphine tolerance but not withdrawal in a test-dependent manner in mice.","date":"2022","source":"Behavioural pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/35942845","citation_count":3,"is_preprint":false},{"pmid":"40320649","id":"PMC_40320649","title":"HIF-1α-Induced GPR171 Expression Mediates CCL2 Secretion by Mast Cells to Promote Gastric Inflammation During Helicobacter pylori Infection.","date":"2025","source":"Helicobacter","url":"https://pubmed.ncbi.nlm.nih.gov/40320649","citation_count":2,"is_preprint":false},{"pmid":"36933620","id":"PMC_36933620","title":"A small molecule ligand for the novel pain target, GPR171, produces minimal reward in mice.","date":"2023","source":"Pharmacology, biochemistry, and behavior","url":"https://pubmed.ncbi.nlm.nih.gov/36933620","citation_count":2,"is_preprint":false},{"pmid":"41576080","id":"PMC_41576080","title":"Gpr171 regulates embryonic hematopoietic stem cell emergence via ERK1/2 and Notch signaling.","date":"2026","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/41576080","citation_count":0,"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":"40318809","id":"PMC_40318809","title":"GPR171 is necessary for normal physiological functions and mood-related behaviors in males, but not females.","date":"2025","source":"Behavioural brain research","url":"https://pubmed.ncbi.nlm.nih.gov/40318809","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10255,"output_tokens":3563,"usd":0.042105,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11332,"output_tokens":3613,"usd":0.073493,"stage2_stop_reason":"end_turn"},"total_usd":0.115598,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"GPR171 is the receptor for the neuropeptide BigLEN (LENSSPQAPARRLLPP), coupling to Gαi/o proteins. The four C-terminal amino acids of BigLEN are sufficient to bind and activate GPR171. The truncated peptide LittleLEN does not activate GPR171. Overexpression of GPR171 increases BigLEN binding and signaling, while knockdown decreases it. shRNA-mediated knockdown of hypothalamic GPR171 reduces BigLEN signaling and alters food intake and metabolism in mice.\",\n      \"method\": \"Ligand-binding assays, receptor-activity assays (Gαi/o coupling), overexpression and shRNA knockdown in Neuro2A cells and mouse hypothalamus, antibody neutralization of BigLEN\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (binding, signaling, OE, KD, in vivo) replicated across cell and animal models in one rigorous study\",\n      \"pmids\": [\"24043826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A small-molecule agonist MS0015203 selectively activates GPR171 (selectivity confirmed against 80 other membrane proteins including family A GPCRs). shRNA knockdown of GPR171 blunts cellular and tissue responses to MS0015203, confirming on-target activity. Peripheral injection of MS0015203 increases food intake and body weight in mice, effects attenuated by hypothalamic GPR171 knockdown.\",\n      \"method\": \"Virtual screen of compound library using GPR171 homology model, radioligand binding selectivity panel (80 membrane proteins), shRNA knockdown, in vivo peripheral injection in mice\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — selectivity panel, receptor knockdown confirmation, and in vivo pharmacology with genetic control\",\n      \"pmids\": [\"27245612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"GPR171 knockdown inhibits proliferation, migration, and invasion of lung cancer cell lines, and inhibition of GPR171 with an anti-GPR171 antibody decreases proliferation and attenuates tumor progression in a mouse xenograft model. GPR171 inhibition synergistically enhances the tumoricidal activity of an EGFR inhibitor.\",\n      \"method\": \"siRNA knockdown, anti-GPR171 antibody treatment, mouse xenograft model, combination treatment with EGFR inhibitor\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD and antibody blockade with defined cellular phenotypes and in vivo model, but no direct molecular mechanism identified for cancer-specific signaling\",\n      \"pmids\": [\"26760963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"GPR171, activated by BigLEN in the basolateral amygdala (BLA), mediates hyperpolarization of BLA pyramidal neurons. A GPR171 antagonist (MS0021570_1) blocks BigLEN-mediated BLA neuron hyperpolarization, inhibits DREADD-mediated feeding induced by activation of BigLEN-containing AgRP neurons, and reduces anxiety-like behavior and fear conditioning following systemic or intra-BLA administration or lentiviral knockdown of GPR171 in the BLA.\",\n      \"method\": \"Electrophysiology (BLA pyramidal neuron hyperpolarization), DREADD chemogenetic activation, systemic and intra-BLA drug administration, lentiviral-mediated shRNA knockdown in BLA, behavioral assays\",\n      \"journal\": \"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (electrophysiology, chemogenetics, pharmacology, genetic KD) converging on same conclusion\",\n      \"pmids\": [\"28425495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Enforced expression of Gpr171 in the myeloblastic cell line 32D and in primary Sca-1+ hematopoietic progenitors decreases myeloid marker expression and increases colony formation in vitro. Conversely, Gpr171 silencing diminishes myeloid marker expression and clonogenic potential. In vivo, mice transplanted with Gpr171-overexpressing hematopoietic progenitors show reduced Mac-1+Gr-1- myeloid cells, establishing that Gpr171 negatively regulates myeloid differentiation.\",\n      \"method\": \"Forced expression and silencing in 32D cells and primary Sca-1+ progenitors, in vitro colony assay, bone marrow transplantation in vivo\",\n      \"journal\": \"Experimental hematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain- and loss-of-function with defined cellular readouts, both in vitro and in vivo, single lab\",\n      \"pmids\": [\"23022127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"GPR171 is expressed in GABAergic neurons within the periaqueductal gray (PAG). A GPR171 agonist enhances and a GPR171 antagonist reduces morphine-induced antinociception. GPR171 antagonism or receptor knockdown decreases mu-opioid receptor (but not delta-opioid receptor) signaling, indicating GPR171 selectively modulates mu-opioid receptor function.\",\n      \"method\": \"Immunofluorescence co-localization (GABAergic marker), behavioral antinociception assays (agonist/antagonist pharmacology), receptor knockdown, opioid receptor signaling assays\",\n      \"journal\": \"The Journal of pharmacology and experimental therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic approaches with selective opioid receptor subtype discrimination, single lab\",\n      \"pmids\": [\"31308196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GPR171 protein expression is induced in T cells upon antigen stimulation. BigLEN interacts with GPR171 to suppress T cell receptor-mediated signaling pathways and inhibit T cell proliferation. Loss of GPR171 in T cells leads to hyperactivity upon antigen stimulation, and GPR171 knockout mice exhibit enhanced antitumor immunity. Blockade of GPR171 signaling by an antagonist promotes antitumor T cell immunity and improves immune checkpoint blockade therapy outcomes.\",\n      \"method\": \"Protein expression analysis, BigLEN-GPR171 interaction in T cells, GPR171 knockout mouse model, antagonist pharmacology, tumor immunology assays, combination with checkpoint blockade\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO, pharmacological antagonism, and ligand-receptor interaction studies with defined immune phenotypes, multiple orthogonal approaches\",\n      \"pmids\": [\"34615877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GPR171 is expressed in a subpopulation of nociceptors and, when activated by its natural peptide ligand (BigLEN) or a synthetic chemical ligand, attenuates nociceptor activity via Gi/o-coupled modulation of nociceptive ion channels, alleviating acute and pathologic pain.\",\n      \"method\": \"Nociceptor expression analysis, electrophysiological recordings of ion channel activity, in vivo nociceptive behavioral assays with natural and synthetic ligands\",\n      \"journal\": \"Biomedicines\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — electrophysiology with Gi/o-coupled mechanism and behavioral validation, single lab\",\n      \"pmids\": [\"33807709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GPR171 deficiency promotes Th17 cell differentiation and lipid metabolic perturbation via the cAMP-pCREB-FABP5 signaling axis. Mechanistically, GPR171 activation suppresses FABP5 expression; in GPR171-deficient Th17 cells, FABP5 is upregulated, driving enhanced Th17 differentiation. Blockage of FABP5 reduces Th17 differentiation in vitro and ameliorates DSS-induced colitis in Gpr171-/- mice.\",\n      \"method\": \"RNA sequencing, lipidomics, GPR171 knockout mice, DSS colitis model, CD45RBhigh T cell transfer colitis model, FABP5 blockade rescue experiments, BigLEN-Fc fusion protein treatment\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO, RNA-seq, lipidomics, rescue experiments with FABP5 blockade, and multiple disease models providing convergent mechanistic evidence\",\n      \"pmids\": [\"40074327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"During Helicobacter pylori infection, HIF-1α is activated in mast cells and directly binds hypoxia response elements in the GPR171 promoter to drive GPR171 transcription. GPR171 upregulation in mast cells then mediates CCL2 secretion via the ERK1/2 signaling pathway; blockade or knockdown of GPR171 partially inhibits CCL2 secretion and reduces gastric mucosal inflammation in vivo.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), dual-luciferase reporter assay, lentiviral knockdown, ELISA, Western blotting, H. pylori infection mouse model, GPR171 inhibitor in vivo\",\n      \"journal\": \"Helicobacter\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ChIP and luciferase reporter establish HIF-1α transcriptional mechanism; KD and pharmacological blockade with ERK1/2 pathway readout, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"40320649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Gpr171 is expressed in hemogenic endothelium and hematopoietic stem and progenitor cells and is required for embryonic hematopoietic stem cell (HSC) specification in zebrafish and mice. Its endogenous ligand (encoded by pcsk1nl/proSAAS) cooperates with Gpr171 to enhance HSC generation. Mechanistically, Gpr171 activates ERK1/2 and Notch signaling pathways independently and synergistically to promote HSC generation. GPR171 deficiency causes severe HSC deficits without impairing vasculogenesis or primitive hematopoiesis. Pharmacological treatment with human GPR171 ligand BigLEN increases HSC numbers in zebrafish embryos.\",\n      \"method\": \"Zebrafish and murine Gpr171 knockout models, pharmacological BigLEN treatment, epistasis with ERK1/2 and Notch pathway inhibitors/activators, cell lineage analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO in two vertebrate species, pharmacological rescue, pathway epistasis with ERK1/2 and Notch, multiple orthogonal methods\",\n      \"pmids\": [\"41576080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GPR171 agonist (MS15203) attenuates morphine tolerance in both female and male mice on the tail-flick test but not the hotplate test, indicating a test-dependent modulation of opioid tolerance. The GPR171 agonist in combination with morphine does not exacerbate morphine-induced tolerance or withdrawal during long-term treatment.\",\n      \"method\": \"Chronic morphine tolerance and withdrawal behavioral assays (tail-flick, hotplate) in male and female mice with GPR171 agonist co-administration\",\n      \"journal\": \"Behavioural pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — well-controlled behavioral pharmacology with sex and test specificity, but mechanism is pharmacological/behavioral without direct molecular pathway identification, single lab\",\n      \"pmids\": [\"35942845\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GPR171 is a Gαi/o-coupled G protein-coupled receptor that is activated by BigLEN (derived from proSAAS/PCSK1N); its four C-terminal amino acids are sufficient for receptor binding and activation, and downstream signaling suppresses T cell activation via the cAMP-pCREB-FABP5 axis, modulates feeding and anxiety through hypothalamic and basolateral amygdala circuits (including hyperpolarization of BLA pyramidal neurons), selectively enhances mu-opioid receptor signaling in periaqueductal gray GABAergic neurons, attenuates nociceptor ion channel activity, promotes embryonic hematopoietic stem cell specification through ERK1/2 and Notch pathways, negatively regulates myeloid differentiation, and in mast cells is transcriptionally induced by HIF-1α binding to its promoter to drive CCL2 secretion via ERK1/2 during Helicobacter pylori infection.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GPR171 is a Gαi/o-coupled G protein-coupled receptor for the proSAAS/PCSK1N-derived neuropeptide BigLEN, whose four C-terminal residues are sufficient for receptor binding and activation [#0]. Through Gi/o coupling it operates as a broadly tuned modulator of neuronal excitability, immune activation, and hematopoietic cell fate [#0, #7, #10]. In the central nervous system, hypothalamic GPR171 controls food intake and metabolism [#0], BigLEN-activated GPR171 hyperpolarizes basolateral amygdala pyramidal neurons to regulate feeding, anxiety, and fear behavior [#3], and receptor activation in periaqueductal gray GABAergic neurons selectively enhances mu- (but not delta-) opioid receptor signaling and morphine antinociception [#5]; in nociceptors it attenuates nociceptive ion channel activity to dampen pain [#7]. A selective small-molecule agonist (MS0015203) and antagonist tools recapitulate these effects with genetic-knockdown confirmation of on-target activity [#1, #3]. In the immune system, GPR171 is induced upon T cell antigen stimulation and suppresses T cell receptor signaling and proliferation, such that its loss enhances antitumor immunity and improves checkpoint blockade [#6]; this suppression operates through a cAMP-pCREB-FABP5 axis whose disruption drives Th17 differentiation and colitis [#8]. GPR171 also negatively regulates myeloid differentiation [#4] and is required for embryonic hematopoietic stem cell specification, acting through ERK1/2 and Notch signaling [#10]. In mast cells during Helicobacter pylori infection, HIF-1α directly binds the GPR171 promoter to induce its transcription, driving ERK1/2-dependent CCL2 secretion and gastric inflammation [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Before any ligand was known, GPR171 was assigned a cellular role in blood cell fate, establishing it as a negative regulator of myeloid differentiation.\",\n      \"evidence\": \"Reciprocal forced expression and silencing in 32D cells and Sca-1+ progenitors with in vitro colony assays and bone marrow transplantation\",\n      \"pmids\": [\"23022127\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No ligand or signaling pathway linked to the myeloid phenotype at this stage\", \"Single lab\", \"Receptor coupling not defined here\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Deorphanization established BigLEN as the endogenous peptide ligand and Gαi/o as the transducer, defining the core receptor-ligand axis and a hypothalamic role in feeding.\",\n      \"evidence\": \"Ligand-binding and Gαi/o signaling assays, overexpression/shRNA knockdown in Neuro2A and mouse hypothalamus, BigLEN antibody neutralization\",\n      \"pmids\": [\"24043826\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Downstream effectors of Gi/o signaling not mapped\", \"Receptor structure unresolved\", \"How C-terminal residues engage the binding pocket not defined structurally\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"A selective small-molecule agonist provided a pharmacological tool and confirmed the receptor's in vivo control of feeding, while parallel work extended GPR171 to a pro-tumor role in lung cancer.\",\n      \"evidence\": \"Virtual screen with homology model, 80-protein radioligand selectivity panel, shRNA knockdown, and in vivo injection (MS0015203); siRNA/antibody blockade with xenograft and EGFR-inhibitor combination\",\n      \"pmids\": [\"27245612\", \"26760963\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No molecular mechanism for cancer-specific signaling identified\", \"Agonist binding mode inferred from homology model only\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Circuit-level work showed BigLEN-GPR171 signaling hyperpolarizes BLA pyramidal neurons, linking the receptor to anxiety, fear, and AgRP-driven feeding.\",\n      \"evidence\": \"Electrophysiology, DREADD chemogenetics, intra-BLA pharmacology and lentiviral knockdown with behavioral assays (antagonist MS0021570_1)\",\n      \"pmids\": [\"28425495\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Ion channel target mediating hyperpolarization not identified\", \"Connection between feeding and anxiety circuits unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"GPR171 was shown to selectively potentiate mu-opioid receptor signaling in PAG GABAergic neurons, distinguishing it from delta-opioid receptor modulation.\",\n      \"evidence\": \"Immunofluorescence co-localization, antinociception pharmacology, receptor knockdown, and opioid receptor subtype signaling assays\",\n      \"pmids\": [\"31308196\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Molecular basis of MOR-selective enhancement not defined\", \"No evidence of direct receptor heteromerization tested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Two studies established GPR171 as a Gi/o-coupled brake on pain signaling in nociceptors and as an inducible suppressor of T cell activation, opening an immuno-oncology axis.\",\n      \"evidence\": \"Nociceptor electrophysiology and behavior with natural/synthetic ligands; GPR171 knockout mice, antagonist pharmacology, and tumor immunology with checkpoint blockade combination\",\n      \"pmids\": [\"33807709\", \"34615877\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Specific nociceptor ion channels modulated not fully resolved\", \"Intracellular signaling linking GPR171 to TCR suppression not yet mapped in 2021\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Pharmacological work refined the opioid interaction, showing GPR171 agonism attenuates morphine tolerance in a test-dependent manner without exacerbating tolerance or withdrawal.\",\n      \"evidence\": \"Chronic morphine tolerance and withdrawal behavioral assays (tail-flick, hotplate) in both sexes with agonist co-administration\",\n      \"pmids\": [\"35942845\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No direct molecular pathway identified for the tolerance effect\", \"Basis of tail-flick vs hotplate difference unexplained\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Mechanistic dissection defined the cAMP-pCREB-FABP5 axis through which GPR171 restrains Th17 differentiation, and revealed HIF-1α-driven transcriptional induction of GPR171 in mast cells driving CCL2 via ERK1/2.\",\n      \"evidence\": \"RNA-seq, lipidomics, knockout mice, colitis models and FABP5 rescue (Gut); ChIP, dual-luciferase, knockdown, ELISA and H. pylori infection model (Helicobacter)\",\n      \"pmids\": [\"40074327\", \"40320649\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"How Gi/o signaling connects mechanistically to FABP5 regulation beyond cAMP-pCREB not fully resolved\", \"Whether mast-cell ERK1/2 activation is ligand-dependent unclear\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Developmental genetics established GPR171 as required for embryonic HSC specification, acting via independent and synergistic ERK1/2 and Notch signaling.\",\n      \"evidence\": \"Zebrafish and murine knockouts, pharmacological BigLEN rescue, and epistasis with ERK1/2 and Notch pathway modulators\",\n      \"pmids\": [\"41576080\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct molecular link between Gi/o receptor and Notch activation not defined\", \"Source and timing of endogenous proSAAS-derived ligand in hemogenic endothelium unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single Gi/o-coupled receptor produces such divergent outputs (neuronal hyperpolarization, cAMP-pCREB-FABP5 immune suppression, ERK1/2/Notch HSC specification) through context-specific effector coupling remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No structural model of the active receptor-BigLEN-G protein complex\", \"Effector-selection logic across cell types unknown\", \"Whether cancer, immune, and neuronal roles share a common proximal signaling node untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 7, 10]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 7, 10]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6, 8, 9]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PCSK1N\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}