Affinage

GPR171

G-protein coupled receptor 171 · UniProt O14626

Length
319 aa
Mass
36.8 kDa
Annotated
2026-04-28
17 papers in source corpus 13 papers cited in narrative 14 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GPR171 is a Gαi/o-coupled receptor of the P2Y GPCR family that transduces signals from its endogenous neuropeptide ligand BigLEN (derived from ProSAAS/PCSK1N) to regulate feeding behavior, pain modulation, anxiety, immune cell function, and hematopoietic stem cell specification. Activation by BigLEN or synthetic agonists inhibits cAMP production and engages downstream ERK1/2, cAMP–pCREB–FABP5, and Notch signaling cascades in a context-dependent manner: in the hypothalamus it promotes food intake, in basolateral amygdala pyramidal neurons it drives hyperpolarization linked to anxiety and fear, in the periaqueductal gray it positively modulates mu-opioid receptor signaling and antinociception, and in T cells it suppresses TCR-mediated proliferation and Th17 differentiation (PMID:24043826, PMID:28425495, PMID:31308196, PMID:34615877, PMID:40074327). GPR171 deficiency in mice enhances antitumor immunity and exacerbates Th17-driven colitis through derepression of the cAMP–pCREB–FABP5 lipid-metabolic axis, while in mast cells HIF-1α–driven GPR171 transcription mediates CCL2 secretion via ERK1/2 during Helicobacter pylori infection (PMID:34615877, PMID:40074327, PMID:40320649). GPR171 is also required for embryonic hematopoietic stem cell specification, where it synergistically activates ERK1/2 and Notch pathways in hemogenic endothelium, and its loss in zebrafish and mouse embryos causes severe HSC deficits (PMID:41576080, PMID:23022127).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2012 Medium

    Before GPR171 was deorphanized, forced expression and silencing in hematopoietic progenitors revealed that GPR171 negatively regulates myeloid differentiation, providing the first indication of a non-neuronal developmental role.

    Evidence Retroviral overexpression and shRNA knockdown in 32D cells and Sca-1+ progenitors with colony assays and in vivo bone marrow transplant

    PMID:23022127

    Open questions at the time
    • Ligand unknown at this time
    • Signaling pathway downstream of GPR171 in hematopoietic cells not identified
    • Single lab, not independently replicated
  2. 2013 High

    The identification of BigLEN as the endogenous ligand and Gαi/o as the coupling partner deorphanized GPR171, and hypothalamic knockdown established the BigLEN–GPR171 axis as a physiological regulator of feeding behavior.

    Evidence Binding/signaling assays in Neuro2A cells, shRNA knockdown in mouse hypothalamus, antibody neutralization, feeding behavior assays

    PMID:24043826

    Open questions at the time
    • Structural basis of BigLEN–GPR171 interaction unresolved
    • Downstream intracellular effectors beyond Gαi/o not yet mapped
    • Genetic knockout model not available at this point
  3. 2016 High

    Discovery of the selective small-molecule agonist MS0015203 via virtual screening provided a pharmacological tool and confirmed GPR171 as a druggable target driving food intake and body weight in vivo.

    Evidence Homology-model virtual screen, selectivity panel (80 membrane proteins), hypothalamic shRNA knockdown plus peripheral MS0015203 injection

    PMID:27245612

    Open questions at the time
    • No crystal or cryo-EM structure of GPR171
    • Metabolic consequences beyond acute feeding not explored
    • Mechanism of body-weight increase (central vs. peripheral) not dissected
  4. 2017 High

    Electrophysiological recordings and behavioral assays in the basolateral amygdala demonstrated that GPR171 mediates BigLEN-induced neuronal hyperpolarization and contributes to anxiety and fear conditioning, extending its CNS role beyond feeding.

    Evidence Patch-clamp electrophysiology, antagonist MS0021570_1, lentiviral shRNA in BLA, conditioned fear and anxiety behavioral assays

    PMID:28425495

    Open questions at the time
    • Ion channel identity mediating hyperpolarization not determined
    • Circuit-level mechanism (interneuron vs. projection neuron contribution) unclear
  5. 2019 Medium

    Localization of GPR171 on GABAergic PAG neurons and its selective modulation of mu-opioid (but not delta-opioid) receptor signaling established a functional cross-talk relevant to pain processing.

    Evidence Immunofluorescence colocalization, pharmacological agonist/antagonist in vivo, receptor knockdown, antinociception assays

    PMID:31308196

    Open questions at the time
    • Physical interaction or heterodimerization with mu-opioid receptor not demonstrated
    • Single lab; independent replication needed
    • Molecular mechanism of selectivity over delta-opioid receptor unknown
  6. 2021 High

    Demonstration that GPR171 is induced on activated T cells, suppresses TCR signaling and proliferation, and that knockout mice show enhanced antitumor immunity revealed GPR171 as an immune checkpoint–like receptor.

    Evidence Western blot, T cell activation assays, Gpr171 knockout mice, syngeneic tumor models, combination with anti-PD-1

    PMID:34615877

    Open questions at the time
    • Precise TCR signaling node inhibited by GPR171 not identified
    • Human T cell relevance not established in this study
    • Whether GPR171 acts cell-autonomously vs. via paracrine BigLEN not resolved
  7. 2021 Medium

    GPR171 expression in nociceptor DRG subpopulations and its Gi/o-mediated attenuation of nociceptive ion channel activity extended the receptor's pain-modulatory role to the peripheral nervous system, complementing the central PAG findings.

    Evidence Immunostaining of DRG, Gi/o pharmacology, ion channel functional assays, in vivo pain behavior

    PMID:33807709 PMID:35295419

    Open questions at the time
    • Specific ion channel targets not molecularly identified
    • Sex-dependent efficacy (male > female) not mechanistically explained
    • Single lab findings
  8. 2022 Medium

    Chronic GPR171 agonism attenuated morphine tolerance without worsening withdrawal, refining the functional interaction with mu-opioid receptor signaling and suggesting therapeutic potential.

    Evidence Chronic morphine tolerance and withdrawal paradigms, tail-flick and hotplate tests, sex-stratified analysis

    PMID:35942845

    Open questions at the time
    • Assay-dependent result (tail-flick but not hotplate) unexplained mechanistically
    • Single lab
    • Molecular basis of GPR171–MOR cross-talk still unknown
  9. 2023 Medium

    Mapping GPR171 and ProSAAS across limbic/reward circuits and showing that GPR171 agonism does not activate VTA dopamine neurons or produce conditioned place preference addressed reward-liability concerns for therapeutic development.

    Evidence Immunohistochemistry in hippocampus/BLA/NAc/PFC/VTA, c-Fos quantification, conditioned place preference

    PMID:36933620

    Open questions at the time
    • Functional role of GPR171 on VTA dopamine neurons remains undefined
    • Single lab; no self-administration data
  10. 2025 High

    Definition of the cAMP–pCREB–FABP5 axis downstream of GPR171 in Th17 cells, combined with lipidomic remodeling and rescue of colitis by FABP5 blockade, provided the first detailed intracellular signaling pathway linking GPR171 to adaptive immune regulation.

    Evidence RNA-seq, lipidomics, cAMP/pCREB assays, Gpr171−/− mice, in vitro Th17 differentiation, FABP5 inhibitor, DSS and T cell transfer colitis models

    PMID:40074327

    Open questions at the time
    • Whether the cAMP–pCREB–FABP5 axis operates in other T cell subsets not tested
    • Lipid species functionally driving Th17 fate not individually validated
  11. 2025 High

    ChIP and reporter assays showed HIF-1α directly activates GPR171 transcription in mast cells, and GPR171 drives CCL2 secretion via ERK1/2, connecting GPR171 to innate immune inflammation during H. pylori infection.

    Evidence ChIP on GPR171 promoter, dual-luciferase reporter, lentiviral knockdown, ELISA, western blot, H. pylori mouse model

    PMID:40320649

    Open questions at the time
    • Whether HIF-1α regulation of GPR171 occurs in other cell types not addressed
    • BigLEN source in gastric mucosa not identified
  12. 2026 High

    Demonstration that GPR171 synergistically activates ERK1/2 and Notch in hemogenic endothelium to specify HSCs, with deficiency causing severe HSC deficits in zebrafish and mouse, established a developmental hematopoietic function conserved across vertebrates.

    Evidence Zebrafish gpr171 loss-of-function, mouse genetic knockout, pharmacological BigLEN rescue, ERK1/2 and Notch pathway assays, HSC quantification

    PMID:41576080

    Open questions at the time
    • Whether GPR171 is required for adult definitive hematopoiesis not tested
    • How ERK1/2 and Notch are independently and synergistically engaged is mechanistically unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major open questions include the structural basis of BigLEN and small-molecule binding, the molecular mechanism of GPR171–mu-opioid receptor cross-talk, the identity of the ion channels modulated in nociceptors, and whether GPR171 immune-checkpoint functions translate to human cancer immunotherapy.
  • No experimentally determined GPR171 structure
  • Physical basis of mu-opioid receptor modulation unresolved
  • Human clinical validation of immune checkpoint role absent

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-112316 Neuronal System 3 R-HSA-168256 Immune System 3 R-HSA-1266738 Developmental Biology 2 GO:0003924 GTPase activity 1
Partners
FABP5HIF1AOPRM1PCSK1N

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 GPR171 is the cognate receptor for the neuropeptide BigLEN (LENSSPQAPARRLLPP), coupling through Gαi/o to mediate BigLEN signaling in mouse hypothalamus and Neuro2A cells. The four C-terminal amino acids of BigLEN are sufficient to bind and activate GPR171, whereas the C-terminally truncated peptide LittleLEN does not activate it. Ligand-binding assays, receptor-activity assays, overexpression, shRNA knockdown, orphan GPCR deorphanization screen Proceedings of the National Academy of Sciences of the United States of America High 24043826
2013 shRNA-mediated knockdown of hypothalamic GPR171 decreases BigLEN signaling and reduces food intake; combined knockdown plus BigLEN antibody neutralization nearly eliminates acute feeding in food-deprived mice, establishing the BigLEN-GPR171 system as a regulator of feeding and metabolism. shRNA knockdown in mouse hypothalamus, antibody neutralization, feeding behavior assays Proceedings of the National Academy of Sciences of the United States of America High 24043826
2016 GPR171 is activated by the small-molecule agonist MS0015203, identified by virtual screening of a homology model of GPR171; selectivity confirmed against 80 other membrane proteins including family A GPCRs. Peripheral injection increases food intake and body weight in a GPR171-dependent manner (attenuated by hypothalamic shRNA knockdown). Virtual screen, radioligand binding to 80 GPCRs, shRNA knockdown, in vivo pharmacology Science signaling High 27245612
2017 GPR171 in the basolateral amygdala (BLA) mediates BigLEN-induced hyperpolarization of BLA pyramidal neurons; the small-molecule antagonist MS0021570_1 blocks BigLEN-mediated GPR171 activation in heterologous cells and in neurons, and lentiviral knockdown of GPR171 in the BLA reduces anxiety-like behavior and contextual fear conditioning. Electrophysiology (hyperpolarization assay), heterologous cell activation assay, DREADD-mediated neuronal activation, lentiviral shRNA knockdown, behavioral assays Neuropsychopharmacology High 28425495
2019 GPR171 is expressed in GABAergic neurons within the periaqueductal gray (PAG) and modulates mu-opioid receptor (but not delta-opioid receptor) signaling; GPR171 agonist enhances and antagonist reduces morphine-induced antinociception; receptor knockdown decreases mu-opioid receptor signaling. Immunofluorescence/colocalization, pharmacological agonist/antagonist administration, receptor knockdown, antinociception behavioral assays The Journal of pharmacology and experimental therapeutics Medium 31308196
2021 GPR171 protein expression is induced on T cells upon antigen stimulation; BigLEN binding to GPR171 suppresses TCR-mediated signaling pathways and inhibits T cell proliferation; GPR171 knockout mice exhibit enhanced antitumor immunity; GPR171 antagonism improves immune checkpoint blockade therapy. Western blot (protein induction), T cell activation assays, GPR171 knockout mice, tumor models, immune checkpoint blockade combination Nature communications High 34615877
2021 GPR171 is expressed in nociceptor subpopulations and, when activated by BigLEN or synthetic ligands, attenuates pain signals via Gi/o-coupled modulation of nociceptive ion channel activity, alleviating acute and pathologic pain. Immunostaining of DRG neurons, Gi/o pharmacology, ion channel functional assays, in vivo pain behavior Biomedicines Medium 33807709
2021 GPR171 agonist MS15203 reduces CFA-induced inflammatory pain thermal hypersensitivity and CIPN-induced allodynia in male but not female mice; GPR171 protein levels in the PAG are decreased after neuropathic pain in males, and MS15203 treatment rescues PAG GPR171 protein levels. In vivo pharmacology, CFA and CIPN pain models, western blot of PAG tissue, sex-stratified behavioral analysis Frontiers in pain research Medium 35295419
2022 GPR171 agonist MS15203 attenuates morphine tolerance in both male and female mice on the tail-flick (but not hotplate) test, and does not exacerbate morphine withdrawal during chronic treatment, indicating a test-dependent functional interaction with mu-opioid receptor signaling. Chronic morphine tolerance and withdrawal behavioral paradigms, tail-flick and hotplate tests, sex-stratified analysis Behavioural pharmacology Medium 35942845
2023 GPR171 and its ligand ProSAAS are localized in hippocampus, BLA, nucleus accumbens, prefrontal cortex, and VTA; in the VTA, GPR171 is primarily in dopamine neurons while ProSAAS is outside dopamine neurons. GPR171 agonist MS15203 does not activate VTA neurons (no c-Fos increase) and produces no conditioned place preference, indicating minimal reward liability. Immunohistochemistry, c-Fos quantification in VTA slices, conditioned place preference Pharmacology, biochemistry, and behavior Medium 36933620
2025 GPR171 deficiency promotes Th17 cell differentiation via the cAMP-pCREB-FABP5 axis and alters the lipidome profile of Th17 cells; BigLEN-triggered GPR171 activation inhibits Th17 differentiation in vitro; FABP5 blockade rescues the exacerbated colitis seen in Gpr171-/- mice. RNA-seq, lipidomics, cAMP/pCREB signaling assays, genetic knockout (Gpr171-/-), in vitro Th17 differentiation, FABP5 pharmacological blockade, DSS and T cell transfer colitis models Gut High 40074327
2025 HIF-1α directly binds hypoxia response elements in the GPR171 promoter and drives GPR171 transcription in mast cells during H. pylori infection; GPR171 activation mediates CCL2 secretion via ERK1/2 signaling; loss or blockade of GPR171 reduces CCL2 and gastric mucosal inflammation. ChIP, dual-luciferase reporter assay, lentiviral knockdown, ELISA, western blot, in vivo H. pylori mouse model Helicobacter High 40320649
2026 GPR171 (a P2Y-family GPCR) is expressed in hemogenic endothelium and hematopoietic stem/progenitor cells; its endogenous ligand (encoded by pcsk1nl/BigLEN) cooperates with GPR171 to enhance HSC generation. Mechanistically, GPR171 activates ERK1/2 and Notch signaling pathways independently and synergistically to promote embryonic HSC specification; GPR171-deficient zebrafish and mouse embryos show severe HSC deficits. Zebrafish gpr171 loss-of-function, genetic knockout mice, pharmacological BigLEN administration, ERK1/2 and Notch pathway assays, HSC quantification Proceedings of the National Academy of Sciences of the United States of America High 41576080
2012 Enforced expression of Gpr171 in myeloblastic 32D cells and primary Sca-1+ hematopoietic progenitors decreases myeloid marker expression and increases clonogenic colony formation; conversely, Gpr171 silencing reduces myeloid markers. In vivo, transplantation of Gpr171-overexpressing progenitors reduces Mac-1+Gr-1- myeloid cells, demonstrating that Gpr171 negatively regulates myeloid differentiation. Retroviral overexpression, shRNA silencing, colony-forming assays, in vivo bone marrow transplant Experimental hematology Medium 23022127

Source papers

Stage 0 corpus · 17 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 GPR171 is a hypothalamic G protein-coupled receptor for BigLEN, a neuropeptide involved in feeding. Proceedings of the National Academy of Sciences of the United States of America 71 24043826
2016 Identification of a small-molecule ligand that activates the neuropeptide receptor GPR171 and increases food intake. Science signaling 29 27245612
2017 The BigLEN-GPR171 Peptide Receptor System Within the Basolateral Amygdala Regulates Anxiety-Like Behavior and Contextual Fear Conditioning. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 26 28425495
2021 The GPR171 pathway suppresses T cell activation and limits antitumor immunity. Nature communications 24 34615877
2016 GPR171 expression enhances proliferation and metastasis of lung cancer cells. Oncotarget 19 26760963
2012 Gpr171, a putative P2Y-like receptor, negatively regulates myeloid differentiation in murine hematopoietic progenitors. Experimental hematology 18 23022127
2021 GPR171 Agonist Reduces Chronic Neuropathic and Inflammatory Pain in Male, But Not Female Mice. Frontiers in pain research (Lausanne, Switzerland) 17 35295419
2019 Opioid-Induced Signaling and Antinociception Are Modulated by the Recently Deorphanized Receptor, GPR171. The Journal of pharmacology and experimental therapeutics 13 31308196
2025 GPR171 restrains intestinal inflammation by suppressing FABP5-mediated Th17 cell differentiation and lipid metabolism. Gut 11 40074327
2022 DIRAS3, GPR171 and RAC2 were identified as the key molecular patterns associated with brain metastasis of breast cancer. Frontiers in oncology 10 36212434
2021 GPR171 Activation Modulates Nociceptor Functions, Alleviating Pathologic Pain. Biomedicines 10 33807709
2022 GPR171 activation regulates morphine tolerance but not withdrawal in a test-dependent manner in mice. Behavioural pharmacology 3 35942845
2025 HIF-1α-Induced GPR171 Expression Mediates CCL2 Secretion by Mast Cells to Promote Gastric Inflammation During Helicobacter pylori Infection. Helicobacter 2 40320649
2023 A small molecule ligand for the novel pain target, GPR171, produces minimal reward in mice. Pharmacology, biochemistry, and behavior 2 36933620
2026 Gpr171 regulates embryonic hematopoietic stem cell emergence via ERK1/2 and Notch signaling. Proceedings of the National Academy of Sciences of the United States of America 0 41576080
2025 GPR171 is necessary for normal physiological functions and mood-related behaviors in males, but not females. Behavioural brain research 0 40318809
2025 ProSAAS neuropeptides and receptors GPR171 and GPR83: Potential therapeutic applications for pain, anxiety, and body weight regulation. The Journal of pharmacology and experimental therapeutics 0 40450835