Affinage

GPR39

G-protein coupled receptor 39 · UniProt O43194

Length
453 aa
Mass
51.3 kDa
Annotated
2026-04-28
100 papers in source corpus 41 papers cited in narrative 40 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GPR39 is a constitutively active class A GPCR that functions as a zinc-sensing receptor (ZnR) and integrates extracellular Zn²⁺, bile acid, and GPNMB signals into diverse intracellular cascades across epithelial, neuronal, endothelial, and immune cell types. Zn²⁺ binds via His17/His19 in the N-terminal domain while Asp313 in ECL3 serves as both a tethered inverse agonist and pH sensor; the receptor couples to Gαq (PLC–IP3–Ca²⁺–ERK1/2), Gαs (cAMP), and Gα12/13 (RhoA–SRE transcription), with desensitization proceeding through a ROCK-dependent internalization pathway (PMID:16959833, PMID:18588883, PMID:22879599, PMID:28619258). In neurons, synaptically released Zn²⁺ activates GPR39 to upregulate KCC2 surface expression via Gαq/PLC/ERK1/2, shifting GABA_A reversal potential and enhancing inhibitory tone, while in colonocytes and other epithelia GPR39 drives tight junction assembly, ion cotransporter (KCC1/3, NHE) regulation, and proliferation/differentiation through ERK1/2–AKT–mTOR signaling (PMID:21900570, PMID:24967969, PMID:28093242). GPR39 also serves as a receptor for 3-O-sulfated lithocholic acids mediating bile acid–induced Ca²⁺ signaling and pancreatic acinar cell injury, and for macrophage-derived GPNMB promoting post-myocardial infarction cardiac repair (PMID:38306436, PMID:39455836).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1997 Medium

    Cloning of GPR39 established it as a novel orphan GPCR within the GHS-R/neurotensin receptor family, setting the stage for ligand identification and functional characterization.

    Evidence cDNA cloning, genomic hybridization, and sequence analysis in human tissues

    PMID:9441746

    Open questions at the time
    • No ligand or signaling pathway identified
    • Functional role entirely unknown
    • Expression pattern only broadly characterized
  2. 2007 High

    Identification of Zn²⁺ as the endogenous GPR39 agonist resolved the orphan receptor problem and revealed multi-pathway G protein coupling (Gαq–PLC, Gαs–cAMP, Gα13–RhoA–SRE), while definitively excluding obestatin as a ligand.

    Evidence HPLC fractionation of fetal bovine serum with ICP-MS identification, cell-based IP turnover, cAMP, β-arrestin, and reporter assays; pharmacological pathway dissection with PLC inhibitor and pertussis toxin

    PMID:16959833 PMID:17054911 PMID:17885920 PMID:18180304

    Open questions at the time
    • Zn²⁺ binding site on receptor not yet mapped
    • Physiological contexts of each G protein pathway unclear
    • In vivo relevance of zinc sensing not demonstrated
  3. 2008 High

    Systematic mutagenesis defined the structural determinants of GPR39 activation: His17/His19 as the Zn²⁺ coordination site, Asp313 as a tethered inverse agonist, and a non-conserved disulfide (Cys11–Cys191) as a negative modulator of receptor sensitivity.

    Evidence Alanine-scanning and cysteine mutagenesis with inositol phosphate assays, TCEP reduction, and free sulfhydryl labeling

    PMID:18588883 PMID:18693759

    Open questions at the time
    • No crystal or cryo-EM structure available
    • Contribution of each residue to G protein selectivity unknown
    • Mechanism by which Asp313 enforces inverse agonism at the structural level unresolved
  4. 2010 High

    Establishing GPR39 as the molecular identity of the zinc-sensing receptor (ZnR) in keratinocytes and colonocytes linked it to physiological processes including wound healing and epithelial cytoprotection.

    Evidence siRNA silencing of GPR39 abolishes Zn²⁺-dependent Ca²⁺ responses, MAP kinase activation, and scratch wound closure in keratinocytes; GPR39 KO mouse colon validates colonocyte signaling

    PMID:20522546 PMID:22545109

    Open questions at the time
    • In vivo wound healing phenotype in GPR39 KO mice not yet tested at this stage
    • Relative contribution of GPR39 vs. other zinc importers to zinc sensing unclear
  5. 2011 High

    Discovery that synaptically released Zn²⁺ activates postsynaptic GPR39 to upregulate KCC2 and shift GABAergic inhibition established GPR39 as a neuronal zinc sensor regulating excitation-inhibition balance.

    Evidence GPR39 KO and ZnT3 KO mice, hippocampal slice electrophysiology, KCC2 surface expression assay, EGABA measurement

    PMID:21900570

    Open questions at the time
    • Whether GPR39 loss contributes to neuropsychiatric disease in humans unknown
    • Role in other brain regions beyond hippocampal mossy fibers not explored
  6. 2012 High

    Identification of Asp313 as a pH sensor (distinct from the Zn²⁺-binding His17/His19) revealed that GPR39 integrates two extracellular signals—zinc concentration and pH—to modulate downstream ERK1/2 and AKT activation.

    Evidence Site-directed mutagenesis of Asp313, His17, His19 with Ca²⁺ imaging and ERK/AKT/NHE activity at varying pH

    PMID:22879599

    Open questions at the time
    • Whether pH and Zn²⁺ bind the same or distinct receptor conformations is unresolved
    • In vivo relevance of pH sensing (e.g., in ischemic tissue) not tested
  7. 2014 High

    Multiple studies converged to show GPR39 governs colonocyte proliferation, differentiation, and tight junction integrity via ERK1/2–AKT–mTOR, and participates in Hedgehog pathway regulation by modulating Gli transcription factor activity.

    Evidence siRNA/KO in colonocytes measuring differentiation markers, TEER, and tight junction proteins; reciprocal gain/loss-of-function in Hh reporter assays

    PMID:24633354 PMID:24967969

    Open questions at the time
    • Direct GPR39–SUFU interaction not yet demonstrated at this stage
    • Relationship between Zn²⁺ and Hedgehog modulation not clarified
    • Whether epithelial barrier effects are cell-autonomous in vivo unknown
  8. 2015 High

    GPR39 KO mice showed dramatically enhanced seizure susceptibility, establishing the Gαq/PLC/ERK–KCC2 axis as physiologically critical for neuronal inhibitory tone and revealing GPR39 as a seizure susceptibility modifier.

    Evidence GPR39 KO mice subjected to kainic acid, hippocampal electrophysiology, KCC2 surface expression, PLC/ERK inhibitors

    PMID:25562657

    Open questions at the time
    • Human genetic association with epilepsy not demonstrated
    • Therapeutic potential of GPR39 agonists in seizure models not tested at this point
  9. 2017 Medium

    GPR39 desensitization was shown to proceed through a unique ROCK-dependent internalization mechanism downstream of Gα12/13, distinguishing it from canonical GRK/β-arrestin–mediated GPCR desensitization, and colonic KCC1 regulation linked GPR39 to chloride absorption and diarrheal disease protection.

    Evidence ROCK inhibitor Y-27632 and biased agonist experiments for desensitization; GPR39 KO mice in cholera toxin fluid secretion model with Ussing chamber ion transport

    PMID:28093242 PMID:28619258

    Open questions at the time
    • Whether ROCK-dependent desensitization occurs for all GPR39-expressing cell types unknown
    • Structural basis for biased agonism at GPR39 not defined
  10. 2021 Medium

    GPR39 was linked to cardiac hypertrophy (via AMPK inhibition–mTOR activation), neuroprotection (via SIRT1/PGC-1α/Nrf2), GLP-1 secretion from intestinal L cells (via Gαq/Gαi/o), and thymic regeneration (via BMP4), greatly expanding its physiological scope beyond zinc sensing.

    Evidence AAV9-mediated knockdown in TAC model; CRISPR KO in neonatal HIE model; BRET G protein biosensors and GPR39 KO organoids; GPR39 KO mice in bone marrow transplant model

    PMID:33554444 PMID:33711555 PMID:34645465 PMID:35357432

    Open questions at the time
    • Ligand identity driving GPR39 in cardiac hypertrophy unclear (Zn²⁺ vs. other)
    • Whether GPR39 agonists are therapeutically viable in these contexts untested in humans
    • Relative contribution of Gαq vs. Gαi/o to GLP-1 secretion not fully dissected
  11. 2022 High

    Direct physical interaction between GPR39 and SUFU provided a mechanistic basis for GPR39's suppression of Hedgehog/GLI1 signaling, and GPR39 KO enhanced revascularization, placing GPR39 at the intersection of GPCR and Hedgehog pathways.

    Evidence Co-immunoprecipitation of GPR39 and SUFU, SUFU overexpression rescue, GPR39 KO in diabetic hindlimb ischemia model

    PMID:36574661

    Open questions at the time
    • Whether the GPR39–SUFU interaction is zinc-dependent unknown
    • Structural basis of GPR39–SUFU binding uncharacterized
    • Relevance to developmental Hedgehog signaling not tested
  12. 2024 High

    GPR39 was deorphanized further as a receptor for 3-O-sulfated bile acids (mediating pancreatitis) and for macrophage-derived GPNMB (mediating post-MI cardiac repair), establishing GPR39 as a multi-ligand receptor with tissue-specific disease roles.

    Evidence GPR39-expressing cell Ca²⁺ sufficiency assays, GPR39 KO mice in bile acid–induced pancreatitis and post-MI models, genetic epistasis with GPNMB KO

    PMID:38306436 PMID:39455836

    Open questions at the time
    • How Zn²⁺, bile acids, and GPNMB compete or cooperate at the receptor binding site is unknown
    • Structural basis for multi-ligand recognition not resolved
    • Whether bile acid and GPNMB signals use the same or distinct G protein pathways through GPR39 is undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • No high-resolution structure of GPR39 exists, and the mechanisms by which three chemically distinct ligands (Zn²⁺, sulfated bile acids, GPNMB) activate the same receptor—potentially through distinct binding sites and biased signaling—remain unresolved.
  • No cryo-EM or crystal structure
  • Allosteric vs. orthosteric binding of each ligand class not mapped
  • In vivo hierarchy of ligands in different tissues unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 5
Localization
GO:0005886 plasma membrane 4
Pathway
R-HSA-162582 Signal Transduction 8 R-HSA-382551 Transport of small molecules 4 R-HSA-1643685 Disease 3 R-HSA-1266738 Developmental Biology 2 R-HSA-168256 Immune System 1
Partners
CASRGALR1GPNMBHTR1APKIBSUFU

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 GPR39 was cloned as a member of the GHS-R/neurotensin receptor family, sharing structural features including a conserved acidic residue (E124) in TM-3 essential for GHS-R activation; expressed in brain and peripheral tissues. cDNA cloning, genomic hybridization, sequence analysis Genomics Medium 9441746
2006 Zn2+ activates GPR39 signaling (inositol phosphate turnover, cAMP production, arrestin mobilization, CRE- and SRE-dependent transcriptional activity) in GPR39-expressing cells; obestatin does not activate GPR39 or bind to it. Cell-based signaling assays (IP turnover, cAMP, arrestin recruitment, reporter gene), radioligand binding, quantitative PCR Endocrinology High 16959833 17054911
2007 Zn2+ was isolated as an endogenous GPR39 agonist from fetal bovine serum; its calcium-mobilizing activity is abolished by PLC inhibitor U73122 but not pertussis toxin, demonstrating Gαq-PLC coupling; conserved across mouse and rat GPR39. HPLC fractionation of FBS, ICP-MS identification, intracellular calcium mobilization assay, pharmacological inhibitors Journal of receptor and signal transduction research High 17885920
2007 GPR39 exists as a full-length 7TM form (GPR39-1a) with constitutive activity and a truncated 5TM splice variant (GPR39-1b); promoter analysis identified HNF-1α, HNF-4α, and SP1 binding sites controlling GPR39 expression. RT-PCR, quantitative RT-PCR, functional promoter analysis Molecular endocrinology Medium 17488974
2008 Zn2+ agonism of GPR39 requires His17 and His19 in the N-terminal extracellular segment; Asp313 in ECL3 functions as a tethered inverse agonist, and its substitution eliminates Zn2+-induced activation while greatly increasing constitutive signaling. Alanine-scanning mutagenesis, inositol phosphate production assay FEBS letters High 18588883
2008 GPR39 contains two disulfide bridges: a conserved bridge (Cys108–Cys210) required for cell surface expression and agonist-induced signaling, and a non-conserved bridge (Cys11–Cys191) that dampens receptor activation; disruption of the second bridge increases Zn2+ potency ~10-fold. Cysteine mutagenesis, TCEP reduction, free sulfhydryl labeling, inositol phosphate assay Biochemistry High 18693759
2008 GPR39 constitutive activity signals via Gα13 → RhoA → SRE-mediated transcription, leading to upregulation of PEDF secretion and protection from cell death; RGS16 was identified as a signaling component linking GPR39 to Gα13. Transcriptome array, co-expression with dominant-negative RhoA/SRF, GPR39 overexpression/silencing, PEDF conditioned medium assay Journal of Biological Chemistry Medium 18180304
2010 GPR39 is the molecular identity of the zinc-sensing receptor (ZnR) in keratinocytes; silencing GPR39 abolishes Zn2+-dependent metabotropic Ca2+ responses, downstream MAP kinase activation, NHE1 upregulation, and scratch closure. siRNA silencing of GPR39, fluorometric Ca2+ imaging, MAP kinase assay, scratch wound assay Journal of Biological Chemistry High 20522546
2011 Synaptic Zn2+ activates GPR39 (mZnR) postsynaptically to upregulate KCC2 surface expression and Cl- transport activity, producing a hyperpolarizing shift in GABAA reversal potential and enhancing inhibitory tone in hippocampal neurons. GPR39 knockout mice, mossy fiber stimulation in hippocampal slices, ZnT3-KO mice, EGABA measurement, KCC2 surface expression assay Journal of Neuroscience High 21900570
2012 GPR39 is identified as the molecular moiety of ZnR in colonocytes; GPR39 silencing abolishes Zn2+-dependent Ca2+ release, Na+/H+ exchange upregulation, and butyrate-induced cell death protection; the protection is mediated by GPR39-dependent clusterin upregulation. GPR39 siRNA silencing, Ca2+ imaging, NHE activity assay, GPR39 KO mouse tissue, clusterin knockdown PLoS ONE High 22545109
2012 Extracellular pH regulates ZnR/GPR39 activity through Asp313: substitution of Asp313 to Ala abolishes pH sensitivity, while His17 and His19 replacements do not affect pH dependence, identifying Asp313 as both a Zn2+-binding modulator and pH sensor. Site-directed mutagenesis (Asp313, His17, His19), Ca2+ imaging, ERK1/2 and AKT activation assays, NHE activity assay at varying pH Journal of Biological Chemistry High 22879599
2014 GPR39 activates Gαq/11-RhoA signaling to sustain YAP activity in oral squamous cell carcinoma; inhibition of GPR39 reduces YAP-driven tumor growth. GPR39 overexpression/knockdown, signaling pathway analysis, tumor growth assays Journal of Dental Research Medium 32325008
2014 GPR39 is identified as the receptor mediating Hedgehog pathway inhibition by CMAP compounds downstream of Smoothened; RNA interference knockdown or cDNA overexpression of GPR39 confirmed necessity for compound activity and Gli transcription factor modulation. siRNA knockdown, cDNA overexpression, GPCR mRNA expression correlation, Hh pathway reporter assay, IP turnover assay Nature Chemical Biology High 24633354
2014 ZnR/GPR39 interacts with the Ca2+-sensing receptor (CaSR) to synergistically enhance Zn2+-dependent Ca2+ signaling; CaSR silencing or dominant-negative CaSR reduces ZnR/GPR39 activity; co-expression is sufficient to trigger enhanced responses. siRNA silencing of CaSR, dominant-negative CaSR, GPR39 overexpression in HEK293, Ca2+ imaging, MAPK/PI3K assays Journal of Cellular Physiology Medium 24264723
2014 ZnR/GPR39 controls colonocyte proliferation and differentiation via ERK1/2, AKT, and mTOR/p70S6K pathways; silencing ZnR/GPR39 impairs alkaline phosphatase activity (differentiation marker) and reduces tight junction protein (occludin, ZO-1, E-cadherin) expression; GPR39 KO mouse colon shows decreased ZO-1 and occludin. siRNA silencing, Western blot (ERK1/2, AKT, mTOR, caspase-3), alkaline phosphatase assay, TEER measurement, GPR39 KO mice Cell Death & Disease High 24967969
2014 Protein kinase inhibitor β (PKIB) interacts with the C-terminus of GPR39 (identified by Y2H screen); co-expression enhances GPR39 constitutive (Gα13/RhoA/SRE) but not zinc-mediated signaling; zinc causes PKIB dissociation from GPR39, creating a negative-feedback loop on Gs pathway. Yeast-2-hybrid screen, co-expression, SRE reporter assay, cell protection assay, PKIB mutational analysis Biochemical Journal Medium 24869658
2015 GPR39 forms heteroreceptor complexes with 5-HT1A and GalR1; these interactions are modulated by zinc; the 5-HT1A-GPR39 heterocomplex shows additive signaling functionality compared to individual receptors. FRET, co-immunopurification, signaling assays upon receptor activation Biochimica et Biophysica Acta Medium 26365466
2015 mZnR/GPR39 activation by synaptic Zn2+ release upregulates KCC2 via Gαq/phospholipase C/ERK1/2 signaling cascade; mZnR/GPR39 KO mice have dramatically enhanced seizure susceptibility to kainic acid. GPR39 KO mice, kainic acid seizure model, hippocampal slice electrophysiology, KCC2 surface expression assay, PLC/ERK inhibitors Neurobiology of Disease High 25562657
2015 In human myoblasts, obestatin/GPR39 system controls myogenesis: mitogenic ERK1/2/JunD signaling is G protein-dependent, while cell cycle exit and differentiation require β-arrestin 1/2 scaffolding, Src activation, and EGFR transactivation via matrix metalloproteinases. β-arrestin knockdown, EGFR transactivation assays, co-immunoprecipitation, phosphorylation assays, myogenic differentiation markers Cellular and Molecular Life Sciences Medium 26211463
2015 mZnR/GPR39 upregulates neuronal Na+/H+ exchanger (NHE) activity via ERK1/2-dependent pathway, enhancing recovery from intracellular acidification; this signaling is abolished at acidic extracellular pH (6.5), providing a homeostatic pH regulation mechanism. GPR39 KO neurons, ERK1/2 phosphorylation assay, NHE activity assay, pH manipulation, hippocampal neurons in vitro Journal of Neurochemistry High 26375174
2016 Small-molecule GPR39 agonists (LY2784544, GSK2636771) and GPR39-C3 show probe-dependent and pathway-dependent allosteric modulation by physiological zinc concentrations, revealing zinc as an allosteric potentiator of small-molecule GPR39 activation. β-arrestin recruitment assay (PRESTO-Tango), cAMP assay, Gq signaling assay, allosteric modulation experiments Molecular Pharmacology Medium 27754899
2017 GPR39 desensitization occurs via a unique Rho kinase (ROCK)-dependent mechanism: receptor activation induces ROCK-dependent internalization of GPR39; a biased agonist lacking G12/13 activation does not induce desensitization, linking G12/13-ROCK signaling to feedback regulation. ROCK inhibitor (Y-27632), GFP-tagged GPR39 internalization assay, cAMP, IP1, SRF-RE, β-arrestin recruitment assays, biased agonist comparison Biochemical Pharmacology Medium 28619258
2017 ZnR/GPR39 upregulates basolateral KCC1 in colonocytes to enhance Cl- absorption and reduce cholera toxin-induced fluid loss; this effect requires both dietary Zn2+ and ZnR/GPR39, as both are absent in ZnR/GPR39 KO mice. ZnR/GPR39 KO mice, cholera toxin fluid secretion model, KCC activity assay, Caco-2 cells, Ussing chambers Biochimica et Biophysica Acta - Molecular Basis of Disease High 28093242
2017 Zn2+ acting via ZnR/GPR39 activates Gαq-PLC signaling in endothelial cells, promoting cell survival/growth through cAMP and AKT, VEGF-A and PDGF-αR upregulation, and cytoskeletal reorganization; siRNA knockdown of GPR39 abolishes these effects. GPR39 siRNA, Ca2+ imaging, Gαq-PLC pathway analysis, GPR39 KO endothelial cells, tube formation assay American Journal of Physiology - Cell Physiology Medium 29351417
2017 Zn2+ signals via ZnR/GPR39 to induce IL-6 production from skin fibroblasts through GPR39-mediated pathways; ZnT2 transporter is required for Zn2+ release from mast cell granules; wound healing is impaired in GPR39 KO and IL-6 KO mice. GPR39 KO mice, IL-6 KO mice, ZnT2 KO mice, wound healing model, cytokine measurement Scientific Reports Medium 31346193
2017 Zinc supplementation via GPR39 upregulates PKCζ, which enhances ZO-1 expression and epithelial integrity in Salmonella-infected Caco-2 cells; siRNA silencing of GPR39 reduces zinc-activated PKCζ and blocks zinc's protective effect on barrier integrity. siRNA silencing of GPR39 and PKCζ, TEER measurement, Western blot, tight junction protein analysis Journal of Nutrition Medium 28515165
2018 ZnR/GPR39 activates tight junction assembly in intestinal epithelial cells via a PLC-CaMKKβ-AMPK signaling cascade; PLC and CaMKKβ inhibitors abolish GPR39 agonist-induced AMPK activation and tight junction assembly. GPR39 agonist TC-G 1008, pharmacological inhibitors (PLC, CaMKKβ, AMPK), TEER, Western blot for AMPK phosphorylation, ZO-1 immunofluorescence European Journal of Pharmacology Medium 30459126
2018 ZnR/GPR39 upregulates KCC3 (not KCC4) activity in tamoxifen-resistant breast cancer cells, promoting cell migration and proliferation; KCC3 silencing or ZnR/GPR39 silencing abolishes Zn2+-dependent K+/Cl- co-transport and scratch closure. siRNA silencing of ZnR/GPR39 and KCC isoforms, NH4+ transport assay (pH surrogate for K+/Cl- transport), scratch closure assay, KCC inhibitor DIOA Cell Calcium Medium 31146164
2016 Amyloid-β attenuates mZnR/GPR39-dependent Ca2+ responses, ERK1/2 phosphorylation, and clusterin upregulation in neurons by binding Zn2+ and preventing receptor activation; AKT phosphorylation is not mZnR/GPR39-dependent and is unaffected by Aβ. GPR39 KO mouse cortical neurons, SHSY-5Y cells, Ca2+ imaging, ERK1/2/AKT phosphorylation, Aβ treatment, mZnR/GPR39 siRNA silencing Journal of Neurochemistry High 27501363
2018 GPR39 KO osteoblasts have disorganized matrix deposition with abnormally low collagen and high mineral contents; Gpr39-/- mice show reduced Zip13 expression and downregulation of zinc-dependent ADAMTS metalloprotease family members involved in collagen processing. GPR39 KO mice and primary osteoblast cultures, FTIR spectroscopy, histology, Western blot, Zn transporter expression analysis FASEB Journal Medium 29295862
2021 GPR39 agonism promotes osteoblast differentiation via AMPK-mediated Runx-2 induction; AMPK inhibition by Compound C abolishes TC-G 1008-mediated ALP, osteocalcin, and collagen induction. GPR39 agonist TC-G 1008, AMPK inhibitor Compound C, ALP activity assay, calcium deposition, Western blot for Runx-2 and AMPK Artificial Cells, Nanomedicine, and Biotechnology Medium 31448639
2021 GPR39 agonism protects against neuroinflammation post-hypoxic-ischemia via SIRT1/PGC-1α/Nrf2 pathway; GPR39 CRISPR, PGC-1α CRISPR, and SIRT1 inhibitor EX527 abolish TC-G 1008 neuroprotection. CRISPR knockout of GPR39 and PGC-1α, SIRT1 inhibitor, neonatal rat HIE model, Western blot, immunofluorescence Journal of Neuroinflammation Medium 34645465
2021 GPR39-mediated pericyte contraction during reduced coronary perfusion pressure causes capillary constriction leading to 'no reflow' after myocardial infarction; GPR39 KO and GPR39 inhibitor (VC43) treatment reduce no-reflow zones and infarct size. GPR39 KO mice, coronary occlusion/reperfusion model, GPR39 inhibitor VC43, immunohistochemistry for capillary density and diameter American Journal of Physiology - Heart and Circulatory Physiology Medium 34623177
2021 Oral GPR39 agonist (Cpd1324) increases GLP-1 secretion via Gαq and Gαi/o (but not Gαs) signaling in intestinal L cells; this is GPR39-dependent as GPR39 KO organoids do not respond; acute food intake is decreased and GLP-1 levels are elevated in HFD-fed mice. Bioluminescence resonance energy transfer (BRET) biosensors for G protein activation, mouse/human intestinal organoids, GPR39 KO organoids, plasma hormone measurement Molecular Metabolism High 33711555
2022 Extracellular Zn2+ released from thymocytes after HCT conditioning activates GPR39 on endothelial cells to stimulate BMP4 production, promoting thymic regeneration and T-cell reconstitution; GPR39 agonist enhances thymic function without requiring prior Zn2+ accumulation. GPR39 KO mice, bone-marrow transplantation model, lineage tracing, small-molecule GPR39 agonist, measurement of BMP4 and recent thymic emigrants Blood Medium 35357432
2022 GPR39 directly binds SUFU (suppressor of fused), an endogenous inhibitor of the Sonic Hedgehog pathway; overexpression or activation of GPR39 suppresses basal and ligand-dependent GLI1 activation and EC migration; GPR39 KO enhances revascularization in diabetic hindlimb ischemia. Co-immunoprecipitation of GPR39 and SUFU, adenoviral GPR39 overexpression, siRNA knockdown, SUFU overexpression rescue, GPR39 KO mouse ischemia model PNAS High 36574661
2024 GPR39 is an evolutionarily conserved receptor for bile acids, particularly 3-O-sulfated lithocholic acids; GPR39 is sufficient for bile acid-induced Ca2+ elevation in cultured cells and mediates Ca2+ elevation and necrosis in pancreatic acinar cells; GPR39 KO mice show significantly reduced bile acid-induced acute pancreatitis. Cell-line Ca2+ assay with GPR39 expression, pancreatic acinar cell Ca2+ and necrosis assays, GPR39 KO mice in bile acid-induced pancreatitis model Science Advances High 38306436
2024 Bone-marrow macrophage-derived GPNMB binds directly to GPR39 as a ligand; GPR39 mediates GPNMB's beneficial effects on post-MI cardiac repair; GPR39 KO abrogates the protective effects of GPNMB on myocyte contraction and fibroblast activation. Lineage tracing, bone-marrow transplantation, genetic loss-of-function (GPNMB KO, GPR39 KO), viral GPNMB delivery, single-cell transcriptomics, receptor binding identification Nature Cardiovascular Research High 39455836
2024 ZnR/GPR39 modulates hepatic insulin receptor signaling: KO mice show elevated insulin receptor expression and AKT activation, higher fasting glucose, hepatic lipid accumulation, increased OCR and ROS, and marked liver fibrosis with elevated collagen; ZnR/GPR39 also regulates ERK1/2 phosphorylation in liver. GPR39 KO mice, Western blot (insulin receptor, AKT, ERK1/2), hepatic OCR/ROS measurement, LPS-induced ALI model, serum cytokines, collagen staining Redox Biology Medium 39514940
2021 GPR39 promotes cardiac hypertrophy by inhibiting AMPK, leading to mTOR and S6K1 activation and increased de novo protein synthesis; adeno-associated virus GPR39 knockdown suppresses TAC-induced hypertrophy, and rapamycin blocks GPR39 overexpression-induced protein synthesis. AAV9-mediated GPR39 knockdown, adenovirus GPR39 overexpression, TAC mouse model, mTOR inhibitor rapamycin, Western blot for AMPK/mTOR/S6K1, cardiomyocyte size measurement Cell Biology International Medium 33554444

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 GPR39 signaling is stimulated by zinc ions but not by obestatin. Endocrinology 344 16959833
1997 Cloning and characterization of two human G protein-coupled receptor genes (GPR38 and GPR39) related to the growth hormone secretagogue and neurotensin receptors. Genomics 240 9441746
2006 Obestatin does not activate orphan G protein-coupled receptor GPR39. Biochemical and biophysical research communications 192 17054911
2006 Altered gastrointestinal and metabolic function in the GPR39-obestatin receptor-knockout mouse. Gastroenterology 135 17030183
2006 Normal food intake and body weight in mice lacking the G protein-coupled receptor GPR39. Endocrinology 121 17095592
2011 Upregulation of KCC2 activity by zinc-mediated neurotransmission via the mZnR/GPR39 receptor. The Journal of neuroscience : the official journal of the Society for Neuroscience 116 21900570
2010 GPR39: a Zn(2+)-activated G protein-coupled receptor that regulates pancreatic, gastrointestinal and neuronal functions. Cellular and molecular life sciences : CMLS 101 20812023
2006 GPR39 receptor expression in the mouse brain. Neuroreport 98 16708020
2010 Zinc released from injured cells is acting via the Zn2+-sensing receptor, ZnR, to trigger signaling leading to epithelial repair. The Journal of biological chemistry 96 20522546
2018 The Zinc Sensing Receptor, ZnR/GPR39, in Health and Disease. International journal of molecular sciences 88 29389900
2017 Zinc regulates vascular endothelial cell activity through zinc-sensing receptor ZnR/GPR39. American journal of physiology. Cell physiology 81 29351417
2007 Isolation of Zn2+ as an endogenous agonist of GPR39 from fetal bovine serum. Journal of receptor and signal transduction research 81 17885920
2007 GPR39 splice variants versus antisense gene LYPD1: expression and regulation in gastrointestinal tract, endocrine pancreas, liver, and white adipose tissue. Molecular endocrinology (Baltimore, Md.) 78 17488974
2014 The zinc sensing receptor, ZnR/GPR39, controls proliferation and differentiation of colonocytes and thereby tight junction formation in the colon. Cell death & disease 76 24967969
2014 GPR39 (zinc receptor) knockout mice exhibit depression-like behavior and CREB/BDNF down-regulation in the hippocampus. The international journal of neuropsychopharmacology 76 25609596
2013 The involvement of the GPR39-Zn(2+)-sensing receptor in the pathophysiology of depression. Studies in rodent models and suicide victims. Neuropharmacology 67 24333148
2015 Homeostatic regulation of KCC2 activity by the zinc receptor mZnR/GPR39 during seizures. Neurobiology of disease 65 25562657
2008 The constitutively active orphan G-protein-coupled receptor GPR39 protects from cell death by increasing secretion of pigment epithelium-derived growth factor. The Journal of biological chemistry 63 18180304
2012 The role of the GPR39 receptor in zinc deficient-animal model of depression. Behavioural brain research 58 23089648
2008 Molecular mechanism of Zn2+ agonism in the extracellular domain of GPR39. FEBS letters 55 18588883
2014 Target identification for a Hedgehog pathway inhibitor reveals the receptor GPR39. Nature chemical biology 51 24633354
2018 An agonist of a zinc-sensing receptor GPR39 enhances tight junction assembly in intestinal epithelial cells via an AMPK-dependent mechanism. European journal of pharmacology 46 30459126
2021 Zinc ameliorates human aortic valve calcification through GPR39 mediated ERK1/2 signalling pathway. Cardiovascular research 44 32259211
2020 GPR39 protects against corticosterone-induced neuronal injury in hippocampal cells through the CREB-BDNF signaling pathway. Journal of affective disorders 44 32553391
2016 Discovery and Characterization of Novel GPR39 Agonists Allosterically Modulated by Zinc. Molecular pharmacology 44 27754899
2019 microRNA-1914, which is regulated by lncRNA DUXAP10, inhibits cell proliferation by targeting the GPR39-mediated PI3K/AKT/mTOR pathway in HCC. Journal of cellular and molecular medicine 43 31576658
2007 The obestatin receptor (GPR39) is expressed in human adipose tissue and is down-regulated in obesity-associated type 2 diabetes mellitus. Clinical endocrinology 43 17371481
2011 Deficiency of the GPR39 receptor is associated with obesity and altered adipocyte metabolism. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 42 21784784
2021 Activation of GPR39 with TC-G 1008 attenuates neuroinflammation via SIRT1/PGC-1α/Nrf2 pathway post-neonatal hypoxic-ischemic injury in rats. Journal of neuroinflammation 41 34645465
2016 The zinc sensing receptor, ZnR/GPR39, triggers metabotropic calcium signalling in colonocytes and regulates occludin recovery in experimental colitis. Philosophical transactions of the Royal Society of London. Series B, Biological sciences 41 27377730
2012 Zinc sensing receptor signaling, mediated by GPR39, reduces butyrate-induced cell death in HT29 colonocytes via upregulation of clusterin. PloS one 41 22545109
2021 The Zinc-Sensing Receptor GPR39 in Physiology and as a Pharmacological Target. International journal of molecular sciences 39 33918078
2021 Mechanism and potential treatment of the "no reflow" phenomenon after acute myocardial infarction: role of pericytes and GPR39. American journal of physiology. Heart and circulatory physiology 39 34623177
2019 Mast cells play role in wound healing through the ZnT2/GPR39/IL-6 axis. Scientific reports 39 31346193
2014 Discovery of 2-Pyridylpyrimidines as the First Orally Bioavailable GPR39 Agonists. ACS medicinal chemistry letters 39 25313322
2014 GPR39 Zn(2+)-sensing receptor: a new target in antidepressant development? Journal of affective disorders 39 25490458
2017 Zinc Supplementation, via GPR39, Upregulates PKCζ to Protect Intestinal Barrier Integrity in Caco-2 Cells Challenged by Salmonella enterica Serovar Typhimurium. The Journal of nutrition 37 28515165
2012 GI functions of GPR39: novel biology. Current opinion in pharmacology 37 22884904
2020 GPR39 Overexpression in OSCC Promotes YAP-Sustained Malignant Progression. Journal of dental research 35 32325008
2019 Long-Term Effects of Zinc Deficiency and Zinc Supplementation on Developmental Seizure-Induced Brain Damage and the Underlying GPR39/ZnT-3 and MBP Expression in the Hippocampus. Frontiers in neuroscience 35 31551684
2016 A possible significant role of zinc and GPR39 zinc sensing receptor in Alzheimer disease and epilepsy. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 35 27044837
2016 Potential antidepressant-like properties of the TC G-1008, a GPR39 (zinc receptor) agonist. Journal of affective disorders 35 27235821
2012 The obestatin/GPR39 system is up-regulated by muscle injury and functions as an autocrine regenerative system. The Journal of biological chemistry 35 22992743
2013 GPR39 up-regulation after selective antidepressants. Neurochemistry international 34 23474197
2015 The zinc binding receptor GPR39 interacts with 5-HT1A and GalR1 to form dynamic heteroreceptor complexes with signaling diversity. Biochimica et biophysica acta 33 26365466
2015 GPR39 activates proliferation and differentiation of porcine intramuscular preadipocytes through targeting the PI3K/AKT cell signaling pathway. Journal of receptor and signal transduction research 33 26524639
2014 The ZnR/GPR39 interacts with the CaSR to enhance signaling in prostate and salivary epithelia. Journal of cellular physiology 33 24264723
2017 Model-Based Discovery of Synthetic Agonists for the Zn2+-Sensing G-Protein-Coupled Receptor 39 (GPR39) Reveals Novel Biological Functions. Journal of medicinal chemistry 31 28045522
2015 Study of antidepressant drugs in GPR39 (zinc receptor⁻/⁻) knockout mice, showing no effect of conventional antidepressants, but effectiveness of NMDA antagonists. Behavioural brain research 31 25827929
2011 GPR39, a receptor of the ghrelin receptor family, plays a role in the regulation of glucose homeostasis in a mouse model of early onset diet-induced obesity. Journal of neuroendocrinology 31 21470317
2022 Activation of the zinc-sensing receptor GPR39 promotes T-cell reconstitution after hematopoietic cell transplant in mice. Blood 30 35357432
2017 The zinc sensing receptor, ZnR/GPR39, in health and disease. Frontiers in bioscience (Landmark edition) 30 28199213
2017 The Zn2+-sensing receptor, ZnR/GPR39, upregulates colonocytic Cl- absorption, via basolateral KCC1, and reduces fluid loss. Biochimica et biophysica acta. Molecular basis of disease 29 28093242
2015 Up-regulation of the GPR39 Zn2+-sensing receptor and CREB/BDNF/TrkB pathway after chronic but not acute antidepressant treatment in the frontal cortex of zinc-deficient mice. Pharmacological reports : PR 29 26481532
2015 Investigation of the GPR39 zinc receptor following inhibition of monoaminergic neurotransmission and potentialization of glutamatergic neurotransmission. Brain research bulletin 28 25917396
2011 Overexpression of GPR39 contributes to malignant development of human esophageal squamous cell carcinoma. BMC cancer 28 21352519
2018 Long-lasting antidepressant-like activity of the GPR39 zinc receptor agonist TC-G 1008. Journal of affective disorders 27 30419533
2020 Protective Effects of Co-administration of Zinc and Selenium Against Streptozotocin-Induced Alzheimer's Disease: Behavioral, Mitochondrial Oxidative Stress, and GPR39 Expression Alterations in Rats. Neurotoxicity research 26 32504391
2016 Amyloid β attenuates metabotropic zinc sensing receptor, mZnR/GPR39, dependent Ca2+ , ERK1/2 and Clusterin signaling in neurons. Journal of neurochemistry 26 27501363
2008 A second disulfide bridge from the N-terminal domain to extracellular loop 2 dampens receptor activity in GPR39. Biochemistry 26 18693759
2008 Is GPR39 the natural receptor of obestatin? Peptides 26 18977259
2021 Role of GPR39 in Neurovascular Homeostasis and Disease. International journal of molecular sciences 25 34360964
2020 Zinc-mediated Neurotransmission in Alzheimer's Disease: A Potential Role of the GPR39 in Dementia. Current neuropharmacology 25 31272355
2015 Regulation of neuronal pH by the metabotropic Zn(2+)-sensing Gq-coupled receptor, mZnR/GPR39. Journal of neurochemistry 25 26375174
2019 Activation of GPR39 with the agonist TC-G 1008 ameliorates ox-LDL-induced attachment of monocytes to endothelial cells. European journal of pharmacology 24 31202806
2015 GPR39 marks specific cells within the sebaceous gland and contributes to skin wound healing. Scientific reports 24 25604641
2011 β-Cell Specific Overexpression of GPR39 Protects against Streptozotocin-Induced Hyperglycemia. International journal of endocrinology 24 22164158
2021 Interaction between Zinc, GPR39, BDNF and Neuropeptides in Depression. Current neuropharmacology 23 33632103
2018 Perturbed bone composition and integrity with disorganized osteoblast function in zinc receptor/Gpr39-deficient mice. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 23 29295862
2015 β-Arrestin scaffolds and signaling elements essential for the obestatin/GPR39 system that determine the myogenic program in human myoblast cells. Cellular and molecular life sciences : CMLS 23 26211463
2021 Interaction between zinc, the GPR39 zinc receptor and the serotonergic system in depression. Brain research bulletin 22 33549699
2012 Extracellular pH regulates zinc signaling via an Asp residue of the zinc-sensing receptor (ZnR/GPR39). The Journal of biological chemistry 22 22879599
2024 Discoveries of GPR39 as an evolutionarily conserved receptor for bile acids and of its involvement in biliary acute pancreatitis. Science advances 21 38306436
2019 GPR39 agonist TC-G 1008 promotes osteoblast differentiation and mineralization in MC3T3-E1 cells. Artificial cells, nanomedicine, and biotechnology 21 31448639
2017 Rho kinase-dependent desensitization of GPR39; a unique mechanism of GPCR downregulation. Biochemical pharmacology 21 28619258
2016 The role of the obestatin/GPR39 system in human gastric adenocarcinomas. Oncotarget 21 26716511
2015 Novel Zn2+ Modulated GPR39 Receptor Agonists Do Not Drive Acute Insulin Secretion in Rodents. PloS one 21 26720709
2021 GPR39 promotes cardiac hypertrophy by regulating the AMPK-mTOR pathway and protein synthesis. Cell biology international 20 33554444
2021 GPR39 localization in the aging human brain and correlation of expression and polymorphism with vascular cognitive impairment. Alzheimer's & dementia (New York, N. Y.) 20 34692987
2019 The protective effects of the GPR39 agonist TC-G 1008 against TNF-α-induced inflammation in human fibroblast-like synoviocytes (FLSs). European journal of pharmacology 20 31539553
2022 Inhibition of GPR39 restores defects in endothelial cell-mediated neovascularization under the duress of chronic hyperglycemia: Evidence for regulatory roles of the sonic hedgehog signaling axis. Proceedings of the National Academy of Sciences of the United States of America 19 36574661
2019 Modulation of Gpr39, a G-protein coupled receptor associated with alcohol use in non-human primates, curbs ethanol intake in mice. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 19 30610192
2018 Enhanced ZnR/GPR39 Activity in Breast Cancer, an Alternative Trigger of Signaling Leading to Cell Growth. Scientific reports 18 29802348
2024 Bone-marrow macrophage-derived GPNMB protein binds to orphan receptor GPR39 and plays a critical role in cardiac repair. Nature cardiovascular research 17 39455836
2021 Selective release of gastrointestinal hormones induced by an orally active GPR39 agonist. Molecular metabolism 17 33711555
2019 ZnR/GPR39 upregulation of K+/Cl--cotransporter 3 in tamoxifen resistant breast cancer cells. Cell calcium 17 31146164
2015 GPR39 receptors and actions of trace metals on pancreatic beta cell function and glucose homoeostasis. Acta diabetologica 17 26112416
2013 Chemical Probe Identification Platform for Orphan GPCRs Using Focused Compound Screening: GPR39 as a Case Example. ACS medicinal chemistry letters 17 24900608
2019 Zn2+ stimulates salivary secretions via metabotropic zinc receptor ZnR/GPR39 in human salivary gland cells. Scientific reports 16 31776425
2014 Protein kinase inhibitor β enhances the constitutive activity of G-protein-coupled zinc receptor GPR39. The Biochemical journal 15 24869658
2021 miR-182 mediated the inhibitory effects of NF-κB on the GPR39/CREB/BDNF pathway in the hippocampus of mice with depressive-like behaviors. Behavioural brain research 14 34743948
2016 Changes in obestatin gene and GPR39 receptor expression in peripheral tissues of rat models of obesity, type 1 and type 2 diabetes. Journal of diabetes 14 27106635
2024 GPR39 Agonist TC-G 1008 Promoted Mitochondrial Biogenesis and Improved Antioxidative Capability via CREB/PGC-1α Pathway Following Intracerebral Hemorrhage in Mice. Translational stroke research 13 38485864
2022 GPR39 Knockout Worsens Microcirculatory Response to Experimental Stroke in a Sex-Dependent Manner. Translational stroke research 13 36181628
2019 Agonism of GPR39 displays protective effects against advanced glycation end-product (AGE)-induced degradation of extracellular matrix in human SW1353 cells. Archives of biochemistry and biophysics 13 31678046
2015 Immune malfunction in the GPR39 zinc receptor of knockout mice: Its relationship to depressive disorder. Journal of neuroimmunology 13 26857489
2011 Administration of antisense DNA for GPR39-1b causes anxiolytic-like responses and appetite loss in rats. Neuroscience research 13 22192464
2006 Molecular characterization of sequence and expression of chicken GPR39. General and comparative endocrinology 13 17239877
2017 Zac1/GPR39 phosphorylating CaMK-II contributes to the distinct roles of Pax3 and Pax7 in myogenic progression. Biochimica et biophysica acta. Molecular basis of disease 12 29079520
2024 ZnR/GPR39 regulates hepatic insulin signaling, tunes liver bioenergetics and ROS production, and mitigates liver fibrosis and injury. Redox biology 11 39514940