Affinage

GPR39

G-protein coupled receptor 39 · UniProt O43194

Length
453 aa
Mass
51.3 kDa
Annotated
2026-06-10
100 papers in source corpus 39 papers cited in narrative 39 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GPR39 is a multifunctional zinc-sensing G-protein-coupled receptor that couples extracellular Zn2+ fluctuations to ion transport, cell survival, proliferation, and tissue repair across epithelial, neuronal, vascular, and immune contexts (PMID:16959833, PMID:17885920, PMID:20522546). Zn2+ was identified as its endogenous agonist by biochemical purification from serum, acting through His17/His19 in the N-terminal extracellular domain rather than the classical transmembrane pocket, with Asp313 in extracellular loop 3 serving as both a constitutive-activity modulator and an extracellular pH sensor (PMID:17885920, PMID:18588883, PMID:22879599). Receptor output is tuned by structural and protein partners: a conserved Cys108–Cys210 disulfide is required for agonist-induced signaling while a non-conserved Cys11–Cys191 bridge dampens activation, and constitutive Gα13/RhoA/SRF signaling drives PEDF secretion and cytoprotection against oxidative and ER stress (PMID:18693759, PMID:18180304). Ligand-evoked signaling proceeds chiefly through Gαq/PLC to Ca2+/ERK1/2/AKT, with additional cAMP, AMPK, and mTOR/S6K1 branches (PMID:17885920, PMID:24967969, PMID:30459126, PMID:33554444). Through these pathways GPR39 regulates ion transporters—upregulating NHE in keratinocytes, colonocytes, and neurons, KCC2 in hippocampal neurons, KCC1 and KCC3 in colon and breast cancer cells—and controls epithelial tight-junction integrity, barrier function, and proliferation in the intestine (PMID:20522546, PMID:21900570, PMID:22545109, PMID:26375174, PMID:28093242, PMID:31146164, PMID:24967969, PMID:27377730, PMID:28515165). In the nervous system, synaptic Zn2+-driven KCC2 upregulation provides homeostatic protection against seizures, and a G-protein-independent GPR39–glycine-receptor complex maintains glycinergic inhibition in spinal interneurons to restrain inflammatory pain (PMID:25562657, PMID:38306424). Physiologically GPR39 also promotes intestinal GLP-1 secretion via Gαq and Gαi/o, gastric somatostatin secretion, thymic endothelial BMP4 production, pericyte-mediated microvascular tone, and osteoblast collagen processing (PMID:33711555, PMID:28045522, PMID:35357432, PMID:34623177, PMID:29295862). Beyond Zn2+, GPR39 functions as a receptor for 3-O-sulfated bile acids, mediating bile acid-induced Ca2+ signaling and pancreatic acinar necrosis, and for the macrophage-derived protein GPNMB, through which it confers cardioprotection after myocardial infarction (PMID:38306436, PMID:39455836).

Mechanistic history

Synthesis pass · year-by-year structured walk · 37 steps
  1. 2006 High

    Establishing the endogenous agonist resolved what activates GPR39, ruling out the previously proposed peptide obestatin and identifying Zn2+ as a functional agonist that drives multiple second-messenger pathways.

    Evidence Cell-based IP turnover, cAMP, arrestin recruitment, and reporter assays plus radioligand binding in GPR39-transfected versus mock cells

    PMID:16959833 PMID:17054911

    Open questions at the time
    • Did not identify the physiological source of activating Zn2+
    • Did not map the Zn2+ binding site
  2. 2007 High

    Biochemical isolation of Zn2+ from serum and inhibitor dissection established that GPR39 is a bona fide zinc receptor coupling to Gαq–PLC, defining its core signaling logic.

    Evidence HPLC fractionation of FBS with ICP-MS identification and Ca2+ mobilization with U73122 and pertussis toxin

    PMID:17885920

    Open questions at the time
    • Did not address coupling to other G-protein classes
    • Did not localize the agonist binding residues
  3. 2008 High

    Mutagenesis and disulfide mapping defined the molecular architecture of zinc sensing—an N-terminal His17/His19 site distinct from the TM pocket, an Asp313 modulator of constitutive activity, and two disulfide bridges with opposing roles in activation.

    Evidence Site-directed and cysteine mutagenesis with TCEP reduction, sulfhydryl labeling, and IP production assays

    PMID:18588883 PMID:18693759

    Open questions at the time
    • No high-resolution structure of the zinc-bound receptor
    • Did not establish coordination geometry of bound Zn2+
  4. 2008 High

    Linking constitutive Gα13/RhoA/SRF signaling to PEDF secretion and cytoprotection revealed a ligand-independent survival function of GPR39.

    Evidence Overexpression, siRNA, transcriptome array, dominant-negative RhoA/SRF and RGS16 co-expression, conditioned-medium transfer, and PEDF ELISA

    PMID:18180304

    Open questions at the time
    • Did not test relevance in primary tissues
    • Mechanism of constitutive Gα13 engagement not structurally defined
  5. 2010 High

    Identifying GPR39 as the molecular ZnR in keratinocytes connected zinc sensing to physiological wound responses via MAPK, NHE1, and scratch closure.

    Evidence siRNA knockdown with Ca2+ imaging, MAPK and NHE1 assays, scratch-wound and Zn2+ imaging in HaCaT cells

    PMID:20522546

    Open questions at the time
    • Did not establish in vivo skin repair requirement
    • Source of injury-released Zn2+ not quantified
  6. 2011 High

    Reciprocal GPR39 and ZnT3 knockouts proved GPR39 is the neuronal metabotropic zinc receptor and that synaptic Zn2+ drives KCC2 upregulation, linking it to inhibitory transmission.

    Evidence GPR39 KO and ZnT3 KO mice with hippocampal electrophysiology, KCC2 surface biotinylation, and mossy fiber stimulation

    PMID:21900570

    Open questions at the time
    • Did not define the signaling cascade to KCC2 in this study
    • Did not address behavioral consequences
  7. 2011 Medium

    Metabolic phenotyping of GPR39 KO mice tied the receptor to diet-induced thermogenesis and adipose lipolytic signaling.

    Evidence GPR39 KO mice on high-fat diet with VO2 metabolic phenotyping and Western blots for HSL, ATGL, ERK1/2

    PMID:21784784

    Open questions at the time
    • Did not establish whether adipose effects are cell-autonomous
    • Ligand driving adipose signaling not identified
  8. 2012 High

    Demonstration in colonocytes that GPR39 drives NHE upregulation and clusterin-dependent survival, confirmed in KO colon tissue, extended its ZnR role to gut epithelium.

    Evidence siRNA, Ca2+ imaging, SNARF pH/NHE assays, GPR39 KO colon, and clusterin siRNA survival assays

    PMID:22545109

    Open questions at the time
    • Did not resolve upstream signaling to clusterin
    • Did not address barrier function directly
  9. 2012 High

    Identification of Asp313 as the extracellular pH sensor showed that GPR39 integrates local acidification with zinc sensing.

    Evidence Mutagenesis with Ca2+ imaging at varying pH and ERK1/2/AKT/NHE readouts

    PMID:22879599

    Open questions at the time
    • Did not establish physiological pH ranges where modulation matters
    • No structural basis for proton sensing
  10. 2014 High

    Defining ERK1/2/AKT/mTOR-p70S6K control of colonocyte proliferation, differentiation, and tight-junction proteins linked GPR39 to epithelial homeostasis and barrier integrity.

    Evidence siRNA in HT29/Caco-2, Western blots, alkaline phosphatase, TEER, tight-junction immunostaining, and GPR39 KO colon

    PMID:24967969

    Open questions at the time
    • Did not separate proliferation from differentiation signaling branches
    • In vivo barrier challenge not tested here
  11. 2014 Medium

    Y2H and functional assays identified PKIB as a C-terminal partner that biases GPR39 toward constitutive Gα13/SRE signaling and creates a zinc-triggered PKA feedback loop.

    Evidence Yeast-2-hybrid screen, co-expression of PKIB mutants, SRE-luciferase, PKA activity, and survival assays

    PMID:24869658

    Open questions at the time
    • Zinc-induced PKIB dissociation not shown by structural or direct binding method
    • Single lab, no in vivo confirmation
  12. 2014 Medium

    GPR39 was shown to functionally interact with CaSR to synergistically amplify Zn2+ Ca2+ responses, indicating cross-talk with another sensing receptor.

    Evidence CaSR siRNA and dominant-negative constructs, GPR39 overexpression, Ca2+ imaging, MAPK/PI3K and S100A4 readouts

    PMID:24264723

    Open questions at the time
    • Physical heterodimerization not directly demonstrated
    • In vivo relevance not established
  13. 2014 Medium

    An Hh-pathway screen placed GPR39 downstream of Smoothened as both necessary and sufficient for small-molecule modulation of Gli signaling, implicating it in developmental signaling.

    Evidence Phenotypic Hh screen, expression-activity correlation, RNAi knockdown, cDNA overexpression, and IP generation

    PMID:24633354

    Open questions at the time
    • Endogenous ligand for this function not defined
    • Mechanism linking GPR39 to Gli not resolved here
  14. 2015 High

    GPR39 KO seizure studies established that the zinc-KCC2 axis provides homeostatic protection against hyperexcitability through Gαq/PLC/ERK1/2.

    Evidence GPR39 KO mice, kainic acid seizures, gamma-oscillation recording, Zn2+ chelation, KCC2 biotinylation, and pathway inhibitors

    PMID:25562657

    Open questions at the time
    • Did not test therapeutic agonism in seizure models
    • Spatial dynamics of synaptic Zn2+ not quantified
  15. 2015 Medium

    Demonstration of GPR39 heteroreceptor complexes with 5-HT1A and GalR1 raised the possibility of zinc-modulated cross-receptor signaling.

    Evidence FRET, co-immunopurification, and signaling assays in heterocomplex-expressing cells with zinc modulation

    PMID:26365466

    Open questions at the time
    • Endogenous-tissue evidence absent
    • Functional output of trimeric complex incompletely defined
  16. 2015 Medium

    GPR39-driven NHE upregulation in neurons via ERK1/2 was shown to promote recovery from intracellular acidification, with acidosis itself attenuating receptor signaling.

    Evidence Intracellular pH imaging, ERK1/2 assays, and pharmacological/pH manipulation in hippocampal neurons

    PMID:26375174

    Open questions at the time
    • In vivo neuronal pH regulation not tested
    • Single lab
  17. 2015 Medium

    In myoblasts, obestatin/GPR39 signaling was linked to a temporally biased program: G-protein-driven proliferation early and β-arrestin/Src/EGFR transactivation driving differentiation later.

    Evidence Human myoblasts with obestatin stimulation, β-arrestin siRNA, Src/MMP inhibition, and cell-cycle/differentiation markers

    PMID:26211463

    Open questions at the time
    • Conflicts with reports that obestatin does not signal at GPR39
    • Single lab, not genetically validated
  18. 2016 Medium

    GPR39 KO colitis studies tied zinc-induced occludin expression to epithelial barrier protection and recovery from intestinal injury.

    Evidence GPR39 KO mice in DSS colitis with occludin Western blot, BrdU proliferation, TEER, and survival

    PMID:27377730

    Open questions at the time
    • Signaling cascade to occludin not fully resolved here
    • Single lab
  19. 2016 Medium

    Amyloid beta was shown to impair neuronal GPR39 signaling by sequestering Zn2+, providing a mechanistic link between zinc availability and disrupted ZnR signaling.

    Evidence Ca2+ imaging in SHSY-5Y and GPR39 WT/KO neurons, siRNA, Aβ treatment, and ERK1/clusterin readouts

    PMID:27501363

    Open questions at the time
    • In vivo disease relevance not established
    • Did not test rescue strategies beyond excess Zn2+
  20. 2017 Medium

    Discovery of a ROCK-dependent, β-arrestin/G-protein-independent desensitization and internalization mechanism distinguished GPR39 regulation from canonical GPCRs.

    Evidence cAMP, IP1, SRF-RE, β-arrestin recruitment, GFP-GPR39 internalization with Y-27632, and biased agonist comparison in HEK293

    PMID:28619258

    Open questions at the time
    • Molecular link from ROCK to receptor internalization unresolved
    • Not validated in native cells
  21. 2017 High

    GPR39 was shown to enhance colonic Cl- absorption through basolateral KCC1 and to counteract cholera-toxin-induced fluid secretion, an anti-secretory ion-transport role confirmed in KO mice.

    Evidence GPR39 KO mice, cholera toxin loop model, Caco-2 KCC activity, KCC1 localization, and Ussing chambers

    PMID:28093242

    Open questions at the time
    • Signaling pathway to KCC1 not dissected here
    • Human in vivo relevance untested
  22. 2017 Medium

    Synthetic agonists revealed GPR39 as a regulator of gastric somatostatin secretion, with zinc acting as an allosteric enhancer of some ligands.

    Evidence Homology-model virtual screening, signaling assays, and somatostatin measurement in GPR39 KO gastric tissue

    PMID:28045522

    Open questions at the time
    • Endogenous activating ligand in stomach not defined
    • Single lab
  23. 2017 Medium

    GPR39 was established as a Gαq-PLC-coupled receptor in endothelial cells promoting survival, adhesion, and tubulogenesis via cAMP, Akt, PDGFR-α, and VEGF-A.

    Evidence GPR39 siRNA and KO endothelial cells with Ca2+ imaging, cAMP, Akt, and tube-formation assays

    PMID:29351417

    Open questions at the time
    • In vivo angiogenic role not tested here
    • Conflicts with later anti-angiogenic findings
  24. 2017 Medium

    A GPR39→PKCζ→ZO-1 axis was defined that protects intestinal barrier integrity against Salmonella, linking zinc sensing to pathogen defense.

    Evidence Reciprocal GPR39 and PKCζ siRNA in Caco-2 with TEER, permeability, Western blots, and S. typhimurium infection

    PMID:28515165

    Open questions at the time
    • In vivo infection model not used
    • Single lab
  25. 2018 Medium

    Tight-junction assembly was shown to proceed via a GPR39–PLC–CaMKKβ–AMPK pathway, defining the kinase cascade underlying barrier formation.

    Evidence TC-G 1008 agonism in T84 cells with AMPK, PLC, and CaMKKβ inhibitors, TEER, and ZO-1 staining

    PMID:30459126

    Open questions at the time
    • In vivo confirmation absent
    • Single lab
  26. 2018 Medium

    GPR39 KO bone studies revealed a role in osteoblast collagen processing, with downregulation of zinc-dependent Zip13 and ADAMTS collagen-processing enzymes.

    Evidence GPR39 KO mice with FTIR bone spectroscopy, histomorphometry, in vitro osteoblast collagen assays, and Zip13/ADAMTS Western blots

    PMID:29295862

    Open questions at the time
    • Direct signaling link from GPR39 to ADAMTS/Zip13 not established
    • Single lab
  27. 2019 Medium

    A mast-cell ZnT2→Zn2+→GPR39→IL-6 axis from skin fibroblasts was shown to promote wound healing, integrating zinc release with cytokine-driven repair.

    Evidence ZnT2-deficient and GPR39 KO mice with wound healing assays and IL-6/cytokine profiling

    PMID:31346193

    Open questions at the time
    • Signaling pathway to IL-6 not dissected
    • Single lab
  28. 2019 Medium

    GPR39 was shown to upregulate KCC3 specifically to drive migration of tamoxifen-resistant breast cancer cells, extending its KCC-regulatory role to cancer.

    Evidence siRNA of GPR39 and KCC3/KCC4, SNARF transport assays, scratch-wound assay, and DIOA inhibitor

    PMID:31146164

    Open questions at the time
    • In vivo metastasis not tested
    • Mechanism of KCC3 selectivity unresolved
  29. 2020 Medium

    In oral squamous carcinoma, GPR39 was linked to YAP transcriptional activity through Gαq/11–RhoA, implicating it in tumor growth control.

    Evidence GPR39 overexpression/siRNA in OSCC cells with YAP assays, Gαq/11 and RhoA inhibitors, and in vitro/in vivo growth

    PMID:32325008

    Open questions at the time
    • Activating ligand in tumor context not defined
    • Single lab
  30. 2021 High

    BRET pathway analysis established that GPR39 agonism drives intestinal GLP-1 secretion via Gαq and Gαi/o (not Gαs) and regulates food intake in vivo.

    Evidence GPR39 KO mice, calorimetry, human/mouse organoids, GLP-1 assays, BRET G-protein biosensors, and Ussing chambers

    PMID:33711555

    Open questions at the time
    • Endogenous L-cell ligand not pinpointed
    • Did not resolve receptor desensitization in vivo
  31. 2021 Medium

    GPR39 was shown to drive cardiac hypertrophy by inhibiting AMPK and activating mTOR/S6K1-dependent protein synthesis, defining a pathological cardiac role.

    Evidence Adenoviral GPR39 overexpression, AAV9 knockdown, TAC model, AMPK/mTOR/S6K1 Western blots, and rapamycin rescue

    PMID:33554444

    Open questions at the time
    • Activating ligand in heart not identified
    • Single lab
  32. 2021 Medium

    GPR39-mediated pericyte contraction was identified as a cause of microvascular no-reflow after myocardial infarction, validated by KO and pharmacological inhibition.

    Evidence GPR39 KO mice, coronary occlusion/reperfusion, VC43 inhibitor, and capillary density/diameter histology

    PMID:34623177

    Open questions at the time
    • Downstream contractile signaling not dissected
    • Single lab
  33. 2021 Medium

    Thymocyte-released Zn2+ activating endothelial GPR39 to produce BMP4 was shown to promote post-transplant T-cell reconstitution, demonstrating a regenerative immune role.

    Evidence GPR39 KO mice, HCT model, lineage tracing, BMP4 and Zn2+ imaging, small-molecule agonist, and flow cytometry

    PMID:35357432

    Open questions at the time
    • BMP4 induction pathway not fully mapped
    • Single lab
  34. 2022 Medium

    GPR39 was shown to suppress endothelial angiogenesis by binding SUFU to inhibit GLI1, revealing a non-canonical Hh-linked physical-interaction mechanism.

    Evidence GPR39 overexpression/siRNA, KO aortic ECs, GPR39–SUFU co-IP, GLI1 assays, angiogenesis assays, and hind-limb ischemia model

    PMID:36574661

    Open questions at the time
    • Reconciliation with pro-survival endothelial role (28045522 era) unresolved
    • Single lab
  35. 2024 High

    Identification of GPR39 as a receptor for 3-O-sulfated bile acids expanded its ligand repertoire beyond zinc and linked it to bile acid-induced pancreatic acinar necrosis and pancreatitis.

    Evidence Cell-based sufficiency Ca2+ imaging, pancreatic acinar Ca2+/necrosis assays, and GPR39 KO acute pancreatitis model

    PMID:38306436

    Open questions at the time
    • Bile acid binding site relative to His17/His19 not mapped
    • Did not define downstream necrosis effectors
  36. 2024 High

    A G-protein-independent GPR39–glycine-receptor complex was shown to maintain spinal glycinergic inhibition and restrain inflammatory pain, defining a non-signaling scaffolding function.

    Evidence Immunostaining, GPR39–GlyR co-IP, SOM+ interneuron-targeted knockdown, electrophysiology, CFA pain behavior, and pharmacological agonism

    PMID:38306424

    Open questions at the time
    • Structural basis of GPR39–GlyR interaction not resolved
    • Relationship between this and canonical zinc signaling unclear
  37. 2024 High

    Macrophage-derived GPNMB was identified as a protein ligand for GPR39 mediating cardioprotection after myocardial infarction, adding a peptide/protein ligand modality.

    Evidence Lineage tracing, GPNMB and GPR39 KO mice, bone-marrow transplant, MI model, single-cell transcriptomics, viral GPNMB delivery, and co-IP

    PMID:39455836

    Open questions at the time
    • GPNMB binding interface on GPR39 not mapped
    • Downstream cardioprotective signaling pathway not fully defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single receptor integrates structurally diverse ligands (Zn2+, bile acids, GPNMB), switches between G-protein-dependent and G-protein-independent (scaffolding) modes, and selects among Gαq/Gαs/Gα12-13/Gαi-o outputs in different tissues remains unresolved.
  • No experimental structure of ligand-bound GPR39
  • Determinants of tissue-specific G-protein and effector selection unknown
  • Whether the multiple ligands share or use distinct binding sites unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0140299 molecular sensor activity 4 GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-382551 Transport of small molecules 4 R-HSA-112316 Neuronal System 3 R-HSA-8953897 Cellular responses to stimuli 3
Partners
CASRGALR1GLRA (GLYCINE RECEPTOR)GPNMBHTR1APKIBSUFU
Complex memberships
GPR39–glycine receptor (GlyR) complexGalR1–5-HT1A–GPR39 heteroreceptor complex

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 Zinc ions (Zn2+) are a functional agonist of GPR39, stimulating inositol phosphate turnover, cAMP production, arrestin mobilization, CRE-dependent and SRE-dependent transcriptional activity in GPR39-expressing cells. Obestatin showed no reproducible binding or signaling at GPR39. Functional cell-based signaling assays (IP turnover, cAMP, arrestin recruitment, reporter gene assays) in GPR39-transfected cells vs. mock-transfected controls; radioligand binding assays with iodinated obestatin Endocrinology High 16959833
2006 GPR39 can be activated by high concentrations of Zn2+, triggering a Ca2+ response via the phospholipase C pathway; obestatin did not activate GPR39 and did not affect Zn2+-induced responses. Luminescent cAMP reporter gene assay; fluorometric Ca2+ flux with promiscuous and chimeric G-proteins; Ca2+ imaging Biochemical and biophysical research communications High 17054911
2007 Zn2+ ion was isolated as the endogenous GPR39 agonist from fetal bovine serum. GPR39-mediated Ca2+ mobilization by Zn2+ is abolished by the PLC inhibitor U73122 but not by pertussis toxin, demonstrating Gαq–PLC pathway coupling. The Zn2+-sensing function is conserved across mouse and rat GPR39. HPLC fractionation of FBS; inductively coupled plasma mass spectrometry for agonist identification; Ca2+ mobilization assay with pharmacological inhibitors Journal of receptor and signal transduction research High 17885920
2008 The Zn2+ agonist binding site of GPR39 involves His17 and His19 in the N-terminal extracellular domain; combined Ala substitution of these residues eliminates Zn2+ stimulation. Ala substitution of the main transmembrane pocket residues did not reduce Zn2+ potency, indicating Zn2+ does not act via the classical TM binding pocket. Asp313 in extracellular loop 3 modulates constitutive signaling and Zn2+-induced activation—substitution greatly increases ligand-independent signaling and apparently eliminates Zn2+-induced activation. Site-directed mutagenesis of candidate metal-ion binding residues; inositol phosphate production assays in receptor-expressing cells FEBS letters High 18588883
2008 GPR39 contains two disulfide bridges: a conserved bridge (Cys108–Cys210) and a non-conserved bridge (Cys11–Cys191). Disruption of the conserved bridge reduces surface expression and abolishes agonist-induced IP production but enhances constitutive signaling. Disruption of the non-conserved bridge increases Zn2+ potency ~10-fold, indicating it dampens receptor activation by restricting access to the ligand binding pocket. Cysteine mutagenesis; treatment with reducing agent TCEP; labeling procedure for free sulfhydryl groups; inositol phosphate production assays Biochemistry High 18693759
2008 GPR39 constitutive activity signals through Gα13 and the RhoA–SRF pathway, leading to PEDF secretion. Overexpression of GPR39 protects cells against oxidative stress, ER stress, and caspase activation. Co-expression with RGS16 (inhibitor of Gα13), dominant-negative RhoA, or serum response factor abolished cell protection. Up-regulation of RGS16 was identified as downstream of constitutive GPR39 signaling. GPR39 overexpression and siRNA silencing; transcriptome array; co-expression with dominant-negative constructs and RGS16; SRE-luciferase reporter; conditioned medium transfer; PEDF ELISA; cell death assays The Journal of biological chemistry High 18180304
2010 GPR39 is the molecular identity of the zinc-sensing receptor ZnR in HaCaT keratinocytes. Extracellular Zn2+ triggers metabotropic Ca2+ responses that are abolished by GPR39 siRNA silencing. ZnR/GPR39 signaling activates MAP kinase, upregulates NHE1 activity, and promotes keratinocyte scratch closure in vitro. Zn2+ is also released following cellular injury. siRNA knockdown of GPR39; Ca2+ imaging; MAP kinase assay; NHE1 activity assay; scratch-wound closure assay; Zn2+ imaging with ZnAF-2 fluorescent probe The Journal of biological chemistry High 20522546
2011 Synaptic activation of mZnR/GPR39 by vesicular Zn2+ in hippocampal neurons enhances KCC2 surface expression and transport activity, producing a hyperpolarizing shift in the GABAA reversal potential. This effect is absent in GPR39 knockout mice, establishing GPR39 as the functional neuronal mZnR. Mossy fiber stimulation-dependent KCC2 upregulation requires synaptic Zn2+ (absent in ZnT3-deficient mice). GPR39 knockout mice; ZnT3 knockout mice; electrophysiology (GABAA reversal potential); KCC2 surface biotinylation; mossy fiber stimulation in hippocampal slices The Journal of neuroscience High 21900570
2011 GPR39 deficiency in high-fat diet mice leads to selective increase in fat mass, near-elimination of diet-induced thermogenesis, and decreased phosphorylation of hormone-sensitive lipase (HSL) and reduced adipose triglyceride lipase (ATGL) levels, as well as reduced ERK1/2 signaling in adipose tissue after food withdrawal. GPR39 knockout mice on high-fat diet; metabolic phenotyping (VO2 measurement); Western blot for HSL phosphorylation, ATGL, ERK1/2 FASEB journal Medium 21784784
2012 GPR39 mediates ZnR-dependent Ca2+ release and Zn2+-dependent survival of butyrate-treated HT29 colonocytes. ZnR/GPR39 activation upregulates Na+/H+ exchange activity; this NHE upregulation is also observed in native colon tissue from WT but not GPR39 knockout mice. GPR39 activation upregulates anti-apoptotic protein clusterin, which is required for Zn2+-dependent survival. GPR39 siRNA silencing; Ca2+ imaging; pH-sensitive dye (SNARF) for NHE activity; native colon tissue from GPR39 KO mice; clusterin siRNA; cell survival assays PloS one High 22545109
2012 Extracellular pH regulates ZnR/GPR39 activity through Asp313 in the extracellular domain. Asp313→Ala substitution abolishes pH sensitivity while preserving Zn2+-induced Ca2+ responses at both pH 7.4 and 6.5, identifying Asp313 as the extracellular pH sensor of GPR39. Site-directed mutagenesis of His and Asp residues; Ca2+ imaging at varying extracellular pH; ERK1/2 and AKT activation assays; NHE activity assay The Journal of biological chemistry High 22879599
2014 ZnR/GPR39 controls colonocyte proliferation and differentiation via ERK1/2, AKT, and mTOR/p70S6K signaling. ZnR/GPR39 silencing inhibited colonocyte proliferation without inducing apoptosis, impaired alkaline phosphatase activity (differentiation marker), and reduced tight junction proteins (occludin, ZO-1, E-cadherin) expression. GPR39 KO mouse colon showed reduced ZO-1 and occludin compared to WT. ZnR/GPR39 siRNA in HT29 and Caco-2 cells; Western blot for ERK1/2, AKT, mTOR/p70S6K; alkaline phosphatase assay; TEER measurement; immunostaining for tight junction proteins; GPR39 KO mouse colon analysis Cell death & disease High 24967969
2014 GPR39 activates Hh signaling pathway downstream of Smoothened via Gli transcription factors. Small-molecule CMAPs activate GPR39 (generating inositol phosphates), and GPR39 is both necessary (RNAi knockdown abolishes CMAP activity) and sufficient (cDNA overexpression restores activity) for CMAP-induced Hh pathway inhibition. Phenotypic Hh pathway screen; correlation of GPCR mRNA expression with compound activity across cell lines; siRNA knockdown; cDNA overexpression; IP generation assay Nature chemical biology Medium 24633354
2014 GPR39 interacts with the C-terminus-interacting protein PKIB (protein kinase A inhibitor β) as identified by yeast-2-hybrid screening. Co-expression of PKIB with GPR39 enhances constitutive (Gα13/SRE) but not ligand-mediated (Gαq/cAMP) cell protection. Zinc causes dissociation of PKIB from GPR39, which liberates PKIB to inhibit PKA, creating a negative-feedback loop on Gs pathway activation. Yeast-2-hybrid (Y2H) screen with GPR39 C-terminus; co-expression of GPR39 and PKIB mutants; SRE-luciferase reporter; PKA activity assay; cell survival assays The Biochemical journal Medium 24869658
2014 ZnR/GPR39 interacts with the Ca2+-sensing receptor (CaSR) to synergistically enhance Ca2+ responses in prostate (PC3) and salivary (HSY) cells. CaSR silencing reduces Zn2+-dependent signaling, and CaSR agonist (spermine, sub-threshold) potentiates ZnR/GPR39 Ca2+ responses. ZnR/GPR39 mediates Zn2+-dependent MAPK and PI3K activation and upregulates S100A4 in PC3 cells. siRNA knockdown of CaSR; dominant-negative CaSR construct; GPR39 overexpression in HEK293 cells; Ca2+ imaging; MAPK and PI3K assays; S100A4 expression analysis Journal of cellular physiology Medium 24264723
2015 mZnR/GPR39-mediated KCC2 upregulation provides homeostatic adaptation to kainate-induced seizures in the hippocampus, requiring Gαq/PLC/ERK1/2 signaling. GPR39 KO mice show dramatically enhanced seizure susceptibility. Kainate-induced synaptic Zn2+ release upregulates KCC2 surface expression and activity in WT but not GPR39 KO neurons. GPR39 KO mice; kainic acid seizure induction; gamma oscillation recording in hippocampal slices; Zn2+ chelation; KCC2 surface biotinylation; ERK1/2 phosphorylation assay; pharmacological inhibitors of Gαq/PLC/ERK pathways Neurobiology of disease High 25562657
2015 GPR39 forms heteroreceptor complexes with 5-HT1A and GalR1. FRET and co-immunopurification show that GPR39 and 5-HT1A interact, and that GalR1–5-HT1A–GPR39 trimeric complexes form. Zinc modulates formation of these heteroreceptor complexes. GPR39–5-HT1A heterocomplex shows additive signaling compared to monomers; the trimeric GalR1–5-HT1A–GPR39 complex displays a different signaling profile. FRET; co-immunopurification; signaling assays on heterocomplex-expressing cells; modulation by zinc Biochimica et biophysica acta Medium 26365466
2015 mZnR/GPR39 activation upregulates Na+/H+ exchanger (NHE) activity in hippocampal neurons via an ERK1/2-dependent mechanism, promoting recovery from intracellular acidification. Reduced extracellular pH (acidosis) attenuates mZnR/GPR39 signaling and abolishes Zn2+-dependent ERK1/2 phosphorylation and NHE upregulation. Hippocampal neuron culture; intracellular pH imaging; ERK1/2 phosphorylation assay; pharmacological inhibition; pH manipulation experiments Journal of neurochemistry Medium 26375174
2016 Amyloid beta (Aβ) attenuates Zn2+-dependent Ca2+ signaling via mZnR/GPR39 in neurons by binding Zn2+ (reducing available Zn2+ for receptor activation). This impairment is rescued by excess Zn2+. Aβ also abolishes mZnR/GPR39-dependent ERK1/2 phosphorylation and clusterin upregulation but not Zn2+-dependent AKT phosphorylation (which is not GPR39-mediated). Ca2+ imaging in SHSY-5Y cells and GPR39 WT vs. KO cortical neurons; GPR39 siRNA silencing; Aβ treatment (acute and chronic); ERK1/2 and AKT phosphorylation assays; clusterin expression analysis Journal of neurochemistry Medium 27501363
2017 GPR39 desensitization occurs via a unique Rho kinase (ROCK)-dependent mechanism. GPR39 agonist (GPR39-C3) induces functional desensitization and internalization of GFP-tagged GPR39; both effects are blocked by ROCK inhibitor Y-27632 but not by Gq/Gs pathway inhibitors or β-arrestin recruitment inhibition. A biased PAM (GSB-118) activating cAMP and β-arrestin but not G12/13–SRF did not cause desensitization. GPR39-expressing HEK293 cells; cAMP assay; IP1 accumulation; SRF-RE reporter; β-arrestin recruitment; GFP-GPR39 internalization assay; ROCK inhibitor Y-27632; biased agonist comparison Biochemical pharmacology Medium 28619258
2017 ZnR/GPR39 enhances Cl- absorption in colonocytes by upregulating basolateral KCC1 activity. In WT mice, Zn2+ acting via ZnR/GPR39 reduces cholera toxin-induced intestinal fluid secretion; this effect is absent in ZnR/GPR39 KO mice or without dietary Zn2+. KCC1 is expressed basolaterally in mouse and human colonocytes. GPR39 KO mice; cholera toxin intestinal loop model; Caco-2 cells; K+/Cl- cotransporter activity assay; basolateral KCC1 localization (immunostaining); Ussing chamber ion transport measurements Biochimica et biophysica acta. Molecular basis of disease High 28093242
2017 Small-molecule GPR39 agonists (identified by homology model-based screening) reveal GPR39 as a novel regulator of gastric somatostatin secretion. Zn2+ acts as an allosteric enhancer for some synthetic ligands. Homology model-based virtual screening; in vitro signaling assays; GPR39 KO mouse gastric tissue; somatostatin secretion measurement Journal of medicinal chemistry Medium 28045522
2018 ZnR/GPR39-dependent tight junction assembly in intestinal epithelial cells is mediated via the PLC–CaMKKβ–AMPK pathway. GPR39 agonist TC-G 1008 induces AMPK activation in a time- and concentration-dependent manner; PLC and CaMKKβ inhibitors block TC-G 1008-induced AMPK activation and tight junction assembly. T84 intestinal epithelial cells; GPR39 agonist TC-G 1008; AMPK inhibitor compound C; PLC and CaMKKβ inhibitors; TEER measurement; Western blot for AMPK; ZO-1 immunostaining European journal of pharmacology Medium 30459126
2019 ZnT2 in mast cells is required for Zn2+ granule release. Released Zn2+ induces IL-6 production from skin fibroblasts via GPR39 signaling, promoting wound healing. Wound healing is impaired in mice lacking IL-6 or GPR39. ZnT2-deficient and GPR39 KO mice; wound healing assays; IL-6 measurement; cytokine profiling Scientific reports Medium 31346193
2019 ZnR/GPR39 upregulates KCC3 (not KCC4) activity in tamoxifen-resistant breast cancer cells, promoting K+/Cl- co-transport, accelerating scratch closure. Silencing ZnR/GPR39 or KCC3 abolishes Zn2+-dependent scratch closure. siRNA knockdown of GPR39 and KCC3/KCC4; intracellular pH assay (SNARF) for NH4+/K+/Cl- transport; scratch-wound assay; DIOA inhibitor Cell calcium Medium 31146164
2020 GPR39 overexpression in OSCC regulates YAP transcriptional coactivator activity through a Gαq/11–RhoA-dependent signaling pathway. Inhibition of GPR39 results in YAP-sustained OSCC growth inhibition. GPR39 overexpression and siRNA in OSCC cells; YAP activity assays; Gαq/11 and RhoA inhibitors; in vitro and in vivo tumor growth assays Journal of dental research Medium 32325008
2021 GPR39-mediated pericyte contraction during reduced coronary perfusion pressure causes capillary constriction resulting in 'no reflow' after AMI. No-reflow zones and infarct sizes are significantly smaller in GPR39 KO mice and in mice treated with GPR39 inhibitor VC43. GPR39 KO and VC43-treated mice show greater capillary density and larger capillary diameter at pericyte locations. 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 GPR39 promotes cardiac hypertrophy by inhibiting AMPK, leading to mTOR and S6K1 activation and enhanced de novo protein synthesis. GPR39 overexpression promotes angiotensin II-induced hypertrophy in neonatal cardiomyocytes; AAV9-mediated GPR39 knockdown suppresses TAC-induced cardiac hypertrophy. Rapamycin (mTOR inhibitor) blocks GPR39-induced protein synthesis and cardiac hypertrophy. Adenovirus-mediated GPR39 overexpression; AAV9-mediated GPR39 knockdown; TAC model; AMPK/mTOR/S6K1 Western blot; protein synthesis assay; rapamycin treatment Cell biology international Medium 33554444
2021 Activation of GPR39 in thymic endothelial cells by extracellular Zn2+ released from thymocytes promotes T-cell reconstitution after HCT by stimulating endothelial BMP4 production. Direct targeting of GPR39 with a small-molecule agonist enhanced thymic function without prior Zn2+ accumulation. GPR39 KO mice; hematopoietic cell transplant model; lineage tracing; BMP4 measurement; Zn2+ imaging; small-molecule GPR39 agonist; flow cytometry for thymic emigrants Blood Medium 35357432
2021 GPR39 agonist TC-G 1008 promotes GLP-1 secretion from intestinal L cells via Gαq and Gαi/o signaling pathways (not Gαs), demonstrated using BRET biosensors in organoids. GPR39 agonism reduces food intake and promotes weight loss in HFD mice. GPR39 KO mice show increased food intake without altered energy expenditure. GPR39 KO mice; calorimetric cages; intestinal organoids from mouse and human; GLP-1 secretion assay; BRET G-protein activation biosensors; Ussing chambers for ion transport Molecular metabolism High 33711555
2022 GPR39 suppresses endothelial cell angiogenesis by binding the SHH pathway inhibitor SUFU, thereby suppressing GLI1 activation and EC migration. GPR39 overexpression attenuates EC proliferation, migration, and tube formation; GPR39 KO ECs show enhanced migration and proliferation. Co-immunoprecipitation revealed direct GPR39–SUFU binding. GPR39 overexpression (adenovirus) and siRNA knockdown; GPR39 KO mouse aortic ECs; co-immunoprecipitation of GPR39 and SUFU; GLI1 activity assay; EC proliferation, migration, tube formation assays; hind limb ischemia model in GPR39 KO DIO mice Proceedings of the National Academy of Sciences Medium 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 BA-induced Ca2+ elevation and necrosis in pancreatic acinar cells. BA-induced acute pancreatitis is significantly reduced in GPR39 KO mice. GPR39 expression in cultured cell lines; Ca2+ imaging with bile acid stimulation; pancreatic acinar cell Ca2+ and necrosis assays; GPR39 KO mouse AP model Science advances High 38306436
2024 GPR39 in spinal cord SOM+ inhibitory interneurons complexes specifically with glycine receptors (GlyRs) and maintains glycinergic transmission independently of G protein signaling. Targeted knockdown of GPR39 in SOM+ interneurons reduces glycinergic inhibition, facilitates excitatory output to spinoparabrachial neurons, and exacerbates inflammatory mechanical pain. Pharmacological GPR39 activation or augmenting GPR39–GlyR interaction at the spinal level alleviates pain. GPR39 localization in SOM+ interneurons (immunostaining); co-immunoprecipitation of GPR39 and GlyR; targeted GPR39 knockdown in SOM+ cells; electrophysiology (glycinergic transmission); behavioral pain assays (CFA model); pharmacological GPR39 agonism Science advances High 38306424
2024 Bone-marrow macrophage-derived GPNMB is a ligand for GPR39. GPNMB is elevated in failing hearts after MI; GPNMB deficiency worsens cardiac outcome while viral GPNMB delivery improves heart function. GPR39 KO mice negate the beneficial effects of GPNMB, establishing GPR39 as the receptor mediating GPNMB's cardioprotective signaling. Lineage tracing; bone-marrow transplantation; GPNMB KO and GPR39 KO mice; MI model; single-cell transcriptomics; viral GPNMB delivery; co-immunoprecipitation (to identify GPR39 as GPNMB receptor) Nature cardiovascular research High 39455836
2015 In skeletal myoblasts, obestatin/GPR39 signaling drives myoblast proliferation via ERK1/2 and JunD through a G-protein-dependent mechanism. At later myogenic stages, β-arrestin 1 and 2 are recruited to the GPR39 membrane complex, activate Src, and transactivate EGFR via matrix metalloproteinases, regulating cell cycle exit (via p21, p57) and differentiation via JNK/c-Jun, CAMKII, Akt, and p38. Human myoblast cells; obestatin stimulation; siRNA for β-arrestin 1 and 2; Src inhibition; MMP inhibition; EGFR signaling assays; cell cycle and differentiation markers (p21, p57, myogenin) Cellular and molecular life sciences Medium 26211463
2018 GPR39 expression is required for normal bone matrix deposition by osteoblasts. GPR39 KO mice have higher mineral-to-matrix ratios, abnormally high numbers of active osteoblasts, and perturbed collagen synthesis and deposition. GPR39 KO osteoblasts in vitro show disorganized matrix with low collagen and high mineral. Expression of zinc transporter Zip13 and ADAMTS metalloproteases (zinc-dependent collagen-processing enzymes) is downregulated in GPR39 KO osteoblasts. GPR39 KO mice; FTIR spectroscopy of bone; histomorphometry; in vitro osteoblast culture; collagen assays; Zip13 and ADAMTS expression by Western blot FASEB journal Medium 29295862
2016 ZnR/GPR39 signaling triggers intracellular Ca2+ signaling in colonocytes, inducing occludin expression. ZnR/GPR39 KO mice show increased susceptibility to DSS-induced colitis with low occludin expression and impaired epithelial barrier; WT mice recover faster from DSS insult with enhanced epithelial cell proliferation and occludin expression. GPR39 KO mice; DSS colitis model; occludin expression (Western blot); epithelial cell proliferation (BrdU); TEER; survival analysis Philosophical transactions of the Royal Society of London. Series B Medium 27377730
2017 GPR39 in endothelial cells signals through Gαq–PLC pathways; siRNA knockdown of GPR39 abolishes Zn2+-triggered Ca2+ responses and downstream Gαq-PLC signaling. Extracellular Zn2+ via ZnR/GPR39 promotes vascular cell survival/growth through cAMP, Akt, PDGFR-α, and VEGF-A activation; enhances cell adhesion, tubule formation, and cytoskeletal reorganization; and regulates inflammatory and vascular tone molecules. GPR39 siRNA in endothelial cells; Ca2+ imaging; cAMP assay; Akt phosphorylation; tube formation assay; GPR39 KO endothelial cells American journal of physiology. Cell physiology Medium 29351417
2019 GPR39 activation by zinc upregulates PKCζ expression, which in turn enhances ZO-1 abundance and protects intestinal barrier integrity against S. typhimurium. siRNA silencing of GPR39 decreases zinc-activated PKCζ and blocks zinc's promotion of epithelial integrity; silencing PKCζ counteracts zinc's protective effect but does not inhibit GPR39 expression, establishing a GPR39→PKCζ→ZO-1 axis. siRNA knockdown of GPR39 and PKCζ in Caco-2 cells; TEER; permeability assay; Western blot for ZO-1, occludin, GPR39, PKCζ; S. typhimurium infection model The Journal of nutrition Medium 28515165

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 347 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 241 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
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 98 20522546
2006 GPR39 receptor expression in the mouse brain. Neuroreport 98 16708020
2018 The Zinc Sensing Receptor, ZnR/GPR39, in Health and Disease. International journal of molecular sciences 90 29389900
2017 Zinc regulates vascular endothelial cell activity through zinc-sensing receptor ZnR/GPR39. American journal of physiology. Cell physiology 84 29351417
2007 Isolation of Zn2+ as an endogenous agonist of GPR39 from fetal bovine serum. Journal of receptor and signal transduction research 83 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.) 79 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 52 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 47 30459126
2016 Discovery and Characterization of Novel GPR39 Agonists Allosterically Modulated by Zinc. Molecular pharmacology 46 27754899
2020 GPR39 protects against corticosterone-induced neuronal injury in hippocampal cells through the CREB-BDNF signaling pathway. Journal of affective disorders 45 32553391
2021 Zinc ameliorates human aortic valve calcification through GPR39 mediated ERK1/2 signalling pathway. Cardiovascular research 44 32259211
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 43 34645465
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
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 43 21784784
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
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 41 34623177
2019 Mast cells play role in wound healing through the ZnT2/GPR39/IL-6 axis. Scientific reports 41 31346193
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
2014 Discovery of 2-Pyridylpyrimidines as the First Orally Bioavailable GPR39 Agonists. ACS medicinal chemistry letters 41 25313322
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 40 33918078
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 38 28515165
2012 GI functions of GPR39: novel biology. Current opinion in pharmacology 37 22884904
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 36 31551684
2016 A possible significant role of zinc and GPR39 zinc sensing receptor in Alzheimer disease and epilepsy. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 36 27044837
2016 Potential antidepressant-like properties of the TC G-1008, a GPR39 (zinc receptor) agonist. Journal of affective disorders 36 27235821
2020 GPR39 Overexpression in OSCC Promotes YAP-Sustained Malignant Progression. Journal of dental research 35 32325008
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
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 33 28045522
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
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
2021 Role of GPR39 in Neurovascular Homeostasis and Disease. International journal of molecular sciences 27 34360964
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 27 32504391
2018 Long-lasting antidepressant-like activity of the GPR39 zinc receptor agonist TC-G 1008. Journal of affective disorders 27 30419533
2020 Zinc-mediated Neurotransmission in Alzheimer's Disease: A Potential Role of the GPR39 in Dementia. Current neuropharmacology 26 31272355
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
2015 GPR39 marks specific cells within the sebaceous gland and contributes to skin wound healing. Scientific reports 25 25604641
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
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
2017 Rho kinase-dependent desensitization of GPR39; a unique mechanism of GPCR downregulation. Biochemical pharmacology 23 28619258
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
2024 Discoveries of GPR39 as an evolutionarily conserved receptor for bile acids and of its involvement in biliary acute pancreatitis. Science advances 22 38306436
2021 Interaction between zinc, the GPR39 zinc receptor and the serotonergic system in depression. Brain research bulletin 22 33549699
2019 GPR39 agonist TC-G 1008 promotes osteoblast differentiation and mineralization in MC3T3-E1 cells. Artificial cells, nanomedicine, and biotechnology 22 31448639
2012 Extracellular pH regulates zinc signaling via an Asp residue of the zinc-sensing receptor (ZnR/GPR39). The Journal of biological chemistry 22 22879599
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 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 20 30610192
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
2024 Bone-marrow macrophage-derived GPNMB protein binds to orphan receptor GPR39 and plays a critical role in cardiac repair. Nature cardiovascular research 18 39455836
2021 Selective release of gastrointestinal hormones induced by an orally active GPR39 agonist. Molecular metabolism 18 33711555
2018 Enhanced ZnR/GPR39 Activity in Breast Cancer, an Alternative Trigger of Signaling Leading to Cell Growth. Scientific reports 18 29802348
2013 Chemical Probe Identification Platform for Orphan GPCRs Using Focused Compound Screening: GPR39 as a Case Example. ACS medicinal chemistry letters 18 24900608
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
2019 Zn2+ stimulates salivary secretions via metabotropic zinc receptor ZnR/GPR39 in human salivary gland cells. Scientific reports 16 31776425
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 15 34743948
2014 Protein kinase inhibitor β enhances the constitutive activity of G-protein-coupled zinc receptor GPR39. The Biochemical journal 15 24869658
2022 GPR39 Knockout Worsens Microcirculatory Response to Experimental Stroke in a Sex-Dependent Manner. Translational stroke research 14 36181628
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 regulated spinal glycinergic inhibition and mechanical inflammatory pain. Science advances 13 38306424
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
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

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