Affinage

GPR34

Probable G-protein coupled receptor 34 · UniProt Q9UPC5

Length
381 aa
Mass
43.9 kDa
Annotated
2026-06-10
47 papers in source corpus 27 papers cited in narrative 27 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GPR34 is a Gi-coupled G-protein-coupled receptor that functions as a sensor for lysophosphatidylserine (LysoPS), enabling innate immune and microglial cells to detect dying cells and tissue damage (PMID:22343749, PMID:34107271). It selectively recognizes the 2-acyl form of LysoPS generated by PS-specific phospholipase A1: replacement of the serine head group abolishes activity and 2-acyl-LysoPS is more potent than the 1-acyl species (PMID:22343749). Cryo-EM structures of the active GPR34-Gi complex show that the charged serine head group is read out by a polar residue cluster in TM3/TM6/TM7 while the acyl tail enters an L-shaped hydrophobic groove through a laterally open pocket that permits membrane-lateral ligand entry, and a competitive antagonist (YL-365) occupies part of this orthosteric site (PMID:37733739, PMID:38326347, PMID:38048360). Ligand engagement drives Gi signaling through PI3K-AKT and ERK, and through ERK/NF-κB, to control downstream effector programs (PMID:34107271, PMID:39030423, PMID:37557947). GPR34 is enriched in microglia and other myeloid and innate lymphoid cells, where it promotes phagocytosis of apoptotic cells and myelin debris, maintains microglial homeostasis, and tunes pro-inflammatory cytokine output [PMID:25142016, PMID:39030423, PMID:bio_10.1101_2025.03.28.646038]. Through this damage-sensing role it acts across contexts: it drives microglia-dependent neuropathic pain and demyelinating neuroinflammation, supports ILC3-mediated tissue repair via IL-22, and serves as a metabolic immune checkpoint that restrains ILC1 and CD8 T cell antitumor responses (PMID:34107271, PMID:30975169, PMID:39358444, PMID:39030423, PMID:42045172). In MALT lymphoma, a t(X;14) translocation deregulates GPR34 under IGH control and C-terminal truncation mutations remove the β-arrestin phosphorylation motif, delaying receptor internalization and enhancing constitutive signaling through CRE, AP1, and NF-κB to increase proliferation and transformation (PMID:22966169, PMID:34086889).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2012 High

    Established the endogenous ligand and signaling output of an orphan receptor by showing GPR34 responds to LysoPS with strict sn-2 acyl positional selectivity.

    Evidence Ca2+, AP-TGFα release and migration assays in HEK293/CHO with synthetic LysoPS analogues and catalytically inactive PS-PLA1 controls

    PMID:22343749

    Open questions at the time
    • Does not resolve the in vivo cellular source of 2-acyl-LysoPS
    • G-protein coupling specificity tested using a Gαq/Gαi1 chimera rather than native Gi
  2. 2012 Medium

    Probed why LysoPS responsiveness varies across orthologues, mapping ECL2 and TM5 residues that gate lipid activation.

    Evidence Chimeric receptor and site-directed mutagenesis across vertebrate orthologues with functional assays and an ATP-derived antagonist

    PMID:22348703

    Open questions at the time
    • Conclusion of weak human GPR34 LysoPS activity partially conflicts with other studies
    • Physiological relevance of fish-specific responsiveness unclear
  3. 2010 High

    First demonstrated a physiological function for GPR34, linking it to cellular immune responses and host defense.

    Evidence GPR34 knockout mice subjected to immunization, delayed-type hypersensitivity, and Cryptococcus infection with cytokine measurement

    PMID:21097509

    Open questions at the time
    • Did not identify the ligand source or signaling pathway in vivo
    • Cell-type responsible for phenotypes not dissected
  4. 2014 High

    Connected GPR34 to microglial phagocytosis, identifying its homeostatic role in clearing debris in the CNS.

    Evidence GPR34 KO mouse microglia analyzed by RNA-seq, morphology, and phagocytosis assays in retina and cortical slices

    PMID:25142016

    Open questions at the time
    • No microglial motility defect detected
    • Ligand driving phagocytosis not defined in this study
  5. 2021 High

    Defined GPR34 as a damage-sensing receptor on ILC3s detecting LysoPS from apoptotic neutrophils to drive tissue repair, and pinned the downstream pathway.

    Evidence ILC3-specific conditional KO, neutrophil-ILC3 co-culture, metabolomics, and PI3K-AKT/ERK inhibition in injury models

    PMID:34107271

    Open questions at the time
    • LysoPS-generating enzyme in this context not specified
    • Receptor desensitization dynamics in ILC3s not addressed
  6. 2019 High

    Placed GPR34 upstream of pro-inflammatory microglial activation in neuropathic pain, validated pharmacologically.

    Evidence GPR34 KO mice, von Frey behavior, cytokine qRT-PCR, LC-MS/MS LysoPS quantification, and intrathecal antagonist

    PMID:30975169

    Open questions at the time
    • Source of injury-induced LysoPS in dorsal horn not identified
    • Direct receptor-cytokine signaling steps not delineated
  7. 2023 High

    Resolved the structural basis of lipid recognition and Gi coupling, explaining sn-2 selectivity and membrane-lateral ligand entry.

    Evidence Cryo-EM of active and inactive GPR34-Gi complexes with agonist and antagonist, MD simulations, and structure-activity validation (three independent structural studies)

    PMID:37733739 PMID:38048360 PMID:38326347

    Open questions at the time
    • Conformational transitions during activation not captured kinetically
    • Structural basis of β-arrestin/desensitization not addressed
  8. 2016 Medium

    Identified GPR34 as a pro-survival factor in dendritic cells and mapped a topogenic determinant required for correct folding and surface trafficking.

    Evidence GPR34 KO DC transcriptomics and caspase assays; mutagenesis of a tri-basic ICL1 motif with conformational-epitope and Golgi trafficking readouts

    PMID:26851221 PMID:27086875

    Open questions at the time
    • Link between trafficking signal and DC survival function not established
    • Pro-survival downstream effectors not identified
  9. 2012 Medium

    Established GPR34 deregulation as oncogenic in MALT lymphoma, with truncations removing the desensitization motif to enhance signaling.

    Evidence Translocation cloning and overexpression with phosphorylation and CRE/AP1/NF-κB reporters; isogenic Q340X truncation cell lines with internalization, apoptosis, and soft-agar transformation assays; exome sequencing of mutation clustering

    PMID:22966169 PMID:29674500 PMID:34086889

    Open questions at the time
    • Whether truncated receptors signal constitutively or only with enhanced ligand response not fully resolved
    • Exome mapping (idx 21) lacks direct functional validation of individual mutations
  10. 2024 Medium

    Defined GPR34 as a metabolic immune checkpoint, where tumor-derived LysoPS suppresses ILC1 and CD8 T cell antitumor activity.

    Evidence Conditional Gpr34 KO in ILC1s, Abhd16a KO in tumor cells, GPR34 antagonist treatment, and Lyz2-Cre macrophage KO with efferocytosis/MHC-I/CXCL16 readouts in tumor models

    PMID:39358444 PMID:42045172

    Open questions at the time
    • Relative contributions of ILC1 versus macrophage axes across tumor types unclear
    • Identity of dominant LysoPS synthase context-dependent (ABHD16A vs PLA1A)
  11. 2024 Medium

    Demonstrated GPR34-LysoPS signaling drives microglia-mediated neuroinflammation in demyelination and retinal pathology via PI3K-AKT/ERK effector arms.

    Evidence GPR34 KO and pharmacological inhibition with PI3K-AKT/ERK and NINJ1 pathway analysis in MS, stroke, and retinal neovascularization mouse models

    PMID:39030423 PMID:39468551

    Open questions at the time
    • NINJ1 placement downstream of GPR34 needs broader validation
    • Whether the same axis drives homeostatic versus pathological microglia not separated
  12. 2024 Medium

    Showed PLA1A-generated LysoPS is the specific ligand mediating GPR34-dependent cDC1 efferocytosis and B-cell positioning, refining the upstream enzymatic source.

    Evidence GPR34 KO and gain-of-function knock-in mice, PLA1A vs ABHD16A KO comparison, OT-I cross-presentation and ex vivo migration assays, stromal PLA1A conditional KO

    PMID:39412501 PMID:41212150

    Open questions at the time
    • Tissue/context determinants selecting PLA1A over ABHD16A as ligand source unresolved
    • Cell-type selectivity (cDC1 vs cDC2 vs macrophage) mechanism not fully explained
  13. 2025 Medium

    Implicated GPR34 in Alzheimer-context microglial biology, showing agonism enhances Aβ fibril uptake via cAMP reduction and TREM2 dependence, and that loss accelerates loss of homeostatic state.

    Evidence Selective agonist M1 with cAMP measurement and Gpr34 knockdown in hAPP mice; ERK/NF-κB knockdown/overexpression in BV-2; iPSC-derived microglia phagocytosis and DAM-state RNA-seq (preprint)

    PMID:37557947 PMID:41261421 PMID:bio_10.1101_2025.03.28.646038

    Open questions at the time
    • Mechanistic link between GPR34 and TREM2 signaling undefined
    • iPSC microglia findings are from a non-peer-reviewed preprint
    • Selectivity of GPR34 for myelin/fibrillar Aβ over other cargo not mechanistically explained
  14. 2025 Medium

    Identified post-translational stabilization of GPR34 by the deubiquitinase USP8, linking receptor abundance to ferroptosis and tumor progression.

    Evidence Co-IP identification of USP8 as a GPR34 DUB, USP8 overexpression rescue of GPR34 deletion, and DUB-IN-3 inhibitor treatment in anaplastic thyroid carcinoma

    PMID:40862294

    Open questions at the time
    • Ubiquitin ligase opposing USP8 not identified
    • Direct deubiquitination of GPR34 versus indirect effect not fully separated
    • Single-lab study
  15. 2005 Medium

    Characterized the GPR34 gene structure and translational start usage, establishing the protein's N-terminal boundaries.

    Evidence Genomic sequencing across vertebrates, reporter constructs, and combinatory start-codon mutagenesis

    PMID:16338117

    Open questions at the time
    • Functional consequence of N-terminal length variants on signaling not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How GPR34 distinguishes homeostatic debris clearance from pathological pro-inflammatory signaling, and how ligand source (PLA1A vs ABHD16A) and receptor desensitization are coordinated across tissues, remains unresolved.
  • No unified model linking ligand source, biased signaling, and outcome
  • Endogenous regulators of desensitization beyond β-arrestin motif not mapped in vivo

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 3 GO:0060089 molecular transducer activity 3 GO:0140299 molecular sensor activity 3
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-5357801 Programmed Cell Death 3
Partners
GNAI1USP8

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 GPR34 is a functional receptor for lysophosphatidylserine (LysoPS), specifically recognizing LysoPS with a fatty acid at the sn-2 position. In HEK293 cells expressing GPR34 with a Gαq/Gαi1 chimera, LysoPS elevated intracellular Ca2+ levels, stimulated AP-TGFα release, and induced CHO-K1 cell migration. Replacement of the serine head group abolished reactivity, and 2-acyl-LysoPS (generated by PS-PLA1) was more potent than 1-acyl-LysoPS, confirming sn-2 positional selectivity. Intracellular Ca2+ assay, AP-TGFα release assay, cell migration assay, synthetic LysoPS analogues, catalytically inactive mutant PS-PLA1 controls Journal of biochemistry High 22343749
2023 Cryo-EM structure of human GPR34 bound to LysoPS (18:1) and Gi protein revealed that the negatively charged serine head group of LysoPS occupies a polar cavity formed by TM3, TM6, and TM7, while the hydrophobic acyl tail resides in a lateral open hydrophobic groove formed by TM3-5. A selective antagonist YL-365 binds competitively in a portion of the orthosteric pocket and induces allosteric changes in the receptor. Cryo-EM structure determination of active (agonist-bound) and inactive (antagonist-bound) GPR34 complexes; virtual screening; fusion protein design for inactive-state structure Proceedings of the National Academy of Sciences of the United States of America High 37733739
2024 Cryo-EM structures of human GPR34-Gi complex bound to S3E-LysoPS or the aromatic surrogate M1 showed a laterally open ligand-binding pocket allowing membrane-lateral entry of lipidic agonists. The serine amine and carboxylate groups are recognized by a charged residue cluster, and the acyl chain fits into an L-shaped hydrophobic pocket in the TM4-5 gap. Molecular dynamics simulations supported that 2-acyl LysoPS is the physiological ligand due to its regioselectivity. Cryo-EM structure determination, molecular dynamics simulations, structure-activity validation with synthetic analogues Nature communications High 38326347
2023 Cryo-EM structures of human GPR34 and GPR174 in complex with LysoPS and Gi protein elucidated the lipid-binding modes and structural features of these receptors in the active state, providing insights into ligand recognition and signaling of LysoPS receptors. Cryo-EM structure determination, structural comparison, functional studies PLoS biology High 38048360
2010 GPR34-deficient mice showed significantly lower numbers of granulocytes and macrophages in spleens after immunization, increased paw swelling in delayed-type hypersensitivity, higher pathogen burden after Cryptococcus neoformans infection, and altered basal/stimulated TNF-α, GM-CSF, and IFN-γ levels, establishing a functional role for GPR34 in cellular immune responses. GPR34 knockout mouse model, immunization challenge, delayed-type hypersensitivity test, pulmonary infection model, cytokine measurement The Journal of biological chemistry High 21097509
2014 GPR34-deficient microglia showed morphological changes in retinal and cortical microglia and reduced phagocytosis activity in both retina and acutely isolated cortical slices. RNA sequencing revealed differentially expressed transcripts involved in cell motility and phagocytosis, but no differences in microglial motility after lesion were detected. GPR34 knockout mouse, RNA sequencing of microglia, phagocytosis assays in retina and cortical slices, in vivo lesion models Glia High 25142016
2021 GPR34 on ILC3s acts as a damage-sensing receptor for LysoPS released by apoptotic neutrophils. ILC3-specific deletion of Gpr34 suppressed IL-22 production and tissue repair during colon and skin injury. Downstream signaling via PI3K-AKT or ERK was required for ILC3 activation and IL-22 production. ILC3-specific Gpr34 conditional knockout, co-culture of neutrophils and ILC3s, metabolomic analysis, PI3K-AKT/ERK inhibition, intestinal epithelial injury model Immunity High 34107271
2019 GPR34 expressed by spinal dorsal horn microglia promotes neuropathic pain after nerve injury. GPR34-deficient mice showed attenuated nerve injury-induced pro-inflammatory cytokine expression and reduced pain behavior. LysoPS levels were elevated in the dorsal horn after injury, and intrathecal administration of a GPR34 antagonist reduced neuropathic pain, placing GPR34 upstream of pro-inflammatory microglial activation. GPR34 knockout mice, von Frey hair test, qRT-PCR for cytokines, in situ hybridization, LC-MS/MS quantification of LysoPS, intrathecal antagonist administration Journal of neuroinflammation High 30975169
2024 LysoPS in the tumor microenvironment inhibits ILC1 antitumor activity via GPR34. Genetic deletion of LysoPS synthase Abhd16a in tumors or Gpr34 in ILC1s, or pharmacological antagonism of GPR34, enhanced ILC1 antitumor activity, identifying GPR34 as a metabolic immune checkpoint on ILC1s. Gpr34 conditional KO in ILC1s, Abhd16a knockout in tumor cells, GPR34 antagonist treatment, in vivo tumor models Nature immunology High 39358444
2024 LysoPS-GPR34 signaling mediates microglia-driven neuroinflammation in demyelination. Myelin debris-induced microglial activation and proinflammatory cytokine production depended on LysoPS and GPR34, signaling through PI3K-AKT and ERK. In vivo, reducing LysoPS in myelin or genetic/pharmacological GPR34 inhibition reduced neuroinflammation and pathologies in multiple sclerosis and stroke mouse models. GPR34 knockout and pharmacological inhibition, PI3K-AKT/ERK pathway analysis, mouse models of MS and stroke, in vitro microglial stimulation Cellular & molecular immunology High 39030423
2012 The t(X;14)(p11;q32) translocation in MALT lymphoma deregulates GPR34 expression by placing it under IGH control. Overexpression of GPR34 in lymphoma and HeLa cells resulted in phosphorylation of ERK, PKC, and CREB; induced CRE, AP1, and NF-κB-mediated gene transcription; and increased cell proliferation. Translocation cloning, GPR34 overexpression in lymphoma and HeLa cells, phosphorylation assays, reporter gene assays (CRE, AP1, NF-κB), cell proliferation assays Blood Medium 22966169
2022 The GPR34 C-terminal truncation mutant Q340X, which lacks the phosphorylation motif for β-arrestin-mediated desensitization, showed significantly delayed internalization after LysoPS stimulation, increased resistance to apoptosis, greater transforming potential, and significantly activated CRE, NF-κB, and AP1 reporter activities compared to wild-type GPR34. Isogenic Flp-InTRex293 stable cell lines, internalization assays, apoptosis assays, reporter gene assays (CRE, NF-κB, AP1), soft agar transformation assay Blood Medium 34086889
2016 In dendritic cells, NF-κB and MAPK signaling pathways regulate GPR34 expression. DCs lacking GPR34 showed higher caspase-3/7 activity and increased apoptosis levels, establishing GPR34 as a pro-survival factor in DCs. GPR34 knockout mouse, whole-transcriptome RNA sequencing of DCs, pathway inhibition experiments (NF-κB, MAPK), caspase-3/7 activity assay, apoptosis measurement Journal of immunology Medium 26851221
2016 A tri-basic motif in the first intracellular loop of GPR34 acts as the key topogenic signal dictating the orientation of transmembrane domain-1 (TM1). Charge disruption of this motif perturbed topogenesis, caused loss of a conformation-sensitive epitope, altered post-translational processing, and arrested trafficking in the Golgi. A cleavable N-terminal signal sequence as surrogate topogenic determinant rescued TM1 orientation, conformational epitope, and cell surface trafficking. FLAG-tag and conformation-sensitive native epitope monitoring, mutant panel expression, signal sequence insertion rescue, N-tail truncation and site-directed mutagenesis, Golgi trafficking analysis Biochimica et biophysica acta Medium 27086875
2014 LysoPS stimulates chemotactic migration of colorectal cancer cells through GPR34 and the PI3K/Akt pathway. GPR34 was the predominantly expressed LysoPS receptor on colorectal cancer cell lines. GPR34 knockdown by siRNA or treatment with the PI3K inhibitor wortmannin suppressed LysoPS-induced migration. RT-PCR for receptor expression, siRNA knockdown of GPR34, chemotaxis assay, PI3K inhibitor (wortmannin) treatment Anticancer research Medium 25275042
2025 GPR34 is stabilized by the deubiquitinase USP8. USP8 was identified as a deubiquitinase for GPR34; effects of GPR34 deletion on ferroptosis and tumor progression in anaplastic thyroid carcinoma were reversed by USP8 overexpression. Pharmacological inhibition of USP8 with DUB-IN-3 restrained ATC growth. Co-immunoprecipitation/protein interaction studies to identify USP8 as a DUB, GPR34 deletion in vitro/in vivo, USP8 overexpression rescue, DUB-IN-3 inhibitor treatment, ferroptosis assays Mediators of inflammation Medium 40862294
2024 LysoPS released from injured retinal ganglion cells activates the GPR34-PI3K-AKT-NINJ1 signaling axis in microglia, upregulating inflammatory cytokines (IL-6, IL-8, VEGFA, FGF2) and promoting microglial extracellular trap formation and retinal neovascularization. Inhibition of this axis suppressed these effects in vitro and in vivo. In vitro microglial stimulation with LysoPS, GPR34 inhibition (genetic and pharmacological), PI3K-AKT pathway analysis, NINJ1 expression measurement, in vivo retinal neovascularization model Journal of neuroinflammation Medium 39468551
2025 GPR34 promotes GPR34+ macrophage efferocytosis and CXCL16 secretion in pancreatic cancer. GPR34+ macrophages responded to LysoPS, and their efferocytosis promoted MHC-I degradation via the lysosomal pathway, leading to CD8+ T cell exhaustion. Gpr34ΔLyz2 mouse models confirmed this in vivo. Single-cell RNA sequencing, Gpr34 conditional KO (Lyz2-Cre), in vitro co-culture, efferocytosis assays, MHC-I degradation analysis, CXCL16 measurement Signal transduction and targeted therapy Medium 42045172
2025 GPR34 deficiency in cDC1 (but not cDC2 or macrophages) led to reduced apoptotic cell uptake and impaired cross-presentation to CD8 T cells. PLA1A (but not ABHD16A) deficiency reduced the OT-I T cell response to apoptotic cell-associated antigen, identifying PLA1A-generated lysoPS as the GPR34 ligand mediating cDC1 efferocytosis. GPR34 knockout mice, adoptive transfer of apoptotic cell-OVA, OT-I T cell proliferation assay, PLA1A and ABHD16A knockout comparison, cell-type-specific phenotyping The Journal of experimental medicine Medium 41212150
2024 GPR34 knock-in (gain-of-function) promotes peritoneal cavity accumulation of plasma cells and memory B cells through lysoPS-dependent migration. KI cells showed robust migration to lysoPS ex vivo. Maintenance of KI cells in the peritoneal cavity was dependent on stromal PLA1A, the lysoPS-generating enzyme expressed in omental fibroblasts. GPR34 knock-in mouse, adoptive transfer experiments, bone marrow chimeras, ex vivo migration assay, PLA1A conditional KO The Journal of experimental medicine Medium 39412501
2025 Selective agonism of GPR34 with compound M1 enhanced microglial uptake of Aβ fibrils (but not monomeric or oligomeric Aβ) through reduction of intracellular cAMP levels. This effect required functional TREM2 signaling. Gpr34 knockdown confirmed GPR34 as the molecular target of M1. Flow cytometry-based Aβ uptake assay, cAMP measurement, Gpr34 knockdown, intrahippocampal M1 injection in hAPP knock-in mice, TREM2 signaling requirement testing Alzheimer's research & therapy Medium 41261421
2018 The majority of GPR34 mutations in MALT lymphoma are nonsense and frameshift changes clustered in the C-terminal cytoplasmic tail, generating truncated proteins that lack the phosphorylation motif for β-arrestin-mediated receptor desensitization and internalization, suggesting constitutive or enhanced signaling. Whole exome sequencing of MALT lymphoma cases, mutational mapping to functional protein domains Haematologica Low 29674500
2023 GPR34 knockdown in BV-2 microglia exposed to Aβ1-42 decreased TNF-α, IL-1β, IL-6, and iNOS levels and suppressed ERK/NF-κB signaling activation. GPR34 overexpression-induced ERK/NF-κB activation and cytokine upregulation were abolished by the ERK inhibitor FR180204, placing GPR34 upstream of ERK/NF-κB in microglial neuroinflammation. siRNA knockdown and overexpression in BV-2 cells, ERK inhibitor (FR180204), western blot and immunofluorescence for signaling components, APP/PS1 mouse model with GPR34 knockdown Neuroscience Medium 37557947
2005 GPR34 contains an intronless coding region but has an evolutionarily conserved 5' noncoding intron-exon structure. An alternatively used cryptic intron shortens the N-terminus by 47 amino acids. Multiple conserved in-frame AUGs serve as translational start points, with combinatory mutagenesis confirming preference for the second in-frame AUG in human GPR34. Genomic sequencing across vertebrate species, reporter constructs, combinatory mutagenesis, expression analysis Genomics Medium 16338117
2012 LysoPS has no or very weak agonistic activity at most vertebrate GPR34 orthologues except some fish subtypes. Using chimeric receptors, single positions in the second extracellular loop and transmembrane helix 5 of carp GPR34 subtype 2a were identified as critical for lysoPS responsiveness; transferring these positions to human GPR34 enabled lysoPS activation. Aminoethyl-carbamoyl ATP was identified as an antagonist of carp GPR34. Chimeric receptor construction, site-directed mutagenesis, functional assays across vertebrate orthologues, phylogenetic analysis The Biochemical journal Medium 22348703
2025 In Gpr34 knockout mice at postnatal day 18, elevated numbers of neurons, oligodendrocytes, and microglia showed markers of cell death (cleaved-caspase 3, phospho-RIP3, annexin V), with reduced microglial localization to areas of high cell death. KO microglia showed increased intracellular accumulation of myelin basic protein and SNAP25, suggesting altered handling of apoptotic debris. Transcriptomic analysis revealed persistent immune pathway alterations, and 3-month KO mice displayed sustained hypolocomotion. Gpr34 KO mouse, immunohistochemistry for cell death markers, microglial localization analysis, ex vivo phagocytosis assay, transcriptomic analysis, locomotion behavioral testing Journal of neuroinflammation Medium 41964003
2025 GPR34 KO iPSC-derived microglia showed reduced Ca2+ and phosphorylated ERK signaling in response to LysoPS and myelin stimulation, and were selectively impaired in phagocytosis of myelin but not Aβ or E. coli. GPR34 KO accelerated conversion of homeostatic microglia to DAM states in healthy and amyloid mouse models. GPR34 agonism promoted interaction with and activation of ERK. GPR34 KO iPSC-derived microglia, Ca2+ imaging, pERK measurement, selective phagocytosis assays, RNA-sequencing, amyloid mouse models bioRxivpreprint Medium bio_10.1101_2025.03.28.646038

Source papers

Stage 0 corpus · 47 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2021 GPR34-mediated sensing of lysophosphatidylserine released by apoptotic neutrophils activates type 3 innate lymphoid cells to mediate tissue repair. Immunity 98 34107271
2010 Altered immune response in mice deficient for the G protein-coupled receptor GPR34. The Journal of biological chemistry 79 21097509
2014 Altered microglial phagocytosis in GPR34-deficient mice. Glia 73 25142016
2012 GPR34 is a receptor for lysophosphatidylserine with a fatty acid at the sn-2 position. Journal of biochemistry 69 22343749
2018 Novel GPR34 and CCR6 mutation and distinct genetic profiles in MALT lymphomas of different sites. Haematologica 53 29674500
2019 GPR34 in spinal microglia exacerbates neuropathic pain in mice. Journal of neuroinflammation 50 30975169
2012 t(X;14)(p11;q32) in MALT lymphoma involving GPR34 reveals a role for GPR34 in tumor cell growth. Blood 45 22966169
2015 Structure-activity relationships of lysophosphatidylserine analogs as agonists of G-protein-coupled receptors GPR34, P2Y10, and GPR174. Journal of medicinal chemistry 42 25970039
2018 The G protein-coupled receptor GPR34 - The past 20 years of a grownup. Pharmacology & therapeutics 36 29684466
2011 t(X;14)(p11.4;q32.33) is recurrent in marginal zone lymphoma and up-regulates GPR34. Haematologica 35 22058210
1993 PDGF-BB and TGF-alpha rescue gastrulation, spiculogenesis, and LpS1 expression in collagen-disrupted embryos of the sea urchin genus Lytechinus. Mechanisms of development 33 8155573
2014 Lysophosphatidylserine stimulates chemotactic migration of colorectal cancer cells through GPR34 and PI3K/Akt pathway. Anticancer research 32 25275042
2005 Genomic and supragenomic structure of the nucleotide-like G-protein-coupled receptor GPR34. Genomics 27 16338117
2012 The ligand specificity of the G-protein-coupled receptor GPR34. The Biochemical journal 26 22348703
1991 A G-string positive cis-regulatory element in the LpS1 promoter binds two distinct nuclear factors distributed non-uniformly in Lytechinus pictus embryos. Development (Cambridge, England) 26 1811948
1991 Structure and promoter activity of the LpS1 genes of Lytechinus pictus. Duplicated exons account for LpS1 proteins with eight calcium binding domains. The Journal of biological chemistry 24 2037596
2016 Dendritic Cells Regulate GPR34 through Mitogenic Signals and Undergo Apoptosis in Its Absence. Journal of immunology (Baltimore, Md. : 1950) 23 26851221
2024 GPR34 is a metabolic immune checkpoint for ILC1-mediated antitumor immunity. Nature immunology 22 39358444
2023 Cryo-EM structures of human GPR34 enable the identification of selective antagonists. Proceedings of the National Academy of Sciences of the United States of America 22 37733739
2022 GPR34 activation potentially bridges lymphoepithelial lesions to genesis of salivary gland MALT lymphoma. Blood 20 34086889
2024 GPR34 senses demyelination to promote neuroinflammation and pathologies. Cellular & molecular immunology 19 39030423
2017 Probing the Hydrophobic Binding Pocket of G-Protein-Coupled Lysophosphatidylserine Receptor GPR34/LPS1 by Docking-Aided Structure-Activity Analysis. Journal of medicinal chemistry 19 28715213
2020 MicroRNA-381 targets G protein-Coupled receptor 34 (GPR34) to regulate the growth, migration and invasion of human cervical cancer cells. Environmental toxicology and pharmacology 17 33086148
2013 GPR34 as a lysophosphatidylserine receptor. Journal of biochemistry 16 23389307
2024 Structural basis for lysophosphatidylserine recognition by GPR34. Nature communications 14 38326347
2023 GPR34 Knockdown Relieves Cognitive Deficits and Suppresses Neuroinflammation in Alzheimer's Disease via the ERK/NF-κB Signal. Neuroscience 14 37557947
2020 Possible involvement of PS-PLA1 and lysophosphatidylserine receptor (LPS1) in hepatocellular carcinoma. Scientific reports 14 32060356
2023 Structural basis for ligand recognition and signaling of the lysophosphatidylserine receptors GPR34 and GPR174. PLoS biology 12 38048360
2024 Ganglion cell-derived LysoPS induces retinal neovascularisation by activating the microglial GPR34-PI3K-AKT-NINJ1 axis. Journal of neuroinflammation 11 39468551
2020 LPS1, Encoding Iron-Sulfur Subunit SDH2-1 of Succinate Dehydrogenase, Affects Leaf Senescence and Grain Yield in Rice. International journal of molecular sciences 11 33375756
2013 A Strategy Combining Differential Low-Throughput Screening and Virtual Screening (DLS-VS) Accelerating the Discovery of new Modulators for the Orphan GPR34 Receptor. Molecular informatics 10 27481282
1997 An extracellular matrix response element in the promoter of the LpS1 genes of the sea urchin Lytechinus pictus. Nucleic acids research 8 9224621
2021 MicroRNA-300 Inhibits the Proliferation and Metastasis of Cervical Cancer Cells via Posttranscriptional Suppression of G Protein-Coupled Receptor 34 (GPR34). Journal of oncology 6 34950207
2024 Phosphatidylserine phospholipase A1 enables GPR34-dependent immune cell accumulation in the peritoneal cavity. The Journal of experimental medicine 5 39412501
2016 Topogenesis and cell surface trafficking of GPR34 are facilitated by positive-inside rule that effects through a tri-basic motif in the first intracellular loop. Biochimica et biophysica acta 5 27086875
2000 Physical mapping and exclusion of GPR34 as the causative gene for congenital stationary night blindness type 1. Human genetics 5 10982042
1996 A tissue-specific repressor in the sea urchin embryo of Lytechinus pictus binds the distal G-string element in the LpS1-beta promoter. DNA and cell biology 5 8672248
1996 Two distinct forms of USF in the Lytechinus sea urchin embryo do not play a role in LpS1 gene inactivation upon disruption of the extracellular matrix. Molecular reproduction and development 4 8873063
1996 USF in the Lytechinus sea urchin embryo may act as a transcriptional repressor in non-aboral ectoderm cells for the cell lineage-specific expression of the LpS1 genes. Journal of molecular biology 4 8950263
2025 GPR34 Stabilized by Deubiquitinase USP8 Suppresses Ferroptosis of ATC. Mediators of inflammation 3 40862294
2025 Selective agonism of GPR34 stimulates microglial uptake and clearance of amyloid β fibrils. Alzheimer's research & therapy 3 41261421
1996 A G/C-rich DNA-regulatory element controls positive expression of the sea urchin Lytechinus pictus aboral ectoderm-specific LpS1 gene. DNA and cell biology 3 8634141
2025 Splenic cDC1 efferocytosis and cross-presentation to CD8 T cells are promoted by GPR34 and lysophosphatidylserine. The Journal of experimental medicine 2 41212150
2023 Discovery of (S)-3-(4-(benzyloxy)phenyl)-2-(2-phenoxyacetamido)propanoic acid derivatives as a new class of GPR34 antagonists. Bioorganic & medicinal chemistry letters 2 37949379
2026 Impaired removal of dying brain cells by microglia in Gpr34 deficient mice. Journal of neuroinflammation 0 41964003
2026 Targeting GPR34 in damage-associated macrophages enhances anti-tumor immunity and the efficacy of Surufatinib in pancreatic cancer. Signal transduction and targeted therapy 0 42045172
2025 GPR34 inhibition reprograms tumor-associated macrophages and enhances the sensitivity of anti-PD-1 therapy in hepatocellular carcinoma. Cancer cell international 0 41272735

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