Affinage

P2RY11

P2Y purinoceptor 11 · UniProt Q96G91

Length
374 aa
Mass
40.3 kDa
Annotated
2026-06-10
82 papers in source corpus 36 papers cited in narrative 36 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

P2RY11 encodes P2Y11, a nucleotide-activated G protein-coupled receptor that uniquely couples to both phospholipase C (IP3/Ca2+) and adenylyl cyclase (cAMP/PKA), with the cAMP arm being weaker and the two pathways operating through independent effectors that can cross-talk via PKC and Ca2+ (PMID:10578132, PMID:11156592, PMID:11015299). The receptor is activated by extracellular ATP and, beyond classical nucleotides, by the pyridine dinucleotides β-NAD+ and NAADP+, producing biphasic Ca2+ signals through combined IP3 and cAMP/cADPR mobilization (PMID:16926152, PMID:17707504). Ligand recognition occurs through a defined binding pocket in which Arg106, Glu186, Arg268, and Arg307 engage the ATP phosphates while Tyr261 acts as an activation switch, and Arg268 specifically dictates stereospecific and triphosphate selectivity (PMID:17338680, PMID:18820714, PMID:11723245). P2Y11 forms hetero-oligomers with P2Y1 that confer the agonist-induced internalization the receptor cannot otherwise undergo and alter its ligand selectivity; this interaction underlies the signaling deficit of the A87T variant (PMID:17824841, PMID:24524250). Functionally, P2Y11 operates predominantly in immune and epithelial contexts through autocrine nucleotide loops: it drives dendritic cell maturation, tolerogenicity (IDO1/CD73-dependent Treg induction), and IL-8 release (PMID:11390464, PMID:19815812, PMID:39899472), delays neutrophil apoptosis (PMID:18056402), directs macrophage M1/M2 polarization and IL-1R/CXCR7 signaling (PMID:23577075, PMID:36107259, PMID:38472446), and spatially organizes cAMP/PKA signaling and mitochondrial trafficking in polarized T cells at the immune synapse to control migration and activation (PMID:32994212, PMID:32531829). In epithelia it transduces α-defensin HD5 signals through bifurcating PKA-protrusion and FAK-adhesion pathways (PMID:39901059, PMID:42144107), and it confers cardioprotection against hypoxia/reoxygenation injury via PKCε (PMID:31406184). A common P2RY11 SNP reducing receptor expression in CD8+ T and NK cells links the gene to narcolepsy, and zebrafish knockout reproduces narcolepsy-like reduction of hypocretin alongside impaired immune-cell recruitment (PMID:21170044, PMID:38771396).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1999 High

    Established the foundational signaling identity of P2Y11 as a dually-coupled nucleotide receptor, answering what second-messenger pathways it engages and its agonist rank order.

    Evidence Recombinant expression in 1321N1 and CHO-K1 cells with IP3/cAMP pharmacological profiling

    PMID:10578132

    Open questions at the time
    • Endogenous physiological agonist and tissue context not addressed
    • Relative coupling strength of the two arms not quantified
  2. 2001 High

    Defined the relationship between the two signaling arms, showing the cAMP arm is weaker than PLC coupling and that PKC/Ca2+ cross-talk potentiates cAMP, while also mapping a Gs-coupling and a key triphosphate-selectivity determinant.

    Evidence IP/cAMP/Ca2+ assays with PKC downregulation and BAPTA chelation; adenylyl cyclase assays in MDCK membranes; Arg265 mutagenesis comparing human and canine receptors

    PMID:11156592 PMID:11408597 PMID:11723245 PMID:11788591

    Open questions at the time
    • Structural basis of dual G protein coupling not resolved
    • Whether cross-talk occurs in native immune cells not tested
  3. 2001 Medium

    Linked P2Y11 signaling to a concrete immune output by showing ATP drives dendritic cell maturation through P2Y11/cAMP/PKA, and revealed an unusual intergenic splicing event producing a functional P2Y11-SSF1 fusion.

    Evidence P2Y11 agonist profiling and H89 PKA inhibition in primary human DCs; cDNA cloning and functional expression of the fusion transcript

    PMID:11278528 PMID:11390464

    Open questions at the time
    • No knockout confirmation in primary DCs
    • Physiological role of the SSF1 fusion protein unknown
  4. 2003 Medium

    Demonstrated agonist-biased signaling and a tissue-context restriction, showing UTP triggers a mechanistically distinct PTX-sensitive Ca2+ response and that DC maturation downregulates functional P2Y11.

    Evidence Ca2+ measurements with PTX and 2-APB in 1321N1 cells; migration assays and receptor expression analysis in DC subsets

    PMID:12649135 PMID:12761346

    Open questions at the time
    • G protein identity underlying biased UTP response not isolated
    • Post-transcriptional regulation mechanism in blood DCs not defined
  5. 2007 High

    Broadened the agonist repertoire beyond nucleotides to the pyridine dinucleotides NAD+ and NAADP+, establishing P2Y11 as a multi-ligand sensor coupling to IP3, cAMP and cADPR in both recombinant and primary cells.

    Evidence Reconstitution in transfected vs wild-type 1321N1 cells with second-messenger measurements; siRNA and NF157 in primary granulocytes

    PMID:16926152 PMID:17707504

    Open questions at the time
    • Whether dinucleotides bind the same pocket as ATP not directly resolved
    • Source/regulation of extracellular dinucleotides in vivo not defined
  6. 2007 High

    Mapped the ligand-binding pocket and identified Tyr261 as an activation switch, providing the structure-function basis for nucleotide recognition and dual coupling.

    Evidence Homology modeling with rhodopsin/P2Y1 templates and systematic mutagenesis with Ca2+/cAMP readouts; neutrophil apoptosis assays with NF157 and PKA inhibitors

    PMID:17338680 PMID:18056402

    Open questions at the time
    • No experimental structure of the receptor
    • Why Gs coupling is more mutation-sensitive than Gq not explained
  7. 2008 High

    Resolved why P2Y11 lacks intrinsic endocytosis by demonstrating obligate hetero-oligomerization with P2Y1 that confers internalization and alters ligand selectivity, and pinpointed Arg268 as the stereospecificity determinant.

    Evidence Co-IP, pulldown and FRET with P2Y1 siRNA and internalization assays; mutagenesis with purified ATP-α-S diastereomers

    PMID:17824841 PMID:18820714

    Open questions at the time
    • Stoichiometry and structural interface of the P2Y11-P2Y1 oligomer unknown
    • Whether oligomerization occurs in native immune cells not shown
  8. 2010 Medium

    Connected P2Y11 to human disease and tissue physiology, linking a expression-lowering SNP to immune-cell survival and identifying autocrine NAD+/ATP loops in stem cells and NK cells.

    Evidence GWAS with eQTL and cell-death assays in CD8+ T and NK cells; Cx43/P2Y11 siRNA in MSCs; pharmacological P2Y11 blockade in NK cytotoxicity assays

    PMID:20668227 PMID:20964598 PMID:21170044

    Open questions at the time
    • SNP effect is on expression level rather than direct receptor function
    • Causal disease mechanism not established biochemically
  9. 2014 High

    Established that disease-associated receptor variants act through the P2Y1 hetero-oligomeric interface, showing the A87T polymorphism impairs signaling and abolishes internalization only when P2Y1 is co-expressed.

    Evidence Site-directed mutagenesis with Ca2+/cAMP/internalization assays in HEK293 (P2Y1+) vs 1321N1 cells; pharmacological P2Y11 work in CF airway epithelia

    PMID:24524250 PMID:24588705

    Open questions at the time
    • Whether A87T contributes to specific clinical phenotypes not demonstrated
    • Generalizability of P2Y1-dependence to other variants untested
  10. 2019 High

    Defined autocrine ATP-release-coupled P2Y11 circuits as drivers of inflammatory output, controlling macrophage M1 polarization, keratinocyte IL-6, T-cell immunosuppression, and cardioprotective PKCε signaling.

    Evidence VNUT/SLC17A9 and P2Y11 siRNA with in vivo LPS model; P2Y11 knockdown and pharmacology in keratinocytes and T cells; NF546/NF340 in AC16 cardiomyocytes

    PMID:23461851 PMID:23577075 PMID:30787105 PMID:31406184

    Open questions at the time
    • Source of physiological ATP varies by cell type and is incompletely mapped
    • Branch-point determining pro- vs anti-inflammatory outcome unclear
  11. 2020 High

    Revealed a spatial signaling mechanism in which P2Y11 redistributes within polarized T cells to compartmentalize cAMP/PKA and mitochondrial activity, coordinating migration and immune-synapse activation with P2X4 and pannexin-1.

    Evidence Live-cell imaging of receptor redistribution, mitochondrial metabolism imaging, and P2X4/P2Y11 pharmacology in human CD4 T cells

    PMID:32531829 PMID:32994212

    Open questions at the time
    • Molecular machinery driving receptor redistribution unknown
    • How global ATP elevation overrides the spatial loop not mechanistically detailed
  12. 2022 High

    Expanded P2Y11 signaling networks in macrophages, linking it to IL-1R/CXCR7 cross-regulation, Epac1-differential targets, and a CXCR4-PDE4 cAMP checkpoint.

    Evidence Transcriptome/secretome profiling with P2Y11 knockout cells, PDE4/Epac1 inhibition, CXCR7 siRNA, and chemokine-receptor pharmacology

    PMID:36107259 PMID:38472446

    Open questions at the time
    • Direct physical interaction between P2Y11 and IL-1R/CXCR7 not shown
    • Generalizability beyond M2 macrophages untested
  13. 2024 Medium

    Identified P2Y11 as a defensin receptor and established its in vivo role in epithelial cytoskeletal remodeling and host-pathogen interaction, while a zebrafish knockout connected the gene to hypocretin and immune-cell recruitment.

    Evidence Multi-omics receptor identification with organoid, gut-on-chip and in vivo Shigella models; CRISPR/Cas9 zebrafish knockout with sleep, HCRT and wound-recruitment phenotypes

    PMID:38771396 PMID:39901059

    Open questions at the time
    • Direct HD5-P2Y11 binding affinity not quantified
    • Mechanistic basis of the hypocretin link not established
  14. 2025 Medium

    Showed cell-state-dependent pathway bifurcation downstream of P2Y11, with PKA driving protrusion in adhered cells and a FAK/paxillin/Rac1 axis driving adhesion and barrier repair in injured cells, and a tolerogenic NF-κB/IDO1 arm in dendritic cells.

    Evidence Primary colonic epithelial cells, organoids and gut-on-chip with FAK/paxillin phosphorylation and PKA/Rac1 analysis; pathway-inhibitor studies and Treg induction assays in DCs

    PMID:39899472 PMID:42144107

    Open questions at the time
    • Switch mechanism selecting PKA vs FAK output not molecularly defined
    • Single-lab findings for the FAK axis

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single receptor integrates multiple ligand classes and selects among cAMP/PKA, FAK, PKCε, and oligomerization-dependent outputs in a cell-state- and context-specific manner remains the central open mechanistic question.
  • No experimental receptor structure or active-state model
  • Determinants of pathway and partner selection across cell types undefined
  • In vivo physiological agonist for each context not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-168256 Immune System 4 R-HSA-162582 Signal Transduction 3
Partners
ACKR3CXCR4P2RX4P2RX7P2RY1
Complex memberships
P2Y11-P2Y1 hetero-oligomer

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 P2Y11 receptor is dually coupled to both phosphoinositide (PLC) and adenylyl cyclase (cAMP) pathways upon activation by ATP. The rank order of agonist potency was: ATPγS ≈ BzATP > dATP > ATP > ADPβS > 2MeSATP. Suramin acted as a competitive antagonist (Ki ~0.82 µM). AR-C67085 was identified as the most potent agonist. Stable recombinant expression in 1321N1 astrocytoma cells (IP3 assay) and CHO-K1 cells (cAMP assay); pharmacological characterization with agonists and antagonists British journal of pharmacology High 10578132
2001 P2Y11 receptor mediates ATP-induced maturation of human monocyte-derived dendritic cells through the P2Y11/cAMP/protein kinase A signaling pathway. The rank order of potency of ATP analogs matched the P2Y11 receptor profile, and the PKA inhibitor H89 blocked nucleotide-induced DC maturation (CD83 upregulation and IL-12 secretion). Pharmacological profiling with P2Y11-selective agonists/antagonists; PKA inhibitor (H89) functional assay; cAMP measurement in DCs Journal of immunology Medium 11390464
2001 The P2Y11 gene and the adjacent SSF1 gene are co-transcribed and undergo intergenic splicing, producing a chimeric P2Y11-SSF1 fusion transcript that is ubiquitously expressed in human tissues. The fusion protein retains P2Y11 receptor function (cAMP response to ATP) when stably expressed in CHO-K1 cells. cDNA library screening; RT-PCR; stable expression in CHO-K1 cells; cAMP assay; Western blotting The Journal of biological chemistry Medium 11278528
2001 Coupling of the human P2Y11 receptor to adenylyl cyclase is significantly weaker than coupling to phospholipase C (ATP is ~15-fold less potent for cAMP vs. IP accumulation). PKC activation and intracellular Ca2+ mobilization (downstream of PLC) potentiate P2Y11-mediated cAMP accumulation, indicating cross-talk between the two signaling arms. Stable expression in 1321N1 and CHO cells; IP/cAMP assays; PKC downregulation with phorbol ester; intracellular Ca2+ chelation with BAPTA British journal of pharmacology High 11156592
2001 The canine P2Y11 receptor shows preferential activation by ADP nucleotides (opposite to the human P2Y11 which prefers ATP nucleotides). Mutational analysis revealed that Arg-265 at the juxtaposition of TM6 and the third extracellular loop in hP2Y11 is a key determinant of triphosphate selectivity; substituting it with glutamine (as found in cP2Y11) shifts selectivity toward diphosphates. Stable expression of human and canine P2Y11 in CHO-K1 and 1321N1 cells; IP/cAMP assays; Ca2+ mobilization; site-directed mutagenesis of Arg265 Molecular pharmacology High 11723245
2001 P2Y11 receptor couples to Gs to directly activate adenylyl cyclase in canine MDCK-D1 cells, stimulating PI hydrolysis, Ca2+ mobilization, and cAMP accumulation. Microscopy and short-circuit current measurements demonstrated primarily basolateral targeting of P2Y11 receptors in polarized MDCK-D1 cell monolayers. Cloning and stable expression of cP2Y11-GFP; fluorescence microscopy; Ussing chamber electrophysiology; PKC inhibition; eicosanoid inhibition controls Molecular pharmacology Medium 11408597
2002 P2Y11 receptors in MDCK-D1 cells activate adenylyl cyclase via Gs, producing indo-resistant cAMP. ADP analogs (ADPβS, MT-ADP) activated adenylyl cyclase in MDCK membranes directly, and the response was synergistic with forskolin, confirming Gs-coupling. Overexpressed GFP-tagged P2Y11 receptors confirmed this pharmacological profile. Stable expression of GFP-tagged P2Y11 in MDCK-D1 cells; cAMP assays; adenylyl cyclase activity assay in membranes; antagonist pharmacology; indomethacin treatment The Journal of biological chemistry Medium 11788591
2003 UTP activates a Ca2+ mobilizing response at P2Y11 receptors that is mechanistically distinct from the ATP-mediated response: UTP-induced Ca2+ is less dependent on extracellular Ca2+, is sensitive to pertussis toxin (unlike ATP), and is more easily desensitized. No P2Y2 or P2Y4 mRNA was detected in the expressing cells, confirming the response is P2Y11-mediated. This represents agonist-specific (biased) signaling at a single receptor. Stable expression in 1321N1 cells; intracellular Ca2+ measurements; RT-PCR for P2Y2/P2Y4; pertussis toxin pretreatment; 2-APB treatment; desensitization experiments Molecular pharmacology Medium 12761346
2003 P2Y11 receptor activation inhibits migration of monocyte-derived DCs (MoDCs) and CD1a+ dermal DCs in a dose-dependent manner. On maturation, MoDCs downregulated P2Y11 receptor expression and became less sensitive to ATP-mediated migration inhibition. Blood DC subtypes did not respond to P2Y11R agonists despite mRNA expression, indicating post-transcriptional regulation of functional receptor expression. P2Y receptor agonist/antagonist pharmacology; Ca2+ flux studies; migration assays; flow cytometry; RT-PCR Blood Medium 12649135
2006 Extracellular β-NAD+ is an agonist of the P2Y11 receptor. In hP2Y11-transfected 1321N1 astrocytoma cells, but not untransfected cells, NAD+ promoted IP3, cAMP, and cADPR production and biphasic Ca2+ elevation. In human granulocytes, selective P2Y11 inhibition (NF157) and P2Y11 siRNA knockdown prevented NAD+-induced Ca2+ increase and chemotaxis. Stable transfection in 1321N1 cells; IP3/cAMP/cADPR measurements; Ca2+ imaging; siRNA knockdown; pharmacological inhibition with NF157 in primary granulocytes The Journal of biological chemistry High 16926152
2007 P2Y11 receptor mediates ATP-induced inhibition of neutrophil apoptosis via downstream activation of type I cAMP-dependent protein kinases (PKA). Brief (10 min) ATP exposure caused long-lasting apoptosis delay. The P2Y11 antagonist NF157 abrogated the anti-apoptotic effect; the mechanism was not mediated by adenosine (ATP breakdown product). Morphology, annexin V/To-Pro3 staining, mitochondrial membrane permeabilization assay; NF157 antagonism; PKA inhibition; receptor expression studies; cAMP measurements Journal of immunology Medium 18056402
2007 NAADP+ is an agonist of the human P2Y11 receptor. In hP2Y11-transfected 1321N1 cells (but not wild-type), extracellular NAADP+ triggered concentration-dependent biphasic Ca2+ elevation via IP3 (rapid phase) and cAMP/cADPR (sustained phase). In human granulocytes, NF157 confirmed endogenous P2Y11 mediated NAADP+-induced cell activation. Stable transfection in 1321N1 cells; IP3/cAMP/cADPR measurements; Ca2+ imaging; NF157 pharmacological inhibition in primary granulocytes Cell calcium High 17707504
2007 Computational homology modeling combined with mutagenesis identified the ligand-binding site residues of P2Y11: Arg106, Glu186, Arg268, and Arg307 interact ionically with ATP phosphate moieties; Tyr261 acts as a molecular switch (Y261A mutant is inactive); Phe109 provides minor π-stacking with adenine; Ser206 H-bonds to γ-phosphate; Ala313 contributes to a hydrophobic pocket near C-2 of ATP. Gs coupling efficacy was more variable across mutants than Gq coupling. Homology modeling with bovine rhodopsin and hP2Y1-ATP templates; site-directed mutagenesis of Arg106, Glu186, Arg268, Arg307, Phe109, Tyr261, Ser206, Ala313, Met310; Ca2+ and cAMP functional assays The Biochemical journal High 17338680
2008 P2Y11 and P2Y1 receptors form hetero-oligomers when co-expressed. This association (detected by co-pulldown, immunoprecipitation, and FRET) promotes agonist-induced internalization of P2Y11, which by itself cannot undergo endocytosis. P2Y11 co-internalized with P2Y1 upon ATP or P2Y1-selective agonist (2-MeS-ADP) stimulation, and siRNA knockdown of endogenous P2Y1 in HEK293 cells reduced GFP-P2Y11 endocytosis. The hetero-oligomerization also altered ligand selectivity of P2Y11. Co-pulldown; immunoprecipitation; FRET; siRNA knockdown of P2Y1; Ca2+ imaging; stable co-expression in HEK293 and 1321N1 cells The Biochemical journal High 17824841
2008 Arg268 in TM6 is the principal determinant of P2Y11 receptor stereospecificity for Pα-substituted ATP derivatives. R268A and R268Q mutations abolished stereoselective recognition of ATP-α-S isomers. Glu186A mutation increased stereoselectivity. The double mutant R268Q/E186A showed additive decrease in potency but no additional stereoselectivity change. Site-directed mutagenesis; Ca2+ assay with purified diastereomers of ATP-α-S; molecular modeling British journal of pharmacology High 18820714
2009 NF546 is the first selective non-nucleotide P2Y11 agonist, acting at the same binding site as ATPγS (as shown by competitive Schild analysis with antagonist NF340, pA2 = 8.02–8.04). NF546 stimulated IL-8 release from monocyte-derived dendritic cells, a P2Y11-mediated effect blocked by NF340. Schild analysis; Ca2+ and cAMP assays in transfected 1321N1 cells; molecular modeling; IL-8 ELISA in primary DCs; NF340 antagonism The Journal of pharmacology and experimental therapeutics High 19815812
2010 The disease-associated P2RY11 SNP (rs2305795) correlates with reduced P2Y11 expression in CD8+ T lymphocytes and NK cells, and reduced P2Y11-mediated resistance to ATP-induced cell death in these cells. This identifies P2Y11 as a regulator of immune-cell survival. Genome-wide association study with replication; eQTL analysis; flow cytometry for cell death in T and NK cells Nature genetics Medium 21170044
2010 P2Y11 receptor activation by extracellular NAD+ (released via Connexin 43 hemichannels) mediates an autocrine cAMP/cADPR/Ca2+ signaling cascade in human mesenchymal stem cells, involving L-type Ca2+ channel opening. This signaling promoted MSC proliferation, migration, prostaglandin E2 release, cytokine release, and downregulation of T lymphocyte proliferation. Cx43 siRNA; NAD+ glycohydrolase treatment; P2Y11 siRNA; cAMP/cADPR/Ca2+ measurements; L-type channel pharmacology; functional assays (proliferation, migration) Stem cells and development Medium 20964598
2010 P2Y11 receptor activation on NK cells mediates ATP-induced inhibition of CX3CL1-directed NK cell chemotaxis and cytotoxicity against endothelial cells. This inhibitory effect correlated with increased intracellular cAMP. Pharmacological inhibition of P2Y11R (or apyrase addition) removed the protective effect on endothelial cells from NK-mediated killing. Pharmacological inhibition of P2Y11R; cAMP measurement; chemotaxis assay; NK cell cytotoxicity assay against HUVECs and coronary artery ECs Blood Medium 20668227
2013 ATP release via vesicular exocytosis (VNUT/SLC17A9-dependent) followed by autocrine P2Y11 receptor activation is a major pathway for LPS-induced macrophage activation and cytokine release. Knockdown of SLC17A9, NF157 (P2Y11 antagonist), or P2Y11 siRNA knockdown suppressed M1 polarization and IL-6 production in THP-1 cells. In vivo, NF157 suppressed LPS-induced proinflammatory cytokines and macrophage M1 polarization. siRNA knockdown of SLC17A9 and P2Y11; ATP release measurement; pharmacological inhibition with NF157; in vivo LPS mouse model PloS one High 23577075
2013 P2Y11 receptor mediates IFN-γ-induced IL-6 production in human keratinocytes (HaCaT cells) via an autocrine ATP loop. IFN-γ stimulated ATP release; NF157 (P2Y11 antagonist), apyrase, suramin, and P2Y11 knockdown all suppressed IL-6 production. A soluble adenylate cyclase inhibitor (KH7) also blocked the effect, implicating cAMP signaling. P2Y11 siRNA knockdown; pharmacological inhibitors (NF157, suramin, apyrase, KH7); IL-6 ELISA; ATP release measurement European journal of pharmacology Medium 23461851
2014 The Ala-87-Thr (A87T) polymorphism of P2Y11 impairs signaling (reduced Ca2+ response to BzATP, reduced cAMP) and completely abolishes agonist-induced receptor internalization in HEK293 cells (which express endogenous P2Y1). The impaired signaling of the A87T mutant was dependent on co-expression with P2Y1, establishing that the A87T pathogenic effect operates through the P2Y1-P2Y11 hetero-oligomeric interaction. Site-directed mutagenesis; stable and transient expression in HEK293 and 1321N1 cells; Ca2+ assay; cAMP assay; receptor internalization assay Journal of neurochemistry High 24524250
2014 P2Y11 receptor activation by LXA4-stimulated apical ATP release (via Pannexin-1 channels) increased intracellular cAMP and Ca2+, restoring airway surface liquid height and promoting epithelial repair in cystic fibrosis airway cells. P2RY11 knockdown abolished the LXA4-induced increase in ASL height and epithelial wound repair. P2Y11 siRNA knockdown; pharmacological inhibitors of Pannexin-1 and P2Y11; cAMP/Ca2+ measurements; ASL height measurement; proliferation/migration/wound repair assays American journal of respiratory cell and molecular biology Medium 24588705
2016 P2Y11R and P2X7R cooperatively inhibit migration of tumor-derived endothelial cells (BTECs) via calcium-dependent adenylyl cyclase 10 (AC10), cAMP release, and EPAC-1 activation. BzATP (P2X7 agonist/P2Y11 internalizer) mimicked the anti-migratory effect; pharmacological or molecular silencing of P2X7R and P2Y11R prevented it. P2Y11R stimulation also enhanced TEC-mediated pericyte attraction and reduced endothelial permeability. Pharmacological silencing and siRNA knockdown of P2X7R and P2Y11R; migration assays; cAMP measurement; AC10 identification; EPAC-1 activation Scientific reports Medium 27586846
2019 LPS stimulation of monocytes induces accumulation of extracellular ATP that suppresses T cell mitochondrial function, migration, IL-2 production, and proliferation via P2Y11 receptor activation on T cells. Enzymatic removal of extracellular ATP or P2Y11 antagonism partially restored T cell functions. This identifies P2Y11 as the receptor mediating LPS/monocyte-induced T cell immunosuppression. Pharmacological P2Y11 blockade; apyrase treatment; IL-2 ELISA; T cell proliferation assay; mitochondrial function assessment; extracellular ATP measurement The Journal of biological chemistry Medium 30787105
2019 P2Y11 receptor stimulation at reoxygenation protected human AC16 cardiomyocytes against hypoxia/reoxygenation injury by reducing mitochondria-derived ROS and activating PKCε signaling pathway. The protection was abolished by P2Y11R antagonism. NF546 (agonist) and NF340 (antagonist) treatment; LDH assay; MTT assay; intracellular ATP measurement; mitochondrial ROS measurement; PKCε signaling pathway analysis Scientific reports Medium 31406184
2020 Autocrine P2Y11 receptor stimulation regulates polarization and migration of human CD4 T cells. P2Y11 redistributes from the front to the back of polarized T cells, where it triggers cAMP/PKA signaling that attenuates mitochondrial metabolism at the rear. The absence of P2Y11 at the front creates hotspots of mitochondrial activity and ATP production that stimulate P2X4 receptors and Ca2+ influx, driving pseudopod protrusion. Excessive global extracellular ATP (inflammation) disrupts this spatial autocrine loop and impairs T cell migration. Live-cell imaging of P2Y11 redistribution; pharmacological inhibition of P2Y11 and P2X4; cAMP/PKA signaling assays; mitochondrial metabolism imaging; migration assays Science signaling High 32994212
2020 P2Y11 receptors are essential for T cell activation at the immune synapse (IS): P2Y11 receptors retract to the back of cells where cAMP/PKA signaling redirects mitochondrial trafficking to the IS. This promotes aggregation of mitochondria with pannexin-1 ATP release channels and P2X4 receptors at the IS, sustaining local ATP production and Ca2+ influx needed for T cell activation. Live-cell imaging; pharmacological inhibition; mitochondria tracking; pannexin-1/P2X4 co-localization studies; Ca2+ measurements Journal of leukocyte biology High 32531829
2022 P2Y11 receptor activation in human M2 macrophages triggers canonical and IL-1 receptor signaling, upregulating IL-1R and its downstream targets (VEGF, CCL20, SOCS3) while downregulating CD39, P2X7, TLRs, and inflammasome components. cAMP elevation (via PDE4 inhibition) enhanced P2Y11-driven sTNFR2 shedding via TACE/ADAM17, with Epac1 differentially regulating downstream targets. Ca2+ and PKC also participated in P2Y11 signaling. Transcriptome/secretome profiling; NF340 antagonism; P2Y11 knockout cells; PDE4 inhibition; Epac1 inhibition; cytokine ELISAs; TACE/ADAM17 identification Cellular and molecular life sciences High 36107259
2024 P2Y11 is the receptor on human colonic epithelial cells mediating HD5 (enteric α-defensin 5)-induced filopodial extensions via cAMP-PKA signaling. Multi-omics screening identified P2Y11 as the HD5 receptor; P2Y11 is distributed apically on colonic epithelium. Inhibitor screening confirmed cAMP-PKA as the main pathway for cytoskeleton-regulating activity of HD5, and P2Y11-mediated filopodia promote Shigella invasion. Multi-omics screening; in vitro cell assays; organoid model; gut-on-chip model; in vivo infection model; cAMP-PKA inhibitor pharmacology; immunolocalization Nature microbiology High 39901059
2024 CXCR7 is an integral component of the P2Y11/IL-1R signaling cascade in human macrophages: P2Y11 activation upregulates CXCR7 and CXCR4, and CXCR7 agonism selectively enhanced P2Y11/IL-1R-mediated CCL20 secretion. CXCR4-associated PDE4 acts as a regulatory checkpoint for cAMP levels downstream of P2Y11; CXCR4 inactivation (which reduces PDE4 activity) removes cAMP degradation and amplifies P2Y11 signaling. Gene expression analysis; RNA interference (CXCR7 siRNA); pharmacological agonists/antagonists for P2Y11, CXCR4, CXCR7; PDE4 inhibition; CCL20 secretome analysis; astrocytoma cell line (natural CXCR7 expression, no CXCR4) Cellular and molecular life sciences Medium 38472446
2025 P2Y11 receptor activates a P2Y11-FAK signaling axis in intestinal epithelial cells (in addition to the previously known PKA pathway). HD5 via P2Y11 induces phosphorylation of FAK and paxillin, promoting focal adhesion formation, with Rac1 acting downstream to support epithelial adhesion and barrier integrity. Cell-state-dependent bifurcation was shown: in well-adhered cells, HD5-P2Y11 engages PKA and induces protrusions; in suspended/injured cells, HD5-P2Y11 preferentially engages FAK for adhesion and barrier restoration. Primary human colonic epithelial cells; colonic organoids; gut-on-chip; FAK/paxillin phosphorylation assays; PKA inhibitor pharmacology; Rac1 pathway analysis; barrier integrity assays Mucosal immunology Medium 42144107
2000 PKC differentially regulates P2Y11-mediated signaling in HL-60 cells: PMA-induced PKC activation inhibited PLC/Ca2+ responses but potentiated cAMP accumulation. PLC and adenylyl cyclase activation by P2Y11 were shown to operate through independent pathways (U-73122 blocked IP3/Ca2+ but not cAMP; SQ22536 blocked AC but not PLC). PKC activation/inhibition with PMA; PLC inhibitor U-73122; AC inhibitor SQ22536; IP3/Ca2+ and cAMP measurements in HL-60 cells British journal of pharmacology Medium 11015299
2000 P2Y11 receptor stimulation activates a cAMP signaling pathway that phosphorylates CREB and ATF-1 and drives renin promoter activity via the cAMP response element (CRE) at -222 in the REN promoter. Mutation of the CRE abolished the ATP/P2Y11 effect on renin reporter activity. Stable P2Y11 overexpression in Calu-6 cells; renin promoter-luciferase reporter assay; CRE mutagenesis; CREB/ATF-1 phosphorylation immunoblot; renin mRNA/protein measurement Hypertension Medium 11116131
2024 P2RY11 deficiency in zebrafish (CRISPR/Cas9 knockout) reduced HCRT (hypocretin/orexin) expression and caused narcolepsy-like features. P2RY11 mutants also showed impaired neutrophil and macrophage recruitment to wound sites, altered cytokine balance (increased il6, tnfa, il1b; decreased il4, il10, tgfb), and reduced anti-inflammatory cytokines after tissue damage. CRISPR/Cas9 knockout; sleep behavior analysis; HCRT immunostaining/expression; neutrophil/macrophage migration assay at wound sites; cytokine expression analysis Cell biology and toxicology Medium 38771396
2025 P2Y11 receptor activation in human dendritic cells drives indoleamine-2,3-dioxygenase 1 (IDO1) upregulation through the noncanonical NF-κB signaling pathway. P2Y11R-mediated IDO1 upregulation was also associated with CD73 upregulation and adenosine production, leading to induction of PD-1-expressing suppressive T regulatory cells via A2AR. P2X7R inflammasome involvement in IDO1 upregulation was not confirmed. Pharmacological inhibition of P2Y11R; P2Y11R activation assays; IDO1/NF-κB pathway inhibitor studies; T regulatory cell induction assays; CD39/CD73/A2AR pharmacology Journal of leukocyte biology Medium 39899472

Source papers

Stage 0 corpus · 82 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 Pharmacological characterization of the human P2Y11 receptor. British journal of pharmacology 209 10578132
2010 Common variants in P2RY11 are associated with narcolepsy. Nature genetics 175 21170044
2001 The P2Y11 receptor mediates the ATP-induced maturation of human monocyte-derived dendritic cells. Journal of immunology (Baltimore, Md. : 1950) 150 11390464
2006 Extracellular NAD+ is an agonist of the human P2Y11 purinergic receptor in human granulocytes. The Journal of biological chemistry 113 16926152
2013 Autocrine regulation of macrophage activation via exocytosis of ATP and activation of P2Y11 receptor. PloS one 110 23577075
2007 Inhibition of neutrophil apoptosis by ATP is mediated by the P2Y11 receptor. Journal of immunology (Baltimore, Md. : 1950) 100 18056402
2003 ATP gradients inhibit the migratory capacity of specific human dendritic cell types: implications for P2Y11 receptor signaling. Blood 95 12649135
2009 NF546 [4,4'-(carbonylbis(imino-3,1-phenylene-carbonylimino-3,1-(4-methyl-phenylene)-carbonylimino))-bis(1,3-xylene-alpha,alpha'-diphosphonic acid) tetrasodium salt] is a non-nucleotide P2Y11 agonist and stimulates release of interleukin-8 from human monocyte-derived dendritic cells. The Journal of pharmacology and experimental therapeutics 88 19815812
2008 Hetero-oligomerization of the P2Y11 receptor with the P2Y1 receptor controls the internalization and ligand selectivity of the P2Y11 receptor. The Biochemical journal 81 17824841
2005 Synthesis and structure-activity relationships of suramin-derived P2Y11 receptor antagonists with nanomolar potency. Journal of medicinal chemistry 80 16250663
2002 Methanocarba modification of uracil and adenine nucleotides: high potency of Northern ring conformation at P2Y1, P2Y2, P2Y4, and P2Y11 but not P2Y6 receptors. Journal of medicinal chemistry 76 11754592
2003 Characterization of a Ca2+ response to both UTP and ATP at human P2Y11 receptors: evidence for agonist-specific signaling. Molecular pharmacology 74 12761346
2016 A critical look at the function of the P2Y11 receptor. Purinergic signalling 65 27246167
2016 Activation of P2X7 and P2Y11 purinergic receptors inhibits migration and normalizes tumor-derived endothelial cells via cAMP signaling. Scientific reports 62 27586846
2014 Role of spinal P2Y6 and P2Y11 receptors in neuropathic pain in rats: possible involvement of glial cells. Molecular pain 61 24886406
2001 Cotranscription and intergenic splicing of human P2Y11 and SSF1 genes. The Journal of biological chemistry 57 11278528
2005 Phospholipase C and cAMP-dependent positive inotropic effects of ATP in mouse cardiomyocytes via P2Y11-like receptors. Journal of molecular and cellular cardiology 56 15893764
2001 Differential coupling of the human P2Y(11) receptor to phospholipase C and adenylyl cyclase. British journal of pharmacology 54 11156592
2010 Regulation of human mesenchymal stem cell functions by an autocrine loop involving NAD+ release and P2Y11-mediated signaling. Stem cells and development 50 20964598
2006 Increased risk of acute myocardial infarction and elevated levels of C-reactive protein in carriers of the Thr-87 variant of the ATP receptor P2Y11. European heart journal 50 17135283
2010 ATP secreted by endothelial cells blocks CX₃CL 1-elicited natural killer cell chemotaxis and cytotoxicity via P2Y₁₁ receptor activation. Blood 49 20668227
2001 P2Y(11), a purinergic receptor acting via cAMP, mediates secretion by pancreatic duct epithelial cells. American journal of physiology. Gastrointestinal and liver physiology 46 11292586
2002 P2Y11 receptors activate adenylyl cyclase and contribute to nucleotide-promoted cAMP formation in MDCK-D(1) cells. A mechanism for nucleotide-mediated autocrine-paracrine regulation. The Journal of biological chemistry 44 11788591
2020 The purinergic receptor P2Y11 choreographs the polarization, mitochondrial metabolism, and migration of T lymphocytes. Science signaling 43 32994212
2017 P2Y11 Receptors: Properties, Distribution and Functions. Advances in experimental medicine and biology 42 29134605
2000 Pharmacological characterisation of the P2Y11 receptor in stably transfected haematological cell lines. Molecular and cellular biochemistry 42 11129961
2014 Participation of peripheral P2Y1, P2Y6 and P2Y11 receptors in formalin-induced inflammatory pain in rats. Pharmacology, biochemistry, and behavior 41 25449358
2007 Involvement of P2Y1 and P2Y11 purinoceptors in parasympathetic inhibition of colonic smooth muscle. The Journal of pharmacology and experimental therapeutics 41 18048695
2007 Structure and ligand-binding site characteristics of the human P2Y11 nucleotide receptor deduced from computational modelling and mutational analysis. The Biochemical journal 40 17338680
2007 NAADP+ is an agonist of the human P2Y11 purinergic receptor. Cell calcium 40 17707504
2001 An arginine/glutamine difference at the juxtaposition of transmembrane domain 6 and the third extracellular loop contributes to the markedly different nucleotide selectivities of human and canine P2Y11 receptors. Molecular pharmacology 39 11723245
2014 Activation of P2RY11 and ATP release by lipoxin A4 restores the airway surface liquid layer and epithelial repair in cystic fibrosis. American journal of respiratory cell and molecular biology 38 24588705
2001 Cloning, expression, signaling mechanisms, and membrane targeting of P2Y(11) receptors in Madin Darby canine kidney cells. Molecular pharmacology 37 11408597
2009 Extracellular NAD(+) induces a rise in [Ca(2+)](i) in activated human monocytes via engagement of P2Y(1) and P2Y(11) receptors. Cell calcium 36 19748117
2017 Carcinoma-specific expression of P2Y11 receptor and its contribution in ATP-induced purinergic signalling and cell migration in human hepatocellular carcinoma cells. Oncotarget 35 28418839
2015 Hypoxia/Reoxygenation Inhibits P2Y11 Receptor Expression and Its Immunosuppressive Activity in Human Dendritic Cells. Journal of immunology (Baltimore, Md. : 1950) 31 26078273
2012 P2Y11 purinoceptor mediates the ATP-enhanced chemotactic response of rat neutrophils. Journal of pharmacological sciences 30 23182888
2019 Lipopolysaccharide suppresses T cells by generating extracellular ATP that impairs their mitochondrial function via P2Y11 receptors. The Journal of biological chemistry 29 30787105
2000 Signal transduction and white cell maturation via extracellular ATP and the P2Y11 receptor. Immunology and cell biology 29 10947861
2015 Calcium signaling and the novel anti-proliferative effect of the UTP-sensitive P2Y11 receptor in rat cardiac myofibroblasts. Cell calcium 27 26324417
2006 Opposite diastereoselective activation of P2Y1 and P2Y11 nucleotide receptors by adenosine 5'-O-(alpha-boranotriphosphate) analogues. British journal of pharmacology 27 16953187
2001 P2Y(11) receptor expression by human lymphocytes: evidence for two cAMP-linked purinoceptors. European journal of pharmacology 27 11527539
2013 Extracellular NAADP affords cardioprotection against ischemia and reperfusion injury and involves the P2Y11-like receptor. Biochemical and biophysical research communications 24 23583195
2013 Involvement of P2Y₁₁ receptor in IFN-γ-induced IL-6 production in human keratinocytes. European journal of pharmacology 23 23461851
2007 New iantherans from the marine sponge Ianthella quadrangulata: novel agonists of the P2Y(11) receptor. Journal of medicinal chemistry 21 17941622
2019 Stimulation of P2Y11 receptor protects human cardiomyocytes against Hypoxia/Reoxygenation injury and involves PKCε signaling pathway. Scientific reports 20 31406184
2020 Frontline Science: P2Y11 receptors support T cell activation by directing mitochondrial trafficking to the immune synapse. Journal of leukocyte biology 19 32531829
2019 The Human G Protein-Coupled ATP Receptor P2Y11 Is Associated With IL-10 Driven Macrophage Differentiation. Frontiers in immunology 19 31447857
2019 ATP-Evoked Intracellular Ca2+ Responses in M-CSF Differentiated Human Monocyte-Derived Macrophage are Mediated by P2X4 and P2Y11 Receptor Activation. International journal of molecular sciences 19 31618941
2000 Capacity for purinergic control of renin promoter via P2Y(11) receptor and cAMP pathways. Hypertension (Dallas, Tex. : 1979) 19 11116131
2022 The P2Y11 receptor of human M2 macrophages activates canonical and IL-1 receptor signaling to translate the extracellular danger signal ATP into anti-inflammatory and pro-angiogenic responses. Cellular and molecular life sciences : CMLS 18 36107259
2021 ATP Inhibits Breast Cancer Migration and Bone Metastasis through Down-Regulation of CXCR4 and Purinergic Receptor P2Y11. Cancers 18 34503103
2017 The effect of purinergic signaling via the P2Y11 receptor on vascular function in a rat model of acute inflammation. Molecular and cellular biochemistry 18 28213772
2014 Alanine-(87)-threonine polymorphism impairs signaling and internalization of the human P2Y11 receptor, when co-expressed with the P2Y1 receptor. Journal of neurochemistry 17 24524250
2013 Intracellular NAADP increase induced by extracellular NAADP via the P2Y11-like receptor. Biochemical and biophysical research communications 17 23726915
2011 P2Y11 impairs cell proliferation by induction of cell cycle arrest and sensitizes endothelial cells to cisplatin-induced cell death. Journal of cellular biochemistry 17 21503959
2021 The human G protein-coupled ATP receptor P2Y11 is a target for anti-inflammatory strategies. British journal of pharmacology 16 33463722
2018 Stimulation of P2Y11 receptor modulates cardiac fibroblasts secretome toward immunomodulatory and protective roles after Hypoxia/Reoxygenation injury. Journal of molecular and cellular cardiology 16 30031814
2014 UTP is not a biased agonist at human P2Y(11) receptors. Purinergic signalling 15 25015314
2008 Diastereoselectivity of the P2Y11 nucleotide receptor: mutational analysis. British journal of pharmacology 15 18820714
2014 Involvement of P2Y11 receptor in silica nanoparticles 30-induced IL-6 production by human keratinocytes. Toxicology 14 24793913
2020 Modulation of P2Y11-related purinergic signaling in inflammation and cardio-metabolic diseases. European journal of pharmacology 11 32142768
2000 Differential regulation of P2Y(11) receptor-mediated signalling to phospholipase C and adenylyl cyclase by protein kinase C in HL-60 promyelocytes. British journal of pharmacology 11 11015299
2019 The antagonist of P2Y11 receptor NF157 ameliorates oxidized LDL-induced vascular endothelial inflammation. Artificial cells, nanomedicine, and biotechnology 10 31066305
2018 Stimulation of murine P2Y11-like purinoreceptor protects against hypoxia/reoxygenation injury and decreases heart graft rejection lesions. The Journal of thoracic and cardiovascular surgery 9 30711276
2013 Sp-2-propylthio-ATP-α-B and Sp-2-propylthio-ATP-α-B,β-γ-dichloromethylene are novel potent and specific agonists of the human P2Y₁₁ receptor. Biochemical pharmacology 9 23810430
2021 P2Y11 Agonism Prevents Hypoxia/Reoxygenation- and Angiotensin II-Induced Vascular Dysfunction and Intimal Hyperplasia Development. International journal of molecular sciences 8 33467058
2019 P2Y11 receptor antagonist NF340 ameliorates inflammation in human fibroblast-like synoviocytes: An implication in rheumatoid arthritis. IUBMB life 8 31301116
2018 A Novel Mechanism of γ-Irradiation-Induced IL-6 Production Mediated by P2Y11 Receptor in Epidermal Keratinocytes. Biological & pharmaceutical bulletin 8 29553088
2021 High nocturnal sleep fragmentation is associated with low T lymphocyte P2Y11 protein levels in narcolepsy type 1. Sleep 7 33710305
2020 P2Y4, P2Y6 and P2Y11 receptors: From the early days of cloning to their function. Biochemical pharmacology 7 33232731
2018 Inhibition of cytokine-mediated JNK signalling by purinergic P2Y11 receptors, a novel protective mechanism in endothelial cells. Cellular signalling 7 30076967
2016 Validation of antibodies for neuroanatomical localization of the P2Y11 receptor in macaque brain. Journal of chemical neuroanatomy 7 27515691
2025 Shigella infection is facilitated by interaction of human enteric α-defensin 5 with colonic epithelial receptor P2Y11. Nature microbiology 6 39901059
2019 Antagonism of P2Y11 receptor (P2Y11R) protects epidermal stem cells against UV-B irradiation. American journal of translational research 6 31497195
2023 Systematic P2Y receptor survey identifies P2Y11 as modulator of immune responses and virus replication in macrophages. The EMBO journal 5 37881155
2018 Adenosine diphosphate-sensitive P2Y11 receptor inhibits endothelial cell proliferation by induction of cell cycle arrest in the S phase and induces the expression of inflammatory mediators. Journal of cellular biochemistry 4 30144157
2024 Deficiency of P2RY11 causes narcolepsy and attenuates the recruitment of neutrophils and macrophages in the inflammatory response in zebrafish. Cell biology and toxicology 3 38771396
2025 Noncanonical NF-κB signaling in dendritic cells is required for ATP-driven indoleamine 2,3-dioxygenase 1 induction through P2Y11 receptor. Journal of leukocyte biology 2 39899472
2024 Crosstalk between purinergic receptor P2Y11 and chemokine receptor CXCR7 is regulated by CXCR4 in human macrophages. Cellular and molecular life sciences : CMLS 2 38472446
2019 Altered surface expression of P2Y11 receptor with narcolepsy-associated mutations. Pharmacological reports : PR 2 31450027
2026 Human enteric defensin 5 protects intestinal barrier integrity via cell state-dependent P2Y11-FAK-Rac1 signaling. Mucosal immunology 0 42144107

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