{"gene":"P2RY6","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":1996,"finding":"Human P2Y6 receptor, cloned from placenta cDNA library, is a Gq-coupled GPCR that stimulates IP3 formation in response to UDP (most potent), with agonist rank order: UDP > 5-bromo-UTP > UTP > ADP > 2-methylthio-ATP >> ATP, establishing it as a pyrimidinergic receptor.","method":"Stable expression in 1321N1 cells, IP3 accumulation assay","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct enzymatic/signaling assay in recombinant system; foundational pharmacological characterization replicated across multiple subsequent studies","pmids":["8670200"],"is_preprint":false},{"year":1997,"finding":"P2Y6 receptor activates IP3 production via a pertussis toxin-insensitive G-protein (Gq) and displays markedly slow desensitization compared to P2Y4: maximal IP3 response takes ~15 min and is maintained for ≥3 h; full second response is obtained after 45 min but lost after 165 min.","method":"IP3 accumulation assay in P2Y6-expressing 1321N1 cells; pertussis toxin treatment","journal":"European journal of pharmacology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro signaling assay with pharmacological dissection; reproduced in multiple downstream studies","pmids":["9226417"],"is_preprint":false},{"year":1999,"finding":"Heterologously expressed rat P2Y6 receptor couples to N-type Ca2+ channels (inhibition ~53–73%) and M-type K+ channels (inhibition up to 71%) in rat sympathetic neurons; N-type Ca2+ channel inhibition is partially PTX-sensitive (via Gi/Go) whereas M-type K+ channel inhibition is PTX-resistant, demonstrating dual G-protein coupling.","method":"cRNA microinjection into rat sympathetic neurons; whole-cell and perforated-patch voltage clamp; pertussis toxin treatment","journal":"British journal of pharmacology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct electrophysiological reconstitution in neurons with pharmacological dissection of G-protein pathways","pmids":["10193782"],"is_preprint":false},{"year":2000,"finding":"P2Y6 receptor stimulation causes translocation of RhoA to the membrane and activates Rho kinase-dependent actin stress fiber formation in aortic myocytes and Swiss 3T3 cells transfected with P2Y6; this is blocked by C3 exoenzyme and the Rho kinase inhibitor Y-27632, and by dominant-negative RhoA.","method":"Transfection of P2Y6 into Swiss 3T3 cells; membrane fractionation for RhoA; phalloidin staining for actin; dominant-negative RhoA and pharmacological inhibitors","journal":"American journal of physiology. Heart and circulatory physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (dominant-negative, pharmacological inhibition, fractionation) in multiple cell types; replicated for multiple P2Y subtypes","pmids":["10843869"],"is_preprint":false},{"year":2000,"finding":"P2Y6 receptor undergoes slow agonist-dependent loss of cell surface receptors that does not recover rapidly after UDP removal (unlike P2Y4 which rapidly recycles); PKC and Ca2+-activated kinases are not involved. C-terminal Ser-333/Ser-334 of P2Y4 mediate rapid phosphorylation/desensitization/internalization — equivalent determinants absent in P2Y6 explain its resistance.","method":"Radioligand binding for surface receptor quantification; [32P]-phosphorylation of wild-type and truncation/point mutants; flow cytometry","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct mutagenesis and phosphorylation assays; mechanistic comparison between P2Y4 and P2Y6 in single study","pmids":["11114308"],"is_preprint":false},{"year":2002,"finding":"UDP acting on P2Y6 receptor promotes vascular smooth muscle cell mitogenesis (DNA and protein synthesis, cell cycle S/G2 progression) via phospholipase C, possibly PKC-δ, and a tyrosine kinase pathway, independent of Gi, eicosanoids, and PKA.","method":"[3H]-thymidine and [3H]-leucine incorporation; flow cytometry; selective P2Y6 agonist UDPβS; pharmacological inhibitors; hexokinase control to exclude UDP→UTP conversion","journal":"American journal of physiology. Heart and circulatory physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal assays with selective agonist and pharmacological pathway dissection; replicated across receptor subtypes","pmids":["11788430"],"is_preprint":false},{"year":2003,"finding":"P2Y6 receptor activation by UDP protects 1321N1 astrocytoma cells against TNFα-induced apoptosis by activating PKCα, PKCε, and PKCζ isotypes and ERK1/2; this is partially blocked by PKC inhibitors (GF109203X, Gö6976) and ERK inhibitors (PD98059, U0126), but not by Akt inhibition or calcium chelation.","method":"Flow cytometry for apoptosis; PKC isotype activation assays; pharmacological kinase inhibitors; ERK phosphorylation assays","journal":"Cellular and molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple kinase pathway dissections with pharmacological inhibitors in single lab study","pmids":["12825835"],"is_preprint":false},{"year":2003,"finding":"Basolateral P2Y6 receptor in colonic epithelium stimulates sustained Cl- secretion via both Ca2+ and cAMP; in Xenopus oocytes co-expressing P2Y6 and CFTR, UDP activates first a transient Ca2+-activated Cl- current and subsequently CFTR current, establishing P2Y6 as a receptor able to elevate both [Ca2+]i and cAMP.","method":"Ussing chamber electrophysiology; cAMP assay in colonic crypts; Xenopus oocyte two-electrode voltage clamp co-expressing P2Y6 + CFTR; RT-PCR and immunohistochemistry","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution in Xenopus oocytes plus native tissue Ussing chamber; multiple orthogonal methods","pmids":["12569163"],"is_preprint":false},{"year":2004,"finding":"Diisothiocyanate derivatives MRS2567 and MRS2578 are potent, insurmountable antagonists selective for P2Y6 over P2Y1, P2Y2, P2Y4, and P2Y11 receptors (IC50 of MRS2578 ~37 nM at human P2Y6); at 1 µM, they completely block UDP-mediated protection from TNFα-induced apoptosis.","method":"PLC/IP3 assay in recombinant P2Y receptor-expressing 1321N1 cells; concentration-response inhibition curves; apoptosis assay","journal":"Biochemical pharmacology","confidence":"High","confidence_rationale":"Tier 1 / Strong — quantitative in vitro pharmacology with selectivity panel; replicated in multiple downstream studies as gold-standard antagonist tool","pmids":["15081875"],"is_preprint":false},{"year":2005,"finding":"P2Y6 receptor activation by UDP or the selective agonist INS48823 activates NF-κB (p65 nuclear translocation) in osteoclasts via a proteasome-dependent pathway, and enhances osteoclast survival; this effect is direct (not dependent on RANK ligand) and blocked by the NF-κB inhibitor SN50.","method":"Immunofluorescence for NF-κB p65; RT-PCR in purified osteoclasts; calcium imaging; cell survival assay; SN50 peptide inhibitor; osteoprotegerin control","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (calcium, NF-κB translocation, survival) with specific pharmacological controls in purified osteoclasts","pmids":["15722352"],"is_preprint":false},{"year":2005,"finding":"HNP (human neutrophil peptide)-induced IL-8 production in lung epithelial cells is mediated predominantly through the P2Y6 signaling pathway, as shown by antisense oligonucleotide knockdown of specific P2Y receptor subtypes.","method":"Antisense oligonucleotide knockdown of P2Y receptors; ELISA for IL-8; comparison with UDP and ATP stimulation","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — specific knockdown approach in endogenous system; single lab but targeted mechanistic interrogation","pmids":["16322472"],"is_preprint":false},{"year":2006,"finding":"P2Y6 receptor mediates positive inotropy in cardiomyocytes via a phospholipase C/IP3 pathway: the selective agonist UDPβS increases cardiomyocyte contraction by 35%, and this is abolished by the P2Y6 blocker MRS2578 and the PLC inhibitor U73122.","method":"Electrically stimulated isolated mouse cardiomyocytes; contraction measurement; pharmacological inhibitors; Western blot and immunohistochemistry for receptor expression","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — selective agonist/antagonist combination with pathway inhibitor in native cardiomyocytes; replicated with consistent mechanistic logic","pmids":["16543499"],"is_preprint":false},{"year":2007,"finding":"UDP acting on microglial P2Y6 receptor triggers phagocytosis of microspheres in a concentration-dependent, P2Y6-dependent manner; P2Y6 mRNA is upregulated in activated microglia after kainic acid-induced neuronal damage; leaked UDP from damaged neurons acts as the endogenous signal.","method":"Microsphere uptake assay; selective antagonist MRS2578; kainic acid in vivo model; RT-PCR and in situ hybridization","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional phagocytosis assay with selective pharmacological tools in both in vitro and in vivo models; published in Nature with clear mechanistic chain","pmids":["17410128"],"is_preprint":false},{"year":2007,"finding":"P2Y6 and P2Y4 receptors form high-order oligomeric complexes (up to dimers) in native neuronal phenotypes; P2Y6 exists as both dimers and monomers in lipid rafts of synaptosomes; UDP ligand activation shifts P2Y6 oligomerization state, whereas P2Y4 is unaffected; in PC12 cells, endogenous P2Y4 forms hetero-oligomers specifically with P2Y6.","method":"Blue Native PAGE; SDS-PAGE; co-immunoprecipitation; sucrose gradient fractionation of lipid rafts; synaptosome preparations","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — native gel and co-IP in endogenous system; single lab, multiple orthogonal methods","pmids":["17481575"],"is_preprint":false},{"year":2008,"finding":"P2Y6 receptor signaling through Gα12/13 in cardiomyocytes triggers pressure overload-induced cardiac fibrosis: mechanical stretch causes ATP/UDP release via pannexin hemichannels, which activates P2Y6 receptors, inducing expression of fibrogenic genes (TGF-β, CTGF, periostin) and ACE upstream of the Ang II–TGF-β pathway.","method":"Transgenic expression of Gα12/13 inhibitory polypeptides; pressure overload model; pannexin hemichannel inhibition; P2Y6 receptor antagonism; gene expression analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic and pharmacological dissection in vivo and in vitro; multiple pathway components validated; published in EMBO Journal","pmids":["19008857"],"is_preprint":false},{"year":2008,"finding":"P2Y6 knockout mice lack UDP-stimulated inositol phosphate production in macrophages (confirming P2Y6 is the sole UDP receptor on macrophages), lack UDP-induced endothelium-dependent aortic relaxation, and lack UDP-induced vasoconstriction when eNOS is blocked, demonstrating distinct roles in macrophages, endothelial cells, and vascular smooth muscle.","method":"P2Y6 gene-targeted knockout mice; inositol phosphate assay in macrophages; aortic ring contractility; cytokine ELISA (IL-6, MIP-2, TNF-α)","journal":"Molecular pharmacology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with multiple cell-type functional readouts; clean loss-of-function validates receptor specificity","pmids":["18523137"],"is_preprint":false},{"year":2008,"finding":"P2Y6 receptor activation by UDP stimulates insulin secretion from pancreatic beta-cells in a glucose-dependent manner via a P2Y6-specific mechanism, blocked by MRS2578; P2Y6 is the dominant pyrimidine receptor expressed in islets and purified beta-cells.","method":"Real-time PCR; insulin/glucagon secretion assay from isolated mouse islets and purified beta-cells; selective agonist UDPβS and antagonist MRS2578","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional secretion assay with selective pharmacological tools in native isolated cells; single lab","pmids":["18387359"],"is_preprint":false},{"year":2009,"finding":"P2Y6 receptors on mast cells cooperate with CysLT1R through reciprocal ligand-mediated cross-talk: P2Y6 antagonist MRS2578 blocks ERK activation and survival responses to both UDP and LTD4; both responses are absent in cells lacking CysLT1R or LTC4 synthase, indicating P2Y6 requires an intact cys-LT autocrine loop for its survival/activation signaling.","method":"ERK phosphorylation assay; mast cell survival assay; selective antagonist MRS2578; CysLT1R-knockout and LTC4 synthase-knockout cells; shRNA knockdown","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO and shRNA combined with pharmacology; multiple cell types and readouts; identifies specific cross-talk mechanism","pmids":["19124756"],"is_preprint":false},{"year":2010,"finding":"UDP/P2Y6 signaling in intestinal epithelial cells induces CXCL8 expression via the PKCδ–MEK1/2–ERK1/2–c-fos/c-jun (AP-1) pathway; mutation of the AP-1 site in the CXCL8 promoter abolishes the UDP-stimulating effect; UDP enemas increase neutrophil recruitment to inflamed mouse mucosa.","method":"Luciferase reporter (AP-1 site mutant); chromatin immunoprecipitation (ChIP); Western blot for phosphorylation; qPCR; pharmacological inhibitors; in vivo colitis model + immunofluorescence","journal":"Inflammatory bowel diseases","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP, reporter mutagenesis, and in vivo validation; multiple orthogonal methods identifying specific transcription factor complex","pmids":["22095787"],"is_preprint":false},{"year":2011,"finding":"UDP/P2Y6 activation of microglia and astrocytes induces CCL2 and CCL3 expression via Gq/PLC/calcium-dependent pathway activating NFATc1/c2 transcription factors; calcineurin inhibition and NFAT inhibitors reduce UDP-induced chemokine synthesis; UDP-treated astrocytes recruit monocytes in transmigration assay.","method":"siRNA knockdown of P2Y6; selective antagonist MRS2578; PLC inhibitor; NFAT inhibitors/calcineurin inhibitor; ELISA; RT-PCR; transmigration assay","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — siRNA knockdown combined with specific antagonist and multiple pathway inhibitors with defined transcription factor identification","pmids":["21317391"],"is_preprint":false},{"year":2011,"finding":"P2Y6 receptor stimulation by extracellular UDP promotes bone resorption: it stimulates osteoclast formation from precursors and enhances mature osteoclast resorptive activity; P2Y6R-/- mice have increased bone mineral content, cortical bone volume, and cortical thickness, with decreased osteoclast surface.","method":"P2Y6 knockout mice; osteoclast resorption pit assay; DEXA scanning; microcomputed tomography; histomorphometry","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse with multiple in vivo skeletal phenotypes plus in vitro functional assays","pmids":["21828185"],"is_preprint":false},{"year":2013,"finding":"P2Y6 receptor activation of PLC mediates hydrolysis of PI(4,5)P2, which inhibits P2X4 channel function in microglia: P2Y6 activation reduces P2X4-mediated Ca2+ entry, current amplitude, activation/desensitization rates, and large-conductance pore dilation (YO-PRO-1 uptake); PI(4,5)P2 depletion underlies this crosstalk; P2Y6 also modulates ATP-dependent microglial migration.","method":"Calcium imaging; YO-PRO-1 uptake assay; whole-cell patch clamp in recombinant systems; PI(4,5)P2 manipulation; primary microglia and LPS-activated microglia; migration assay","journal":"Glia","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution in recombinant system plus primary microglia; electrophysiology with multiple readouts; identified PI(4,5)P2 as mechanistic intermediary","pmids":["24123515"],"is_preprint":false},{"year":2013,"finding":"P2Y6 receptor activation causes bladder overactivity by releasing ATP from the urothelium via pannexin-1 hemichannels; P2Y6 and pannexin-1 co-localize in the urothelium; P2Y6 agonist-induced bladder hyperactivity and ATP release are blocked by pannexin-1 hemichannel inhibitors (10Panx, carbenoxolone) but not systemic routes, establishing a luminal paracrine mechanism.","method":"In vivo urodynamics in anesthetized rats; propidium iodide hemichannel permeability assay; confocal co-localization; ATP bioluminescence; selective P2Y6 agonist PSB0474 and antagonist MRS2578","journal":"Biochemical pharmacology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo functional + in vitro mechanistic + co-localization; multiple orthogonal methods identifying pannexin-1 as downstream effector","pmids":["24269631"],"is_preprint":false},{"year":2013,"finding":"P2Y6 receptor activation in spinal microglia induces CCL2 production via a PLC→Src tyrosine kinase→ERK1/2 and p38 MAPK→NF-κB pathway; selective P2Y6 antagonist MRS2578 blocks CCL2, and UTP effect is not blocked by P2Y2 siRNA, confirming P2Y6 mediates this response.","method":"Primary spinal microglia cultures; ELISA and RT-PCR for CCL2; selective P2Y6 antagonist MRS2578; P2Y2 siRNA knockdown; kinase inhibitors (U0126, SB202190, U73122, PP2); NF-κB assay","journal":"Neuropharmacology","confidence":"High","confidence_rationale":"Tier 2 / Strong — selective knockdown plus pharmacological dissection of signaling cascade in primary cells; multiple pathway nodes validated","pmids":["23916475"],"is_preprint":false},{"year":2014,"finding":"Blocking UDP/P2Y6 signaling (with apyrase, Reactive Blue 2, or MRS2578) prevents microglial phagocytosis of viable neurons (phagoptosis) induced by LPS, lipoteichoic acid, amyloid-β, peroxynitrite, or reactive nitrogen species, and prevents neuronal loss; UDP alone is sufficient to stimulate microglial phagocytosis and cause neuronal loss reversible by microglial elimination.","method":"Mixed neuronal/glial cultures; neuronal viability assay; selective P2Y6 antagonist MRS2578; apyrase; in vivo LPS injection into rat striatum with MRS2578 treatment","journal":"Glia","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple stimuli, pharmacological tools, in vivo validation; establishes P2Y6 as required and sufficient for phagoptosis","pmids":["24838858"],"is_preprint":false},{"year":2014,"finding":"P2Y6 receptor activation in microglia induces NO release via the PLC-PKC-iNOS pathway, which causes apoptosis in neighboring astrocytes but not microglia; this limits astrocyte proliferation and prevents excessive astrogliosis in LPS-treated microglia-astrocyte co-cultures.","method":"Co-cultures of microglia and astrocytes; Griess reaction for NO; TUNEL/Hoechst staining; Western blot and immunofluorescence for P2Y6 and iNOS; PLC, PKC, and NOS inhibitors; selective P2Y6 agonist PSB0474 and antagonist MRS2578","journal":"Journal of neuroinflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — selective pharmacological tools with multiple readouts in co-culture system; single lab","pmids":["25178395"],"is_preprint":false},{"year":2014,"finding":"P2Y6 receptor activation in spinal microglia (but not astrocytes) contributes to neuropathic pain maintenance; minocycline (microglial inhibitor) reduces P2Y6 upregulation but fluorocitrate (astrocyte inhibitor) does not, placing P2Y6 specifically in spinal microglia in this pain pathway.","method":"Spinal nerve ligation model in rats; intrathecal antagonist administration (MRS2578); minocycline and fluorocitrate treatment; Iba-1/GFAP immunostaining; Western blot for P2Y6","journal":"Molecular pain","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo nerve injury model with selective pharmacology and cell-type dissection; single lab","pmids":["24886406"],"is_preprint":false},{"year":2014,"finding":"P2Y6 receptor promotes glucose uptake in skeletal muscle and adipocytes via AMPK phosphorylation, GLUT4 membrane recruitment, and HDAC5 signaling; P2Y6R-knockout adipocytes show no increase in glucose uptake upon P2Y6 agonist treatment; AMPK siRNA or Compound C abolishes P2Y6-mediated glucose uptake.","method":"[3H]2-deoxyglucose uptake assay; GLUT4 membrane recruitment assay; AMPK phosphorylation (Western blot); AMPK siRNA; P2Y6R-KO adipocytes; selective agonist MRS2957 and antagonist MRS2578","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO validation combined with siRNA pathway dissection and multiple functional readouts in two cell types","pmids":["25249240"],"is_preprint":false},{"year":2015,"finding":"AgRP neurons in the arcuate nucleus express P2Y6 receptor; central UDP application promotes AgRP neuron action potential firing, ERK phosphorylation, and cFos expression; central UDP promotes feeding, which is abrogated by P2Y6 knockout or pharmacogenetic inhibition of AgRP neurons; hypothalamic UDP is elevated in obese animals due to increased circulating uridine.","method":"Brain slice electrophysiology; in vivo ERK/cFos assays; intracerebroventricular UDP injection; P2Y6 KO mice; AgRP-specific pharmacogenetics (DREADDs); obese mouse model metabolomics","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — electrophysiology in brain slices, genetic KO, and pharmacogenetics converge on same mechanism; published in Cell","pmids":["26359991"],"is_preprint":false},{"year":2016,"finding":"P2Y6R and AT1R form stable heterodimers that enhance G protein-dependent (Gα-q/12/13) vascular hypertrophy signaling while reducing β-arrestin-dependent AT1R internalization; P2Y6R expression increases with age in vascular smooth muscle cells, converting AT1R signaling from β-arrestin-dependent proliferation to G protein-dependent hypertrophy; MRS2578 disrupts heterodimers and suppresses Ang II-induced hypertension.","method":"Co-immunoprecipitation for heterodimer formation; P2Y6R KO mice; blood pressure measurement; vascular remodeling assays; β-arrestin assay; age-dependent expression analysis; pharmacological disruption with MRS2578","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP for complex, KO mouse phenotype, signaling pathway switch, pharmacological rescue; multiple orthogonal approaches","pmids":["26787451"],"is_preprint":false},{"year":2016,"finding":"P2Y6 receptor is essential for myogenic tone (MT) of resistance arteries: P2Y6 activation is mandatory for RhoA-GTP binding, myosin light chain, p42/44, and JNK phosphorylation in arterial smooth muscle cells; MT is abrogated by P2Y6 blockade and absent in P2ry6-/- arteries; nucleotide release through hemichannels (Cx43, P2X7) triggers autocrine P2Y6 signaling upon pressure.","method":"Arteriography of mesenteric arteries; P2ry6-/- mice; hemichannel inhibitors; Cx43+/- and P2rx7-/- mice; RhoA-GTP pulldown; phosphorylation assays; myocardial infarction model","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic KO mice combined with pharmacology and signaling readouts; distinct mechanistic chain established","pmids":["27255725"],"is_preprint":false},{"year":2017,"finding":"Prostaglandin E2 glyceryl ester (PGE2-G), a COX-2 product of 2-arachidonoylglycerol, is an endogenous agonist of P2Y6 receptor with an EC50 of ~1 pM (vs ~50 nM for UDP), identified via transcriptome-wide RNA-seq subtractive screening and validated in heterologous and endogenous expression systems with multiple functional readouts.","method":"RNA-seq subtractive screening of responder vs non-responder cell lines; Ca2+ mobilization assay; IP1 assay; heterologous P2Y6 expression; endogenous system validation","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic deorphanization with multiple functional assays in both heterologous and endogenous systems; identifies mechanistically distinct ligand","pmids":["28539604"],"is_preprint":false},{"year":2018,"finding":"P2Y6 receptor promotes colorectal tumor cell survival by stabilizing XIAP via AKT-mediated phosphorylation, thereby inhibiting apoptosis and contributing to chemoresistance to 5-fluorouracil; P2ry6-/- mice develop fewer and smaller colorectal tumors after AOM/DSS challenge.","method":"P2ry6-/- mice in AOM/DSS CRC model; HT29 cell apoptosis assay; Western blot for XIAP phosphorylation and AKT activation; tumoroids from CRC; MRS2693 selective agonist; 5-FU resistance assay","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse in vivo tumor model plus mechanistic dissection of AKT-XIAP pathway in vitro; multiple orthogonal approaches","pmids":["29454075"],"is_preprint":false},{"year":2020,"finding":"P2Y6 receptor mediates phagocytosis by microglia via Rac1 and MLCK signaling: P2Y6 inhibition decreases Rac1-pRAC1 and MLCK expression after ischemic stroke; P2Y6-mediated phagocytosis is beneficial in ischemic stroke (P2Y6 inhibition aggravates brain atrophy and neurological deficits).","method":"Transient middle cerebral artery occlusion model; MRS2578 treatment; neurological scoring; Western blot for Rac1 and MLCK; brain volume measurement","journal":"CNS neuroscience & therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo stroke model with pharmacological inhibition and signaling readouts; single lab","pmids":["32154670"],"is_preprint":false},{"year":2020,"finding":"Adipocyte-specific P2Y6R deletion protects mice from diet-induced obesity and improves glucose tolerance via reduced JNK signaling, enhanced PPARα activity and downstream PGC1α, and beiging of white adipose tissue; skeletal muscle-specific P2Y6R deletion reduces glucose uptake, impairing glucose homeostasis.","method":"Conditional adipocyte-specific and skeletal muscle-specific P2Y6R KO mice; metabolic phenotyping; RNA-seq; Western blot for JNK, PPARα, PGC1α; whole-body KO comparison","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific conditional KOs with multiple metabolic and molecular readouts; identifies divergent roles in two metabolic tissues","pmids":["33199639"],"is_preprint":false},{"year":2021,"finding":"Microglial P2Y6R mediates tau- and amyloid-β-induced neuronal and memory loss via phagocytosis of neurons: P2Y6R KO prevents Aβ-injection-induced microglial neuronal phagocytosis, neuronal loss, and memory loss in vivo; in P301S TAU mice, P2Y6R KO prevents TAU-induced neuronal and memory loss; in vitro, P2Y6R KO blocks microglial phagocytosis of live but not dead targets.","method":"P2Y6R KO mice; intracerebral Aβ injection; P301S TAU transgenic model; memory testing; in vitro phagocytosis of live vs dead targets; glial-neuronal co-cultures","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent in vivo neurodegenerative models plus in vitro mechanistic assays; distinguishes live vs dead target phagocytosis","pmids":["34965424"],"is_preprint":false},{"year":2022,"finding":"P2Y6 receptor undergoes redox-dependent alternative internalization (REDAI) independent of β-arrestin: electrophilic isothiocyanate compounds covalently modify Cys220 of P2Y6R, promoting ubiquitylation of Lys137 and receptor internalization and degradation; endogenous electrophiles also promote this pathway; Cys220Ser mutant P2Y6R mice show increased colitis susceptibility, linking REDAI to intestinal inflammation control.","method":"Site-directed mutagenesis (Cys220Ser); ubiquitylation assay; internalization/degradation assays in multiple cell lines; Cys220Ser knock-in mice in DSS colitis model; covalent modification assay","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis combined with biochemical assays and in vivo knock-in mouse; identifies novel Cys220-Lys137 mechanism; published in Science Signaling","pmids":["35015570"],"is_preprint":false},{"year":2024,"finding":"Microglial P2Y6 receptor mediates calcium signaling in epileptogenesis by sensing UDP released during seizures (detected with novel GRABUDP1.0 fluorescent sensor); P2Y6 calcium activity drives lysosome biogenesis and NF-κB-related cytokine production; P2Y6 KO prevents microglia from fully engulfing neurons and attenuates CA3 neuron loss and cognitive deficits in epilepsy; calcium extruder ('CalEx') expression recapitulates P2Y6 KO phenotypes.","method":"Novel UDP fluorescent sensor GRABUDP1.0 (in vivo); P2Y6 KO mice; lysosome biogenesis assay; NF-κB cytokine assay; phagocytosis imaging; CalEx viral expression; cognitive testing","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — novel biosensor for direct UDP detection in vivo, KO mouse model, viral CalEx approach; multiple orthogonal readouts; published in Neuron","pmids":["38614103"],"is_preprint":false},{"year":2025,"finding":"P2Y6R functions as an endogenous receptor for long-chain ceramides (C16:0 ceramide), sensing circulating ceramides to activate Gq/NLRP3 inflammasome signaling in endothelial cells and macrophages, thereby aggravating atherosclerosis; P2Y6R deficiency mitigates ceramide-induced and chronic-kidney-disease-aggravated atherosclerosis without affecting cholesterol/ceramide levels.","method":"Systematic GPCR screen (G-protein-signaling quantification + NLRP3 inflammasome assay); P2Y6R and CYSLTR2 genetic/pharmacological inhibition in atherosclerosis mouse models; structural analysis of ceramide-CYSLTR2-Gq complexes (for CYSLTR2); functional validation in endothelial cells and macrophages","journal":"Nature","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic screen plus KO mouse validation for P2Y6R; structural data is for CYSLTR2, not P2Y6R directly; single study but published in Nature","pmids":["40049228"],"is_preprint":false}],"current_model":"P2Y6 is a Gq-coupled (and also Gα12/13- and partially Gi-coupled) GPCR selectively activated by UDP (and by PGE2-G and long-chain ceramides), which triggers PLC/IP3/Ca2+ signaling, RhoA-Rho kinase activation, PKC-ERK-NF-κB cascades, NFAT activation, and cAMP elevation depending on cell context; it drives microglial phagocytosis of neurons and synapses (via lysosome biogenesis and MLCK/Rac1), mediates vascular myogenic tone and cardiac fibrosis through Gα12/13, forms functional heterodimers with AT1R to promote hypertension, promotes feeding via AgRP neuron activation, and undergoes a novel redox-dependent internalization through covalent modification of Cys220 and ubiquitylation of Lys137."},"narrative":{"mechanistic_narrative":"P2RY6 (P2Y6) is a pyrimidinergic G protein-coupled receptor selectively activated by UDP that couples to Gq/phospholipase C to drive IP3/Ca2+ signaling, and engages additional G protein outputs to regulate inflammation, tissue remodeling, and phagocytosis across many cell types [PMID:8670200, PMID:9226417, PMID:18523137]. UDP/P2Y6 stimulation activates downstream cascades including RhoA-Rho kinase-driven actin reorganization [PMID:10843869], PKC-ERK and Src-p38-NF-κB modules that promote cell survival and chemokine output (CCL2, CCL3, CXCL8) [PMID:12825835, PMID:22095787, PMID:21317391, PMID:23916475], and NFAT and AP-1 transcriptional programs [PMID:22095787, PMID:21317391]. Beyond UDP, P2Y6 is activated by the COX-2 product PGE2-glyceryl ester [PMID:28539604] and by long-chain ceramides that trigger Gq/NLRP3 inflammasome signaling to aggravate atherosclerosis [PMID:40049228]. In the CNS, microglial P2Y6 senses UDP leaked from damaged neurons and drives phagocytosis—both clearance of debris and phagoptosis of stressed-but-viable neurons—through Rac1/MLCK signaling, lysosome biogenesis, and NF-κB-dependent cytokine production, contributing to neuronal and memory loss in amyloid-β and tau models and to neuronal engulfment in epilepsy and stroke [PMID:17410128, PMID:24838858, PMID:32154670, PMID:34965424, PMID:38614103]. In the vasculature and heart, P2Y6 couples through Gα12/13 to mediate myogenic tone, pressure-overload cardiac fibrosis, and—via stable heterodimerization with the angiotensin II receptor AT1R—a shift toward G protein-dependent hypertrophy that promotes hypertension [PMID:19008857, PMID:26787451, PMID:27255725]. P2Y6 also regulates metabolic physiology, promoting AgRP neuron-driven feeding, insulin secretion, and tissue-specific glucose handling [PMID:25249240, PMID:26359991, PMID:33199639]. Unlike the rapidly recycling P2Y4, P2Y6 desensitizes slowly [PMID:9226417, PMID:11114308] and undergoes a distinct β-arrestin-independent redox-dependent internalization in which electrophiles covalently modify Cys220 to drive Lys137 ubiquitylation, degradation, and control of intestinal inflammation [PMID:35015570].","teleology":[{"year":1996,"claim":"Establishing the identity and pharmacology of an orphan-like P2Y receptor defined P2Y6 as a UDP-preferring, Gq-coupled pyrimidinergic receptor distinct from ATP-responsive subtypes.","evidence":"Cloning from placenta cDNA and IP3 accumulation in stably expressing 1321N1 cells with defined agonist rank order","pmids":["8670200"],"confidence":"High","gaps":["Endogenous ligand identity beyond UDP not addressed","No structural basis for nucleotide selectivity"]},{"year":1997,"claim":"Characterizing desensitization kinetics revealed that P2Y6 signaling is unusually slow and sustained, distinguishing it functionally from related P2Y4.","evidence":"IP3 assays with pertussis toxin treatment in P2Y6-expressing 1321N1 cells","pmids":["9226417"],"confidence":"High","gaps":["Molecular basis of slow desensitization not resolved here"]},{"year":1999,"claim":"Reconstitution in neurons showed P2Y6 is not strictly Gq-restricted but exhibits dual G-protein coupling, modulating ion channels through both PTX-sensitive and PTX-resistant pathways.","evidence":"cRNA microinjection and voltage clamp in rat sympathetic neurons with PTX dissection","pmids":["10193782"],"confidence":"High","gaps":["Native neuronal relevance of recombinant coupling not established","Specific Gα subunits not identified"]},{"year":2000,"claim":"Identifying RhoA/Rho-kinase activation and defining the structural determinants of internalization explained both P2Y6's cytoskeletal effects and its resistance to rapid desensitization.","evidence":"Membrane fractionation, dominant-negative RhoA, and phosphorylation/truncation mutagenesis in transfected cells","pmids":["10843869","11114308"],"confidence":"Medium","gaps":["Internalization mechanism characterized by comparison to P2Y4 in single study","G protein linking P2Y6 to RhoA not defined"]},{"year":2003,"claim":"Demonstrating UDP/P2Y6 anti-apoptotic and dual Ca2+/cAMP signaling extended the receptor's outputs to cell survival and epithelial secretion beyond canonical PLC/Ca2+.","evidence":"PKC/ERK pathway dissection in astrocytoma; Ussing chamber and Xenopus oocyte CFTR co-expression","pmids":["12825835","12569163"],"confidence":"High","gaps":["Mechanism of cAMP elevation by a Gq-coupled receptor unresolved","PKC isotype specificity inferred pharmacologically"]},{"year":2004,"claim":"Development of selective insurmountable antagonists (MRS2578/MRS2567) provided the gold-standard tools that enabled subsequent loss-of-function dissection in native systems.","evidence":"PLC/IP3 inhibition curves across a P2Y selectivity panel in 1321N1 cells","pmids":["15081875"],"confidence":"High","gaps":["Off-target effects at high concentrations not fully excluded"]},{"year":2008,"claim":"Genetic knockout confirmed P2Y6 is the sole macrophage UDP receptor and defined its non-redundant roles in macrophage, endothelial, and smooth muscle responses, validating receptor specificity.","evidence":"P2Y6 gene-targeted mice with inositol phosphate assays and aortic ring contractility","pmids":["18523137"],"confidence":"High","gaps":["Cell-autonomous versus systemic contributions not separated"]},{"year":2007,"claim":"Discovery that microglial P2Y6 senses neuronally leaked UDP to trigger phagocytosis established the receptor as a 'find/eat-me' sensor in CNS injury.","evidence":"Microsphere phagocytosis with MRS2578 plus kainic acid in vivo injury model","pmids":["17410128"],"confidence":"High","gaps":["Downstream phagocytic machinery not yet defined","Distinction between debris clearance and viable-cell engulfment not made"]},{"year":2008,"claim":"Linking P2Y6 to Gα12/13 in cardiomyocytes connected mechanical-stress nucleotide release to fibrogenic gene programs, defining a pathological cardiac remodeling axis.","evidence":"Transgenic Gα12/13 inhibitory peptides, pannexin inhibition, and pressure overload model","pmids":["19008857"],"confidence":"High","gaps":["Relative contribution of Gα12/13 versus Gq in vivo not quantified"]},{"year":2011,"claim":"Defining NFAT- and AP-1-driven chemokine programs placed P2Y6 upstream of specific transcription factors governing leukocyte recruitment in glia and epithelium.","evidence":"siRNA/antagonist plus reporter mutagenesis, ChIP, and transmigration assays","pmids":["21317391","22095787"],"confidence":"High","gaps":["In vivo necessity of each transcription factor downstream of P2Y6 not isolated"]},{"year":2013,"claim":"Identifying PI(4,5)P2 hydrolysis-mediated crosstalk with P2X4 and pannexin-1-dependent ATP release revealed how P2Y6 integrates with other purinergic signaling to shape microglial and urothelial responses.","evidence":"Patch clamp, YO-PRO-1 uptake, PI(4,5)P2 manipulation, and in vivo urodynamics with co-localization","pmids":["24123515","24269631"],"confidence":"High","gaps":["Physiological setting where P2Y6-P2X4 crosstalk dominates not defined"]},{"year":2014,"claim":"Demonstrating that UDP/P2Y6 is necessary and sufficient for phagoptosis of viable neurons reframed P2Y6-driven microglial phagocytosis as a driver of neuronal loss, not just debris clearance.","evidence":"Multiple inflammatory stimuli with antagonist/apyrase in mixed cultures and in vivo LPS striatal injection","pmids":["24838858"],"confidence":"High","gaps":["Signals marking neurons as viable phagoptosis targets not fully defined"]},{"year":2016,"claim":"Discovery of stable P2Y6R-AT1R heterodimers and a requirement for P2Y6 in myogenic tone explained an age-dependent signaling switch toward G protein-dependent vascular hypertrophy and hypertension.","evidence":"Co-IP, P2Y6 KO mice, blood pressure and β-arrestin assays; arteriography in P2ry6-/- mice with hemichannel and RhoA readouts","pmids":["26787451","27255725"],"confidence":"High","gaps":["Structural basis of the heterodimer interface unknown","Generality of the AT1R switch across vascular beds not established"]},{"year":2017,"claim":"Deorphanizing P2Y6 toward PGE2-glyceryl ester showed the receptor responds to a lipid agonist with far higher potency than UDP, broadening its ligand repertoire beyond nucleotides.","evidence":"RNA-seq subtractive screen with Ca2+/IP1 assays in heterologous and endogenous systems","pmids":["28539604"],"confidence":"High","gaps":["Physiological contexts where PGE2-G versus UDP dominate not delineated"]},{"year":2018,"claim":"Linking P2Y6 to AKT-mediated XIAP stabilization defined a pro-survival, chemoresistance-promoting role in colorectal tumorigenesis.","evidence":"P2ry6-/- mice in AOM/DSS model with XIAP/AKT biochemistry and 5-FU resistance assays","pmids":["29454075"],"confidence":"High","gaps":["Whether tumor effect is microglial/immune or epithelial-cell-intrinsic not fully resolved"]},{"year":2020,"claim":"Tissue-specific knockouts and stroke models resolved P2Y6's divergent metabolic and phagocytic roles, including opposing outcomes in adipose versus muscle and beneficial phagocytosis in ischemia.","evidence":"Adipocyte- and muscle-specific conditional KO metabolic phenotyping; tMCAO with Rac1/MLCK readouts","pmids":["33199639","32154670"],"confidence":"High","gaps":["Stroke study relies on pharmacology in single lab","Reconciliation of beneficial (stroke) versus detrimental (neurodegeneration) phagocytosis not mechanistically settled"]},{"year":2021,"claim":"Genetic demonstration that microglial P2Y6 drives amyloid-β- and tau-induced neuronal and memory loss via live-cell phagocytosis positioned the receptor as a disease-relevant phagoptosis effector.","evidence":"P2Y6R KO in Aβ injection and P301S TAU models with memory testing and live-versus-dead target phagocytosis assays","pmids":["34965424"],"confidence":"High","gaps":["Therapeutic window for inhibition versus loss of protective clearance not defined"]},{"year":2022,"claim":"Identifying redox-dependent alternative internalization (REDAI) via Cys220 covalent modification and Lys137 ubiquitylation revealed a β-arrestin-independent regulatory mechanism controlling receptor levels and intestinal inflammation.","evidence":"Cys220Ser mutagenesis, ubiquitylation/internalization assays, and Cys220Ser knock-in mice in DSS colitis","pmids":["35015570"],"confidence":"High","gaps":["Endogenous electrophiles driving physiological REDAI not fully cataloged","Ubiquitin ligase mediating Lys137 ubiquitylation not identified"]},{"year":2024,"claim":"Direct in vivo UDP imaging tied microglial P2Y6 calcium activity to lysosome biogenesis and NF-κB cytokine output during epileptogenesis, mechanistically connecting seizure-released UDP to neuronal engulfment.","evidence":"GRABUDP1.0 biosensor, P2Y6 KO, and CalEx calcium-extrusion approach with cognitive testing","pmids":["38614103"],"confidence":"High","gaps":["Translation to human epilepsy not established"]},{"year":2025,"claim":"Identifying long-chain ceramides as P2Y6 agonists that trigger Gq/NLRP3 inflammasome signaling extended the receptor's role to lipid sensing in atherosclerosis.","evidence":"Systematic GPCR/NLRP3 screen with P2Y6R genetic/pharmacological inhibition in atherosclerosis models","pmids":["40049228"],"confidence":"Medium","gaps":["Structural ceramide-binding data were obtained for CYSLTR2, not P2Y6R directly","Single study"]},{"year":null,"claim":"How distinct ligands (UDP, PGE2-G, ceramides) and G-protein outputs (Gq, Gα12/13, Gi) are selected to produce context-specific outcomes—and how protective versus pathological phagocytosis is determined—remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of human P2Y6 with its endogenous ligands","Ligand-biased signaling rules not defined","Determinants distinguishing beneficial from harmful microglial phagocytosis unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,15,31]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[29]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[31,38]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4,13,29]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3,14]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[18,19,38]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[6,32]}],"complexes":["P2Y6R-AT1R heterodimer","P2Y6-P2Y4 hetero-oligomer"],"partners":["AGTR1","P2RY4","P2RX4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15077","full_name":"P2Y purinoceptor 6","aliases":[],"length_aa":328,"mass_kda":36.4,"function":"Receptor for extracellular UDP > UTP > ATP. The activity of this receptor is mediated by G proteins which activate a phosphatidylinositol-calcium second messenger system","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q15077/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/P2RY6","classification":"Not Classified","n_dependent_lines":48,"n_total_lines":1208,"dependency_fraction":0.039735099337748346},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/P2RY6","total_profiled":1310},"omim":[{"mim_id":"603149","title":"INTERLEUKIN 17A; IL17A","url":"https://www.omim.org/entry/603149"},{"mim_id":"602451","title":"PYRIMIDINERGIC RECEPTOR P2Y, G PROTEIN-COUPLED, 6; P2RY6","url":"https://www.omim.org/entry/602451"},{"mim_id":"600041","title":"PURINERGIC RECEPTOR P2Y, G PROTEIN-COUPLED, 2; 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GPCR that stimulates IP3 formation in response to UDP (most potent), with agonist rank order: UDP > 5-bromo-UTP > UTP > ADP > 2-methylthio-ATP >> ATP, establishing it as a pyrimidinergic receptor.\",\n      \"method\": \"Stable expression in 1321N1 cells, IP3 accumulation assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct enzymatic/signaling assay in recombinant system; foundational pharmacological characterization replicated across multiple subsequent studies\",\n      \"pmids\": [\"8670200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"P2Y6 receptor activates IP3 production via a pertussis toxin-insensitive G-protein (Gq) and displays markedly slow desensitization compared to P2Y4: maximal IP3 response takes ~15 min and is maintained for ≥3 h; full second response is obtained after 45 min but lost after 165 min.\",\n      \"method\": \"IP3 accumulation assay in P2Y6-expressing 1321N1 cells; pertussis toxin treatment\",\n      \"journal\": \"European journal of pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro signaling assay with pharmacological dissection; reproduced in multiple downstream studies\",\n      \"pmids\": [\"9226417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Heterologously expressed rat P2Y6 receptor couples to N-type Ca2+ channels (inhibition ~53–73%) and M-type K+ channels (inhibition up to 71%) in rat sympathetic neurons; N-type Ca2+ channel inhibition is partially PTX-sensitive (via Gi/Go) whereas M-type K+ channel inhibition is PTX-resistant, demonstrating dual G-protein coupling.\",\n      \"method\": \"cRNA microinjection into rat sympathetic neurons; whole-cell and perforated-patch voltage clamp; pertussis toxin treatment\",\n      \"journal\": \"British journal of pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct electrophysiological reconstitution in neurons with pharmacological dissection of G-protein pathways\",\n      \"pmids\": [\"10193782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"P2Y6 receptor stimulation causes translocation of RhoA to the membrane and activates Rho kinase-dependent actin stress fiber formation in aortic myocytes and Swiss 3T3 cells transfected with P2Y6; this is blocked by C3 exoenzyme and the Rho kinase inhibitor Y-27632, and by dominant-negative RhoA.\",\n      \"method\": \"Transfection of P2Y6 into Swiss 3T3 cells; membrane fractionation for RhoA; phalloidin staining for actin; dominant-negative RhoA and pharmacological inhibitors\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (dominant-negative, pharmacological inhibition, fractionation) in multiple cell types; replicated for multiple P2Y subtypes\",\n      \"pmids\": [\"10843869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"P2Y6 receptor undergoes slow agonist-dependent loss of cell surface receptors that does not recover rapidly after UDP removal (unlike P2Y4 which rapidly recycles); PKC and Ca2+-activated kinases are not involved. C-terminal Ser-333/Ser-334 of P2Y4 mediate rapid phosphorylation/desensitization/internalization — equivalent determinants absent in P2Y6 explain its resistance.\",\n      \"method\": \"Radioligand binding for surface receptor quantification; [32P]-phosphorylation of wild-type and truncation/point mutants; flow cytometry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct mutagenesis and phosphorylation assays; mechanistic comparison between P2Y4 and P2Y6 in single study\",\n      \"pmids\": [\"11114308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"UDP acting on P2Y6 receptor promotes vascular smooth muscle cell mitogenesis (DNA and protein synthesis, cell cycle S/G2 progression) via phospholipase C, possibly PKC-δ, and a tyrosine kinase pathway, independent of Gi, eicosanoids, and PKA.\",\n      \"method\": \"[3H]-thymidine and [3H]-leucine incorporation; flow cytometry; selective P2Y6 agonist UDPβS; pharmacological inhibitors; hexokinase control to exclude UDP→UTP conversion\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal assays with selective agonist and pharmacological pathway dissection; replicated across receptor subtypes\",\n      \"pmids\": [\"11788430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"P2Y6 receptor activation by UDP protects 1321N1 astrocytoma cells against TNFα-induced apoptosis by activating PKCα, PKCε, and PKCζ isotypes and ERK1/2; this is partially blocked by PKC inhibitors (GF109203X, Gö6976) and ERK inhibitors (PD98059, U0126), but not by Akt inhibition or calcium chelation.\",\n      \"method\": \"Flow cytometry for apoptosis; PKC isotype activation assays; pharmacological kinase inhibitors; ERK phosphorylation assays\",\n      \"journal\": \"Cellular and molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple kinase pathway dissections with pharmacological inhibitors in single lab study\",\n      \"pmids\": [\"12825835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Basolateral P2Y6 receptor in colonic epithelium stimulates sustained Cl- secretion via both Ca2+ and cAMP; in Xenopus oocytes co-expressing P2Y6 and CFTR, UDP activates first a transient Ca2+-activated Cl- current and subsequently CFTR current, establishing P2Y6 as a receptor able to elevate both [Ca2+]i and cAMP.\",\n      \"method\": \"Ussing chamber electrophysiology; cAMP assay in colonic crypts; Xenopus oocyte two-electrode voltage clamp co-expressing P2Y6 + CFTR; RT-PCR and immunohistochemistry\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution in Xenopus oocytes plus native tissue Ussing chamber; multiple orthogonal methods\",\n      \"pmids\": [\"12569163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Diisothiocyanate derivatives MRS2567 and MRS2578 are potent, insurmountable antagonists selective for P2Y6 over P2Y1, P2Y2, P2Y4, and P2Y11 receptors (IC50 of MRS2578 ~37 nM at human P2Y6); at 1 µM, they completely block UDP-mediated protection from TNFα-induced apoptosis.\",\n      \"method\": \"PLC/IP3 assay in recombinant P2Y receptor-expressing 1321N1 cells; concentration-response inhibition curves; apoptosis assay\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — quantitative in vitro pharmacology with selectivity panel; replicated in multiple downstream studies as gold-standard antagonist tool\",\n      \"pmids\": [\"15081875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"P2Y6 receptor activation by UDP or the selective agonist INS48823 activates NF-κB (p65 nuclear translocation) in osteoclasts via a proteasome-dependent pathway, and enhances osteoclast survival; this effect is direct (not dependent on RANK ligand) and blocked by the NF-κB inhibitor SN50.\",\n      \"method\": \"Immunofluorescence for NF-κB p65; RT-PCR in purified osteoclasts; calcium imaging; cell survival assay; SN50 peptide inhibitor; osteoprotegerin control\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (calcium, NF-κB translocation, survival) with specific pharmacological controls in purified osteoclasts\",\n      \"pmids\": [\"15722352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"HNP (human neutrophil peptide)-induced IL-8 production in lung epithelial cells is mediated predominantly through the P2Y6 signaling pathway, as shown by antisense oligonucleotide knockdown of specific P2Y receptor subtypes.\",\n      \"method\": \"Antisense oligonucleotide knockdown of P2Y receptors; ELISA for IL-8; comparison with UDP and ATP stimulation\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — specific knockdown approach in endogenous system; single lab but targeted mechanistic interrogation\",\n      \"pmids\": [\"16322472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"P2Y6 receptor mediates positive inotropy in cardiomyocytes via a phospholipase C/IP3 pathway: the selective agonist UDPβS increases cardiomyocyte contraction by 35%, and this is abolished by the P2Y6 blocker MRS2578 and the PLC inhibitor U73122.\",\n      \"method\": \"Electrically stimulated isolated mouse cardiomyocytes; contraction measurement; pharmacological inhibitors; Western blot and immunohistochemistry for receptor expression\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — selective agonist/antagonist combination with pathway inhibitor in native cardiomyocytes; replicated with consistent mechanistic logic\",\n      \"pmids\": [\"16543499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"UDP acting on microglial P2Y6 receptor triggers phagocytosis of microspheres in a concentration-dependent, P2Y6-dependent manner; P2Y6 mRNA is upregulated in activated microglia after kainic acid-induced neuronal damage; leaked UDP from damaged neurons acts as the endogenous signal.\",\n      \"method\": \"Microsphere uptake assay; selective antagonist MRS2578; kainic acid in vivo model; RT-PCR and in situ hybridization\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional phagocytosis assay with selective pharmacological tools in both in vitro and in vivo models; published in Nature with clear mechanistic chain\",\n      \"pmids\": [\"17410128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"P2Y6 and P2Y4 receptors form high-order oligomeric complexes (up to dimers) in native neuronal phenotypes; P2Y6 exists as both dimers and monomers in lipid rafts of synaptosomes; UDP ligand activation shifts P2Y6 oligomerization state, whereas P2Y4 is unaffected; in PC12 cells, endogenous P2Y4 forms hetero-oligomers specifically with P2Y6.\",\n      \"method\": \"Blue Native PAGE; SDS-PAGE; co-immunoprecipitation; sucrose gradient fractionation of lipid rafts; synaptosome preparations\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — native gel and co-IP in endogenous system; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"17481575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"P2Y6 receptor signaling through Gα12/13 in cardiomyocytes triggers pressure overload-induced cardiac fibrosis: mechanical stretch causes ATP/UDP release via pannexin hemichannels, which activates P2Y6 receptors, inducing expression of fibrogenic genes (TGF-β, CTGF, periostin) and ACE upstream of the Ang II–TGF-β pathway.\",\n      \"method\": \"Transgenic expression of Gα12/13 inhibitory polypeptides; pressure overload model; pannexin hemichannel inhibition; P2Y6 receptor antagonism; gene expression analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic and pharmacological dissection in vivo and in vitro; multiple pathway components validated; published in EMBO Journal\",\n      \"pmids\": [\"19008857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"P2Y6 knockout mice lack UDP-stimulated inositol phosphate production in macrophages (confirming P2Y6 is the sole UDP receptor on macrophages), lack UDP-induced endothelium-dependent aortic relaxation, and lack UDP-induced vasoconstriction when eNOS is blocked, demonstrating distinct roles in macrophages, endothelial cells, and vascular smooth muscle.\",\n      \"method\": \"P2Y6 gene-targeted knockout mice; inositol phosphate assay in macrophages; aortic ring contractility; cytokine ELISA (IL-6, MIP-2, TNF-α)\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with multiple cell-type functional readouts; clean loss-of-function validates receptor specificity\",\n      \"pmids\": [\"18523137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"P2Y6 receptor activation by UDP stimulates insulin secretion from pancreatic beta-cells in a glucose-dependent manner via a P2Y6-specific mechanism, blocked by MRS2578; P2Y6 is the dominant pyrimidine receptor expressed in islets and purified beta-cells.\",\n      \"method\": \"Real-time PCR; insulin/glucagon secretion assay from isolated mouse islets and purified beta-cells; selective agonist UDPβS and antagonist MRS2578\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional secretion assay with selective pharmacological tools in native isolated cells; single lab\",\n      \"pmids\": [\"18387359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"P2Y6 receptors on mast cells cooperate with CysLT1R through reciprocal ligand-mediated cross-talk: P2Y6 antagonist MRS2578 blocks ERK activation and survival responses to both UDP and LTD4; both responses are absent in cells lacking CysLT1R or LTC4 synthase, indicating P2Y6 requires an intact cys-LT autocrine loop for its survival/activation signaling.\",\n      \"method\": \"ERK phosphorylation assay; mast cell survival assay; selective antagonist MRS2578; CysLT1R-knockout and LTC4 synthase-knockout cells; shRNA knockdown\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO and shRNA combined with pharmacology; multiple cell types and readouts; identifies specific cross-talk mechanism\",\n      \"pmids\": [\"19124756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"UDP/P2Y6 signaling in intestinal epithelial cells induces CXCL8 expression via the PKCδ–MEK1/2–ERK1/2–c-fos/c-jun (AP-1) pathway; mutation of the AP-1 site in the CXCL8 promoter abolishes the UDP-stimulating effect; UDP enemas increase neutrophil recruitment to inflamed mouse mucosa.\",\n      \"method\": \"Luciferase reporter (AP-1 site mutant); chromatin immunoprecipitation (ChIP); Western blot for phosphorylation; qPCR; pharmacological inhibitors; in vivo colitis model + immunofluorescence\",\n      \"journal\": \"Inflammatory bowel diseases\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP, reporter mutagenesis, and in vivo validation; multiple orthogonal methods identifying specific transcription factor complex\",\n      \"pmids\": [\"22095787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"UDP/P2Y6 activation of microglia and astrocytes induces CCL2 and CCL3 expression via Gq/PLC/calcium-dependent pathway activating NFATc1/c2 transcription factors; calcineurin inhibition and NFAT inhibitors reduce UDP-induced chemokine synthesis; UDP-treated astrocytes recruit monocytes in transmigration assay.\",\n      \"method\": \"siRNA knockdown of P2Y6; selective antagonist MRS2578; PLC inhibitor; NFAT inhibitors/calcineurin inhibitor; ELISA; RT-PCR; transmigration assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — siRNA knockdown combined with specific antagonist and multiple pathway inhibitors with defined transcription factor identification\",\n      \"pmids\": [\"21317391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"P2Y6 receptor stimulation by extracellular UDP promotes bone resorption: it stimulates osteoclast formation from precursors and enhances mature osteoclast resorptive activity; P2Y6R-/- mice have increased bone mineral content, cortical bone volume, and cortical thickness, with decreased osteoclast surface.\",\n      \"method\": \"P2Y6 knockout mice; osteoclast resorption pit assay; DEXA scanning; microcomputed tomography; histomorphometry\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse with multiple in vivo skeletal phenotypes plus in vitro functional assays\",\n      \"pmids\": [\"21828185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"P2Y6 receptor activation of PLC mediates hydrolysis of PI(4,5)P2, which inhibits P2X4 channel function in microglia: P2Y6 activation reduces P2X4-mediated Ca2+ entry, current amplitude, activation/desensitization rates, and large-conductance pore dilation (YO-PRO-1 uptake); PI(4,5)P2 depletion underlies this crosstalk; P2Y6 also modulates ATP-dependent microglial migration.\",\n      \"method\": \"Calcium imaging; YO-PRO-1 uptake assay; whole-cell patch clamp in recombinant systems; PI(4,5)P2 manipulation; primary microglia and LPS-activated microglia; migration assay\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution in recombinant system plus primary microglia; electrophysiology with multiple readouts; identified PI(4,5)P2 as mechanistic intermediary\",\n      \"pmids\": [\"24123515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"P2Y6 receptor activation causes bladder overactivity by releasing ATP from the urothelium via pannexin-1 hemichannels; P2Y6 and pannexin-1 co-localize in the urothelium; P2Y6 agonist-induced bladder hyperactivity and ATP release are blocked by pannexin-1 hemichannel inhibitors (10Panx, carbenoxolone) but not systemic routes, establishing a luminal paracrine mechanism.\",\n      \"method\": \"In vivo urodynamics in anesthetized rats; propidium iodide hemichannel permeability assay; confocal co-localization; ATP bioluminescence; selective P2Y6 agonist PSB0474 and antagonist MRS2578\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo functional + in vitro mechanistic + co-localization; multiple orthogonal methods identifying pannexin-1 as downstream effector\",\n      \"pmids\": [\"24269631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"P2Y6 receptor activation in spinal microglia induces CCL2 production via a PLC→Src tyrosine kinase→ERK1/2 and p38 MAPK→NF-κB pathway; selective P2Y6 antagonist MRS2578 blocks CCL2, and UTP effect is not blocked by P2Y2 siRNA, confirming P2Y6 mediates this response.\",\n      \"method\": \"Primary spinal microglia cultures; ELISA and RT-PCR for CCL2; selective P2Y6 antagonist MRS2578; P2Y2 siRNA knockdown; kinase inhibitors (U0126, SB202190, U73122, PP2); NF-κB assay\",\n      \"journal\": \"Neuropharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — selective knockdown plus pharmacological dissection of signaling cascade in primary cells; multiple pathway nodes validated\",\n      \"pmids\": [\"23916475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Blocking UDP/P2Y6 signaling (with apyrase, Reactive Blue 2, or MRS2578) prevents microglial phagocytosis of viable neurons (phagoptosis) induced by LPS, lipoteichoic acid, amyloid-β, peroxynitrite, or reactive nitrogen species, and prevents neuronal loss; UDP alone is sufficient to stimulate microglial phagocytosis and cause neuronal loss reversible by microglial elimination.\",\n      \"method\": \"Mixed neuronal/glial cultures; neuronal viability assay; selective P2Y6 antagonist MRS2578; apyrase; in vivo LPS injection into rat striatum with MRS2578 treatment\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple stimuli, pharmacological tools, in vivo validation; establishes P2Y6 as required and sufficient for phagoptosis\",\n      \"pmids\": [\"24838858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"P2Y6 receptor activation in microglia induces NO release via the PLC-PKC-iNOS pathway, which causes apoptosis in neighboring astrocytes but not microglia; this limits astrocyte proliferation and prevents excessive astrogliosis in LPS-treated microglia-astrocyte co-cultures.\",\n      \"method\": \"Co-cultures of microglia and astrocytes; Griess reaction for NO; TUNEL/Hoechst staining; Western blot and immunofluorescence for P2Y6 and iNOS; PLC, PKC, and NOS inhibitors; selective P2Y6 agonist PSB0474 and antagonist MRS2578\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — selective pharmacological tools with multiple readouts in co-culture system; single lab\",\n      \"pmids\": [\"25178395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"P2Y6 receptor activation in spinal microglia (but not astrocytes) contributes to neuropathic pain maintenance; minocycline (microglial inhibitor) reduces P2Y6 upregulation but fluorocitrate (astrocyte inhibitor) does not, placing P2Y6 specifically in spinal microglia in this pain pathway.\",\n      \"method\": \"Spinal nerve ligation model in rats; intrathecal antagonist administration (MRS2578); minocycline and fluorocitrate treatment; Iba-1/GFAP immunostaining; Western blot for P2Y6\",\n      \"journal\": \"Molecular pain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo nerve injury model with selective pharmacology and cell-type dissection; single lab\",\n      \"pmids\": [\"24886406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"P2Y6 receptor promotes glucose uptake in skeletal muscle and adipocytes via AMPK phosphorylation, GLUT4 membrane recruitment, and HDAC5 signaling; P2Y6R-knockout adipocytes show no increase in glucose uptake upon P2Y6 agonist treatment; AMPK siRNA or Compound C abolishes P2Y6-mediated glucose uptake.\",\n      \"method\": \"[3H]2-deoxyglucose uptake assay; GLUT4 membrane recruitment assay; AMPK phosphorylation (Western blot); AMPK siRNA; P2Y6R-KO adipocytes; selective agonist MRS2957 and antagonist MRS2578\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO validation combined with siRNA pathway dissection and multiple functional readouts in two cell types\",\n      \"pmids\": [\"25249240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"AgRP neurons in the arcuate nucleus express P2Y6 receptor; central UDP application promotes AgRP neuron action potential firing, ERK phosphorylation, and cFos expression; central UDP promotes feeding, which is abrogated by P2Y6 knockout or pharmacogenetic inhibition of AgRP neurons; hypothalamic UDP is elevated in obese animals due to increased circulating uridine.\",\n      \"method\": \"Brain slice electrophysiology; in vivo ERK/cFos assays; intracerebroventricular UDP injection; P2Y6 KO mice; AgRP-specific pharmacogenetics (DREADDs); obese mouse model metabolomics\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — electrophysiology in brain slices, genetic KO, and pharmacogenetics converge on same mechanism; published in Cell\",\n      \"pmids\": [\"26359991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"P2Y6R and AT1R form stable heterodimers that enhance G protein-dependent (Gα-q/12/13) vascular hypertrophy signaling while reducing β-arrestin-dependent AT1R internalization; P2Y6R expression increases with age in vascular smooth muscle cells, converting AT1R signaling from β-arrestin-dependent proliferation to G protein-dependent hypertrophy; MRS2578 disrupts heterodimers and suppresses Ang II-induced hypertension.\",\n      \"method\": \"Co-immunoprecipitation for heterodimer formation; P2Y6R KO mice; blood pressure measurement; vascular remodeling assays; β-arrestin assay; age-dependent expression analysis; pharmacological disruption with MRS2578\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP for complex, KO mouse phenotype, signaling pathway switch, pharmacological rescue; multiple orthogonal approaches\",\n      \"pmids\": [\"26787451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"P2Y6 receptor is essential for myogenic tone (MT) of resistance arteries: P2Y6 activation is mandatory for RhoA-GTP binding, myosin light chain, p42/44, and JNK phosphorylation in arterial smooth muscle cells; MT is abrogated by P2Y6 blockade and absent in P2ry6-/- arteries; nucleotide release through hemichannels (Cx43, P2X7) triggers autocrine P2Y6 signaling upon pressure.\",\n      \"method\": \"Arteriography of mesenteric arteries; P2ry6-/- mice; hemichannel inhibitors; Cx43+/- and P2rx7-/- mice; RhoA-GTP pulldown; phosphorylation assays; myocardial infarction model\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic KO mice combined with pharmacology and signaling readouts; distinct mechanistic chain established\",\n      \"pmids\": [\"27255725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Prostaglandin E2 glyceryl ester (PGE2-G), a COX-2 product of 2-arachidonoylglycerol, is an endogenous agonist of P2Y6 receptor with an EC50 of ~1 pM (vs ~50 nM for UDP), identified via transcriptome-wide RNA-seq subtractive screening and validated in heterologous and endogenous expression systems with multiple functional readouts.\",\n      \"method\": \"RNA-seq subtractive screening of responder vs non-responder cell lines; Ca2+ mobilization assay; IP1 assay; heterologous P2Y6 expression; endogenous system validation\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic deorphanization with multiple functional assays in both heterologous and endogenous systems; identifies mechanistically distinct ligand\",\n      \"pmids\": [\"28539604\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"P2Y6 receptor promotes colorectal tumor cell survival by stabilizing XIAP via AKT-mediated phosphorylation, thereby inhibiting apoptosis and contributing to chemoresistance to 5-fluorouracil; P2ry6-/- mice develop fewer and smaller colorectal tumors after AOM/DSS challenge.\",\n      \"method\": \"P2ry6-/- mice in AOM/DSS CRC model; HT29 cell apoptosis assay; Western blot for XIAP phosphorylation and AKT activation; tumoroids from CRC; MRS2693 selective agonist; 5-FU resistance assay\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse in vivo tumor model plus mechanistic dissection of AKT-XIAP pathway in vitro; multiple orthogonal approaches\",\n      \"pmids\": [\"29454075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"P2Y6 receptor mediates phagocytosis by microglia via Rac1 and MLCK signaling: P2Y6 inhibition decreases Rac1-pRAC1 and MLCK expression after ischemic stroke; P2Y6-mediated phagocytosis is beneficial in ischemic stroke (P2Y6 inhibition aggravates brain atrophy and neurological deficits).\",\n      \"method\": \"Transient middle cerebral artery occlusion model; MRS2578 treatment; neurological scoring; Western blot for Rac1 and MLCK; brain volume measurement\",\n      \"journal\": \"CNS neuroscience & therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo stroke model with pharmacological inhibition and signaling readouts; single lab\",\n      \"pmids\": [\"32154670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Adipocyte-specific P2Y6R deletion protects mice from diet-induced obesity and improves glucose tolerance via reduced JNK signaling, enhanced PPARα activity and downstream PGC1α, and beiging of white adipose tissue; skeletal muscle-specific P2Y6R deletion reduces glucose uptake, impairing glucose homeostasis.\",\n      \"method\": \"Conditional adipocyte-specific and skeletal muscle-specific P2Y6R KO mice; metabolic phenotyping; RNA-seq; Western blot for JNK, PPARα, PGC1α; whole-body KO comparison\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific conditional KOs with multiple metabolic and molecular readouts; identifies divergent roles in two metabolic tissues\",\n      \"pmids\": [\"33199639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Microglial P2Y6R mediates tau- and amyloid-β-induced neuronal and memory loss via phagocytosis of neurons: P2Y6R KO prevents Aβ-injection-induced microglial neuronal phagocytosis, neuronal loss, and memory loss in vivo; in P301S TAU mice, P2Y6R KO prevents TAU-induced neuronal and memory loss; in vitro, P2Y6R KO blocks microglial phagocytosis of live but not dead targets.\",\n      \"method\": \"P2Y6R KO mice; intracerebral Aβ injection; P301S TAU transgenic model; memory testing; in vitro phagocytosis of live vs dead targets; glial-neuronal co-cultures\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent in vivo neurodegenerative models plus in vitro mechanistic assays; distinguishes live vs dead target phagocytosis\",\n      \"pmids\": [\"34965424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"P2Y6 receptor undergoes redox-dependent alternative internalization (REDAI) independent of β-arrestin: electrophilic isothiocyanate compounds covalently modify Cys220 of P2Y6R, promoting ubiquitylation of Lys137 and receptor internalization and degradation; endogenous electrophiles also promote this pathway; Cys220Ser mutant P2Y6R mice show increased colitis susceptibility, linking REDAI to intestinal inflammation control.\",\n      \"method\": \"Site-directed mutagenesis (Cys220Ser); ubiquitylation assay; internalization/degradation assays in multiple cell lines; Cys220Ser knock-in mice in DSS colitis model; covalent modification assay\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis combined with biochemical assays and in vivo knock-in mouse; identifies novel Cys220-Lys137 mechanism; published in Science Signaling\",\n      \"pmids\": [\"35015570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Microglial P2Y6 receptor mediates calcium signaling in epileptogenesis by sensing UDP released during seizures (detected with novel GRABUDP1.0 fluorescent sensor); P2Y6 calcium activity drives lysosome biogenesis and NF-κB-related cytokine production; P2Y6 KO prevents microglia from fully engulfing neurons and attenuates CA3 neuron loss and cognitive deficits in epilepsy; calcium extruder ('CalEx') expression recapitulates P2Y6 KO phenotypes.\",\n      \"method\": \"Novel UDP fluorescent sensor GRABUDP1.0 (in vivo); P2Y6 KO mice; lysosome biogenesis assay; NF-κB cytokine assay; phagocytosis imaging; CalEx viral expression; cognitive testing\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — novel biosensor for direct UDP detection in vivo, KO mouse model, viral CalEx approach; multiple orthogonal readouts; published in Neuron\",\n      \"pmids\": [\"38614103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"P2Y6R functions as an endogenous receptor for long-chain ceramides (C16:0 ceramide), sensing circulating ceramides to activate Gq/NLRP3 inflammasome signaling in endothelial cells and macrophages, thereby aggravating atherosclerosis; P2Y6R deficiency mitigates ceramide-induced and chronic-kidney-disease-aggravated atherosclerosis without affecting cholesterol/ceramide levels.\",\n      \"method\": \"Systematic GPCR screen (G-protein-signaling quantification + NLRP3 inflammasome assay); P2Y6R and CYSLTR2 genetic/pharmacological inhibition in atherosclerosis mouse models; structural analysis of ceramide-CYSLTR2-Gq complexes (for CYSLTR2); functional validation in endothelial cells and macrophages\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic screen plus KO mouse validation for P2Y6R; structural data is for CYSLTR2, not P2Y6R directly; single study but published in Nature\",\n      \"pmids\": [\"40049228\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"P2Y6 is a Gq-coupled (and also Gα12/13- and partially Gi-coupled) GPCR selectively activated by UDP (and by PGE2-G and long-chain ceramides), which triggers PLC/IP3/Ca2+ signaling, RhoA-Rho kinase activation, PKC-ERK-NF-κB cascades, NFAT activation, and cAMP elevation depending on cell context; it drives microglial phagocytosis of neurons and synapses (via lysosome biogenesis and MLCK/Rac1), mediates vascular myogenic tone and cardiac fibrosis through Gα12/13, forms functional heterodimers with AT1R to promote hypertension, promotes feeding via AgRP neuron activation, and undergoes a novel redox-dependent internalization through covalent modification of Cys220 and ubiquitylation of Lys137.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"P2RY6 (P2Y6) is a pyrimidinergic G protein-coupled receptor selectively activated by UDP that couples to Gq/phospholipase C to drive IP3/Ca2+ signaling, and engages additional G protein outputs to regulate inflammation, tissue remodeling, and phagocytosis across many cell types [#0, #1, #15]. UDP/P2Y6 stimulation activates downstream cascades including RhoA-Rho kinase-driven actin reorganization [#3], PKC-ERK and Src-p38-NF-\\u03baB modules that promote cell survival and chemokine output (CCL2, CCL3, CXCL8) [#6, #18, #19, #23], and NFAT and AP-1 transcriptional programs [#18, #19]. Beyond UDP, P2Y6 is activated by the COX-2 product PGE2-glyceryl ester [#31] and by long-chain ceramides that trigger Gq/NLRP3 inflammasome signaling to aggravate atherosclerosis [#38]. In the CNS, microglial P2Y6 senses UDP leaked from damaged neurons and drives phagocytosis\\u2014both clearance of debris and phagoptosis of stressed-but-viable neurons\\u2014through Rac1/MLCK signaling, lysosome biogenesis, and NF-\\u03baB-dependent cytokine production, contributing to neuronal and memory loss in amyloid-\\u03b2 and tau models and to neuronal engulfment in epilepsy and stroke [#12, #24, #33, #35, #37]. In the vasculature and heart, P2Y6 couples through G\\u03b112/13 to mediate myogenic tone, pressure-overload cardiac fibrosis, and\\u2014via stable heterodimerization with the angiotensin II receptor AT1R\\u2014a shift toward G protein-dependent hypertrophy that promotes hypertension [#14, #29, #30]. P2Y6 also regulates metabolic physiology, promoting AgRP neuron-driven feeding, insulin secretion, and tissue-specific glucose handling [#27, #28, #34]. Unlike the rapidly recycling P2Y4, P2Y6 desensitizes slowly [#1, #4] and undergoes a distinct \\u03b2-arrestin-independent redox-dependent internalization in which electrophiles covalently modify Cys220 to drive Lys137 ubiquitylation, degradation, and control of intestinal inflammation [#36].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Establishing the identity and pharmacology of an orphan-like P2Y receptor defined P2Y6 as a UDP-preferring, Gq-coupled pyrimidinergic receptor distinct from ATP-responsive subtypes.\",\n      \"evidence\": \"Cloning from placenta cDNA and IP3 accumulation in stably expressing 1321N1 cells with defined agonist rank order\",\n      \"pmids\": [\"8670200\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous ligand identity beyond UDP not addressed\", \"No structural basis for nucleotide selectivity\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Characterizing desensitization kinetics revealed that P2Y6 signaling is unusually slow and sustained, distinguishing it functionally from related P2Y4.\",\n      \"evidence\": \"IP3 assays with pertussis toxin treatment in P2Y6-expressing 1321N1 cells\",\n      \"pmids\": [\"9226417\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of slow desensitization not resolved here\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Reconstitution in neurons showed P2Y6 is not strictly Gq-restricted but exhibits dual G-protein coupling, modulating ion channels through both PTX-sensitive and PTX-resistant pathways.\",\n      \"evidence\": \"cRNA microinjection and voltage clamp in rat sympathetic neurons with PTX dissection\",\n      \"pmids\": [\"10193782\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Native neuronal relevance of recombinant coupling not established\", \"Specific G\\u03b1 subunits not identified\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identifying RhoA/Rho-kinase activation and defining the structural determinants of internalization explained both P2Y6's cytoskeletal effects and its resistance to rapid desensitization.\",\n      \"evidence\": \"Membrane fractionation, dominant-negative RhoA, and phosphorylation/truncation mutagenesis in transfected cells\",\n      \"pmids\": [\"10843869\", \"11114308\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Internalization mechanism characterized by comparison to P2Y4 in single study\", \"G protein linking P2Y6 to RhoA not defined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstrating UDP/P2Y6 anti-apoptotic and dual Ca2+/cAMP signaling extended the receptor's outputs to cell survival and epithelial secretion beyond canonical PLC/Ca2+.\",\n      \"evidence\": \"PKC/ERK pathway dissection in astrocytoma; Ussing chamber and Xenopus oocyte CFTR co-expression\",\n      \"pmids\": [\"12825835\", \"12569163\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of cAMP elevation by a Gq-coupled receptor unresolved\", \"PKC isotype specificity inferred pharmacologically\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Development of selective insurmountable antagonists (MRS2578/MRS2567) provided the gold-standard tools that enabled subsequent loss-of-function dissection in native systems.\",\n      \"evidence\": \"PLC/IP3 inhibition curves across a P2Y selectivity panel in 1321N1 cells\",\n      \"pmids\": [\"15081875\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Off-target effects at high concentrations not fully excluded\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Genetic knockout confirmed P2Y6 is the sole macrophage UDP receptor and defined its non-redundant roles in macrophage, endothelial, and smooth muscle responses, validating receptor specificity.\",\n      \"evidence\": \"P2Y6 gene-targeted mice with inositol phosphate assays and aortic ring contractility\",\n      \"pmids\": [\"18523137\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-autonomous versus systemic contributions not separated\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Discovery that microglial P2Y6 senses neuronally leaked UDP to trigger phagocytosis established the receptor as a 'find/eat-me' sensor in CNS injury.\",\n      \"evidence\": \"Microsphere phagocytosis with MRS2578 plus kainic acid in vivo injury model\",\n      \"pmids\": [\"17410128\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream phagocytic machinery not yet defined\", \"Distinction between debris clearance and viable-cell engulfment not made\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Linking P2Y6 to G\\u03b112/13 in cardiomyocytes connected mechanical-stress nucleotide release to fibrogenic gene programs, defining a pathological cardiac remodeling axis.\",\n      \"evidence\": \"Transgenic G\\u03b112/13 inhibitory peptides, pannexin inhibition, and pressure overload model\",\n      \"pmids\": [\"19008857\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of G\\u03b112/13 versus Gq in vivo not quantified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defining NFAT- and AP-1-driven chemokine programs placed P2Y6 upstream of specific transcription factors governing leukocyte recruitment in glia and epithelium.\",\n      \"evidence\": \"siRNA/antagonist plus reporter mutagenesis, ChIP, and transmigration assays\",\n      \"pmids\": [\"21317391\", \"22095787\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo necessity of each transcription factor downstream of P2Y6 not isolated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identifying PI(4,5)P2 hydrolysis-mediated crosstalk with P2X4 and pannexin-1-dependent ATP release revealed how P2Y6 integrates with other purinergic signaling to shape microglial and urothelial responses.\",\n      \"evidence\": \"Patch clamp, YO-PRO-1 uptake, PI(4,5)P2 manipulation, and in vivo urodynamics with co-localization\",\n      \"pmids\": [\"24123515\", \"24269631\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological setting where P2Y6-P2X4 crosstalk dominates not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrating that UDP/P2Y6 is necessary and sufficient for phagoptosis of viable neurons reframed P2Y6-driven microglial phagocytosis as a driver of neuronal loss, not just debris clearance.\",\n      \"evidence\": \"Multiple inflammatory stimuli with antagonist/apyrase in mixed cultures and in vivo LPS striatal injection\",\n      \"pmids\": [\"24838858\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals marking neurons as viable phagoptosis targets not fully defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Discovery of stable P2Y6R-AT1R heterodimers and a requirement for P2Y6 in myogenic tone explained an age-dependent signaling switch toward G protein-dependent vascular hypertrophy and hypertension.\",\n      \"evidence\": \"Co-IP, P2Y6 KO mice, blood pressure and \\u03b2-arrestin assays; arteriography in P2ry6-/- mice with hemichannel and RhoA readouts\",\n      \"pmids\": [\"26787451\", \"27255725\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the heterodimer interface unknown\", \"Generality of the AT1R switch across vascular beds not established\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Deorphanizing P2Y6 toward PGE2-glyceryl ester showed the receptor responds to a lipid agonist with far higher potency than UDP, broadening its ligand repertoire beyond nucleotides.\",\n      \"evidence\": \"RNA-seq subtractive screen with Ca2+/IP1 assays in heterologous and endogenous systems\",\n      \"pmids\": [\"28539604\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological contexts where PGE2-G versus UDP dominate not delineated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linking P2Y6 to AKT-mediated XIAP stabilization defined a pro-survival, chemoresistance-promoting role in colorectal tumorigenesis.\",\n      \"evidence\": \"P2ry6-/- mice in AOM/DSS model with XIAP/AKT biochemistry and 5-FU resistance assays\",\n      \"pmids\": [\"29454075\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether tumor effect is microglial/immune or epithelial-cell-intrinsic not fully resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Tissue-specific knockouts and stroke models resolved P2Y6's divergent metabolic and phagocytic roles, including opposing outcomes in adipose versus muscle and beneficial phagocytosis in ischemia.\",\n      \"evidence\": \"Adipocyte- and muscle-specific conditional KO metabolic phenotyping; tMCAO with Rac1/MLCK readouts\",\n      \"pmids\": [\"33199639\", \"32154670\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stroke study relies on pharmacology in single lab\", \"Reconciliation of beneficial (stroke) versus detrimental (neurodegeneration) phagocytosis not mechanistically settled\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Genetic demonstration that microglial P2Y6 drives amyloid-\\u03b2- and tau-induced neuronal and memory loss via live-cell phagocytosis positioned the receptor as a disease-relevant phagoptosis effector.\",\n      \"evidence\": \"P2Y6R KO in A\\u03b2 injection and P301S TAU models with memory testing and live-versus-dead target phagocytosis assays\",\n      \"pmids\": [\"34965424\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Therapeutic window for inhibition versus loss of protective clearance not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identifying redox-dependent alternative internalization (REDAI) via Cys220 covalent modification and Lys137 ubiquitylation revealed a \\u03b2-arrestin-independent regulatory mechanism controlling receptor levels and intestinal inflammation.\",\n      \"evidence\": \"Cys220Ser mutagenesis, ubiquitylation/internalization assays, and Cys220Ser knock-in mice in DSS colitis\",\n      \"pmids\": [\"35015570\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous electrophiles driving physiological REDAI not fully cataloged\", \"Ubiquitin ligase mediating Lys137 ubiquitylation not identified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Direct in vivo UDP imaging tied microglial P2Y6 calcium activity to lysosome biogenesis and NF-\\u03baB cytokine output during epileptogenesis, mechanistically connecting seizure-released UDP to neuronal engulfment.\",\n      \"evidence\": \"GRABUDP1.0 biosensor, P2Y6 KO, and CalEx calcium-extrusion approach with cognitive testing\",\n      \"pmids\": [\"38614103\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Translation to human epilepsy not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identifying long-chain ceramides as P2Y6 agonists that trigger Gq/NLRP3 inflammasome signaling extended the receptor's role to lipid sensing in atherosclerosis.\",\n      \"evidence\": \"Systematic GPCR/NLRP3 screen with P2Y6R genetic/pharmacological inhibition in atherosclerosis models\",\n      \"pmids\": [\"40049228\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural ceramide-binding data were obtained for CYSLTR2, not P2Y6R directly\", \"Single study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How distinct ligands (UDP, PGE2-G, ceramides) and G-protein outputs (Gq, G\\u03b112/13, Gi) are selected to produce context-specific outcomes\\u2014and how protective versus pathological phagocytosis is determined\\u2014remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of human P2Y6 with its endogenous ligands\", \"Ligand-biased signaling rules not defined\", \"Determinants distinguishing beneficial from harmful microglial phagocytosis unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 15, 31]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [29]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [31, 38]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4, 13, 29]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3, 14]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [18, 19, 38]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [6, 32]}\n    ],\n    \"complexes\": [\n      \"P2Y6R-AT1R heterodimer\",\n      \"P2Y6-P2Y4 hetero-oligomer\"\n    ],\n    \"partners\": [\n      \"AGTR1\",\n      \"P2RY4\",\n      \"P2RX4\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":{"gene":"P2RY6","tier":"GROUNDING","verdict":"Evidence-grounding concern","subtype":"fabrication","uniprot_band":"sparse","rules_fired":"R7","issue":"R7: fabricated (no corpus paper): 25249240"},"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}