Details for: P2RY12

Gene ID: 64805

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: P2RY12

Ensembl ID: ENSG00000169313

Description: purinergic receptor P2Y12

Cell Significance Landscape

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • central nervous system macrophage CL0000878
    CSI 9.68
    rCSI 32.08%
    PRS 98.23
  • mature microglial cell CL0002629
    CSI 5.2
    rCSI 21.6%
    PRS 96.95
  • ependymal cell CL0000065
    CSI 4.67
    rCSI 9.47%
    PRS 90.96
  • kidney interstitial alternatively activated macrophage CL1000695
    CSI 4.33
    rCSI 11.28%
    PRS 99.09
  • microglial cell CL0000129
    CSI 3.3
    rCSI 13.28%
    PRS 96.94
  • Mueller cell CL0000636
    CSI 2.95
    rCSI 6.72%
    PRS 96.07
  • cardiac neuron CL0010022
    CSI 1.98
    rCSI 6.35%
    PRS 97.83
  • lamp5 GABAergic cortical interneuron CL4023011
    CSI 1.53
    rCSI 2.56%
    PRS 94.86
  • L2/3-6 intratelencephalic projecting glutamatergic neuron CL4023040
    CSI 1.14
    rCSI 2.76%
    PRS 93.27
  • L5 extratelencephalic projecting glutamatergic cortical neuron CL4023041
    CSI 0.78
    rCSI 2.8%
    PRS 93.62

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

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Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [P2RY12](/details-gene/64805), or purinergic receptor P2Y12, is a G protein-coupled receptor (GPCR) that plays a central and well-established role in hemostasis. It functions as a key receptor for adenosine diphosphate (ADP) on the platelet surface, and its activation is critical for platelet aggregation and thrombus formation, making it a major target for antithrombotic drugs ([Link](https://doi.org/10.1038/35051599)). Beyond its role in thrombosis, expression data reveal that [P2RY12](/details-gene/64805) is a highly specific and abundant marker for central nervous system-resident macrophages, particularly microglia. This dual role highlights its importance in both systemic physiological processes like blood clotting and specialized functions related to immune surveillance within the brain. Dysfunctional variants of the receptor are associated with congenital bleeding disorders ([600515](https://omim.org/entry/600515)) ([Link](https://doi.org/10.1073/pnas.0437879100)). ## Cellular Roles and Expression Landscape **Overall**, the expression profile of [P2RY12](/details-gene/64805) demonstrates a remarkably specific enrichment in myeloid cells of the central nervous system. The gene shows its highest significance in [central nervous system macrophage](/details-cell/CL0000878) (CSI: 9.68), [mature microglial cell](/details-cell/CL0002629) (CSI: 5.20), and the broader [microglial cell](/details-cell/CL0000129) category (CSI: 3.30). This pattern establishes [P2RY12](/details-gene/64805) as a canonical marker for homeostatic microglia, where it is thought to mediate surveillance of the neural parenchyma. Its significance extends to other specialized cell types within or associated with the CNS, including [ependymal cell](/details-cell/CL0000065) and the retinal [Mueller cell](/details-cell/CL0000636), suggesting a broader role in glial function and CNS homeostasis. Expression is also noted, albeit at lower levels, in specific neuronal subtypes such as [cardiac neuron](/details-cell/CL0010022) and various cortical glutamatergic neurons. The highly restricted expression pattern underscores its specialized functions, primarily in mediating cellular responses to extracellular nucleotides within the circulatory and central nervous systems. ## Pathways and Molecular Function [P2RY12](/details-gene/64805) is an integral membrane protein whose primary molecular function is [G protein-coupled adp receptor activity](/details-gene/GO:0001621). As a member of the P2Y receptor family, it participates in the [G protein-coupled purinergic nucleotide receptor signaling pathway](/details-gene/GO:0035589). Upon binding its ligand, ADP, the receptor couples to G(i) proteins, initiating downstream signaling cascades detailed in Reactome's [G alpha (i) signalling events](/details-gene/R-HSA-418594). This signaling has two well-characterized major outcomes. First, it leads to the inhibition of adenylate cyclase, as described in the GO process [Adenylate cyclase-inhibiting g protein-coupled receptor signaling pathway](/details-gene/GO:0007193). Second, it activates the PI3K/Akt pathway ([Positive regulation of phosphatidylinositol 3-kinase/protein kinase b signal transduction](/details-gene/GO:0051897)). In platelets, these events are fundamental to the process of [Platelet activation, signaling and aggregation](/details-gene/R-HSA-76002), ultimately contributing to [Hemostasis](/details-gene/R-HSA-109582). In microglia, these same pathways are implicated in regulating cell motility and chemotaxis, such as [Positive regulation of microglial cell migration](/details-gene/GO:1904141), which is critical for the immune surveillance functions of these cells. ## Research Directions The dual, highly specific roles of [P2RY12](/details-gene/64805) in platelets and microglia present distinct avenues for research and therapeutic development. While its function in hemostasis is well-understood, its precise role in microglial biology, particularly in the context of neuroinflammation and neurodegeneration, remains an active area of investigation. Based on its function and expression, several testable hypotheses can be proposed: 1. The downregulation of [P2RY12](/details-gene/64805) expression, which is frequently observed in activated or disease-associated microglia, is a causal driver of the transition from a homeostatic, ramified state to a pro-inflammatory, amoeboid state. Re-establishing [P2RY12](/details-gene/64805) signaling could restore microglial homeostasis and prove neuroprotective. 2. In specialized glial cells like [ependymal cells](/details-cell/CL0000065), [P2RY12](/details-gene/64805) may sense nucleotide concentrations in the cerebrospinal fluid to modulate ciliary beating and fluid flow, thereby playing a role in CNS fluid dynamics. To test the first hypothesis regarding the role of [P2RY12](/details-gene/64805) in maintaining microglial homeostasis, a key experiment would involve the use of a conditional knockout mouse model (e.g., Cx3cr1-CreERT2 driving deletion of a floxed *P2ry12* allele). Following tamoxifen-induced gene deletion in adult microglia, single-cell RNA sequencing could be performed on isolated microglia to determine if their transcriptional state spontaneously shifts away from homeostasis towards a disease-associated profile. Subsequently, these mice could be challenged with a model of neuroinflammation (e.g., intracerebral LPS injection), and the inflammatory response (cytokine levels, immune cell infiltration, and neuronal damage) could be compared between knockout and wild-type animals to assess whether the loss of [P2RY12](/details-gene/64805) exacerbates pathology. From a therapeutic perspective, [P2RY12](/details-gene/64805) is already a validated target for **inhibition** by antithrombotic agents like clopidogrel and ticagrelor ([Link](https://doi.org/10.1038/nature13083)). In the context of neurological disease, its role is more nuanced. Since its expression is high on homeostatic microglia and low on disease-associated microglia, direct inhibition would be counterproductive for treating neuroinflammation. Instead, it may represent a target for **activation** or positive allosteric modulation to promote a return to the neuroprotective, homeostatic microglial state. Furthermore, its high surface expression and specificity make it a potential target for antibody-based strategies to deliver therapeutic cargo specifically to homeostatic microglia.

Genular Protein ID: 2907335515

Symbol: P2Y12_HUMAN

Name: P2Y purinoceptor 12

UniProtKB Accession Codes:

Q9H244 D3DNJ5 Q546J7

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BindingDB 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 1 CTD 1 ChEBI 10 ChEMBL 1 ChiTaRS 1 DIP 1 DMDM 1 DNASU 1 DisGeNET 1 DrugBank 12 DrugCentral 1 EMBL 10 EMDB 1 Ensembl 1 EvolutionaryTrace 1 GO 34 Gene3D 1 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 GuidetoPHARMACOLOGY 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 3 KEGG 1 MANE-Select 1 MIM 3 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 1 OrthoDB 1 PANTHER 2 PDB 5 PDBsum 5 PRINTS 3 PRO 1 PROSITE 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 Reactome 3 RefSeq 3 SIGNOR 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TCDB 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 11196645

Title: Identification of the platelet ADP receptor targeted by antithrombotic drugs.

PubMed ID: 11196645

DOI: 10.1038/35051599

PubMed ID: 11104774

Title: ADP is the cognate ligand for the orphan G protein-coupled receptor SP1999.

PubMed ID: 11104774

DOI: 10.1074/jbc.m009718200

PubMed ID: 11502873

Title: Molecular cloning of the platelet P2T(AC) ADP receptor: pharmacological comparison with another ADP receptor, the P2Y1 receptor.

PubMed ID: 11502873

PubMed ID: 12044878

Title: Identification of G protein-coupled receptor genes from the human genome sequence.

PubMed ID: 12044878

DOI: 10.1016/s0014-5793(02)02775-8

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 24670650

Title: Structure of the human P2Y12 receptor in complex with an antithrombotic drug.

PubMed ID: 24670650

DOI: 10.1038/nature13083

PubMed ID: 24784220

Title: Agonist-bound structure of the human P2Y12 receptor.

PubMed ID: 24784220

DOI: 10.1038/nature13288

PubMed ID: 12578987

Title: Molecular bases of defective signal transduction in the platelet P2Y12 receptor of a patient with congenital bleeding.

PubMed ID: 12578987

DOI: 10.1073/pnas.0437879100

PubMed ID: 25428217

Title: Identification of a new dysfunctional platelet P2Y12 receptor variant associated with bleeding diathesis.

PubMed ID: 25428217

DOI: 10.1182/blood-2013-07-517896

Sequence Information:

  • Length: 342
  • Mass: 39439
  • Checksum: 8553D2746C89176D
  • Sequence:
    • MQAVDNLTSA PGNTSLCTRD YKITQVLFPL LYTVLFFVGL ITNGLAMRIF FQIRSKSNFI 
IFLKNTVISD LLMILTFPFK ILSDAKLGTG PLRTFVCQVT SVIFYFTMYI SISFLGLITI 
DRYQKTTRPF KTSNPKNLLG AKILSVVIWA FMFLLSLPNM ILTNRQPRDK NVKKCSFLKS 
EFGLVWHEIV NYICQVIFWI NFLIVIVCYT LITKELYRSY VRTRGVGKVP RKKVNVKVFI 
IIAVFFICFV PFHFARIPYT LSQTRDVFDC TAENTLFYVK ESTLWLTSLN ACLDPFIYFF 
LCKSFRNSLI SMLKCPNSAT SLSQDNRKKE QDGGDPNEET PM

Genular Protein ID: 1888626019

Symbol: A8K7T1_HUMAN

Name: N/A

UniProtKB Accession Codes:

A8K7T1

Database IDs:

ARBA 4 AlphaFoldDB 1 BioGRID-ORCS 1 CDD 1 CTD 1 DNASU 1 DisGeNET 1 EMBL 2 GO 3 Gene3D 1 InterPro 3 KEGG 1 NCBI Taxonomy 1 OrthoDB 1 PANTHER 2 PRINTS 3 PROSITE 2 PeptideAtlas 1 Pfam 1 RefSeq 2 SAM 2 SUPFAM 1

Sequence Information:

  • Length: 342
  • Mass: 39487
  • Checksum: F25A35603C891779
  • Sequence:
    • MQAVDNLTSA PGNTSLCTRD YKITQVLFPL LYTVLFFVGL ITNGLAMRIF FQIRSKSNFI 
IFLKNTVISD LLMILTFPFK ILSDAKLGTG PLRTFVCQVT SVIFYFTMYI SISFLGLITI 
DRYQKTTRPF KTSNPKNLLG AKILSVVIWA FMFLLSLPNM ILTNRQPRDK NVKKCSFLKS 
EFGLVWHEIV NYICQVIFWI NFLIFIVCYT LITKELYRSY VRTRGVGKVP RKKVNVKVFI 
IIAVFFICFV PFHFARIPYT LSQTRDVFDC TAENTLFYVK ESTLWLTSLN ACLDPFIYFF 
LCKSFRNSLI SMLKCPNSAT SLSQDNRKKE QDGGDPNEET PM