# P2RY12

## Overview
The P2RY12 gene encodes the purinergic receptor P2Y12, a G-protein-coupled receptor (GPCR) that plays a pivotal role in platelet aggregation and hemostasis. This receptor is primarily expressed in platelets, where it is activated by adenosine diphosphate (ADP), leading to a cascade of intracellular events that promote platelet activation and aggregation (von2017Structure; Gachet2012P2Y12). Structurally, the P2Y12 receptor is characterized by a seven transmembrane domain typical of GPCRs, with unique features that distinguish it from other class A GPCRs, such as a straight conformation of helix V and specific interactions with cholesterol molecules (Zhang2014Structure; Cattaneo2015P2Y12). Beyond its role in platelets, P2Y12 is also expressed in vascular smooth muscle cells and immune cells, where it contributes to vasoconstriction and inflammatory responses, respectively (Wihlborg2004ADP; Entsie2023The). The receptor's involvement in these processes underscores its significance in both cardiovascular and immune system functions, making it a critical target for antithrombotic therapies and a subject of interest in various clinical contexts, including cardiovascular diseases and bone remodeling disorders (Su2012The; Su2023Association).

## Structure
The P2Y12 receptor (P2RY12) is a G-protein-coupled receptor (GPCR) characterized by a canonical seven transmembrane (7TM) domain structure, typical of GPCRs, which facilitates its role in platelet aggregation (Zhang2014Agonistbound; Cattaneo2015P2Y12). The receptor is composed of 342 amino acids and includes two potential N-linked glycosylation sites at its extracellular amino terminus, which may influence its activity (Cattaneo2015P2Y12). 

The secondary structure of P2RY12 includes tilted and/or kinked transmembrane helices, with a carboxy-terminal helix VIII parallel to the membrane lipid bilayer (Cattaneo2015P2Y12). The receptor's tertiary structure reveals a unique straight conformation of helix V, distinguishing it from other class A GPCRs, and lacks the conserved proline and corresponding bend in helix V (Zhang2014Structure). 

The receptor's quaternary structure involves interactions with cholesterol molecules, which may play a role in signal transduction (Cattaneo2015P2Y12). The P2Y12 receptor also features a potentially labile disulfide bond between C97 and C175, which is different from other GPCRs (Zhang2014Structure). These structural features are crucial for its function and interaction with ligands.

## Function
The P2RY12 gene encodes the P2Y12 receptor, a G-protein-coupled receptor primarily expressed in platelets and involved in platelet aggregation, a critical process in hemostasis and thrombosis. The receptor is activated by ADP, leading to the inhibition of adenylyl cyclase, which reduces cyclic AMP (cAMP) levels and promotes platelet activation and aggregation (von2017Structure; Gachet2012P2Y12). This receptor is essential for the stabilization of platelet aggregates and the amplification of responses to other agonists like thrombin and thromboxane A2 (TXA2) (Gachet2012P2Y12; Mansour2020P2Y12).

In addition to its role in platelets, P2Y12 is expressed in other cell types, including vascular smooth muscle cells and immune cells such as monocytes and macrophages. In vascular smooth muscle cells, P2Y12 contributes to vasoconstriction and may play a role in atherogenesis (von2017Structure; Wihlborg2004ADP). In immune cells, P2Y12 influences inflammatory responses and cell migration, particularly in macrophages, where it is linked to migration towards ADP-rich areas (Entsie2023The). The receptor's involvement in these processes highlights its importance in both vascular and immune system functions.

## Clinical Significance
Mutations and polymorphisms in the P2RY12 gene have been associated with various cardiovascular and bleeding disorders. The P2RY12 H2 haplotype is linked to an increased risk of acute myocardial infarction (AMI) and peripheral arterial disease (PAD), as it enhances ADP-induced platelet aggregation, a key factor in arterial thrombosis (Su2023Association; Fontana2003P2Y). In Kawasaki disease, the rs7637803 polymorphism in P2RY12 is associated with an increased risk of coronary artery aneurysm, particularly in children and males (Lu2019P2RY12:rs7637803).

The P2RY12 gene also plays a role in clopidogrel resistance, a condition that affects the efficacy of antiplatelet therapy in patients with acute coronary syndrome undergoing percutaneous coronary intervention. Variations at C34T and G52T in the P2RY12 gene significantly increase the risk of clopidogrel resistance and adverse cardiovascular events (Li2017Associations).

In addition to cardiovascular implications, P2RY12 is involved in osteoclast function and bone remodeling. Its deficiency or inhibition can protect against bone loss in conditions like osteoporosis and rheumatoid arthritis, suggesting its role in pathological bone remodeling (Su2012The).

## Interactions
The P2RY12 receptor is a G-protein coupled receptor that primarily interacts with adenosine diphosphate (ADP) to mediate platelet aggregation. It is involved in several signaling pathways, notably through its interaction with Gi/o proteins, which inhibit adenylate cyclase, leading to reduced cAMP levels and subsequent platelet activation (Cornelissen2010Roles). The receptor also forms part of a complex network of interactions with other platelet receptors and proteins, contributing to hemostasis and thrombosis. 

P2RY12 interacts with various ligands, including agonists like 2MeSADP, which bind to specific pockets within the receptor, forming interactions such as π-π interactions with the Y105 side chain and coordination with cationic residues like R256, K280, and Y259 (Zhang2014Agonistbound). The receptor's interaction with antagonists, such as Ticagrelor, is also significant, as these compounds inhibit P2RY12 activity, reducing platelet aggregation and thrombus formation (Chen2022Ginsenoside).

Ginsenoside Rg5 has been shown to allosterically interact with P2RY12, forming a stable complex and antagonizing its activity. This interaction is characterized by a strong binding affinity, similar to that of known antagonists, and involves key amino acid residues such as E188 and R265 (Chen2022Ginsenoside). These interactions highlight the receptor's role in modulating platelet function and its potential as a target for antithrombotic therapies.


## References


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[2. (Chen2022Ginsenoside) Ziyu Chen, Gaorui Wang, Xueqing Xie, Heng Liu, Jun Liao, Hailian Shi, Min Chen, Shusheng Lai, Zhengtao Wang, and Xiaojun Wu. Ginsenoside rg5 allosterically interacts with p2ry12 and ameliorates deep venous thrombosis by counteracting neutrophil netosis and inflammatory response. Frontiers in Immunology, August 2022. URL: http://dx.doi.org/10.3389/fimmu.2022.918476, doi:10.3389/fimmu.2022.918476. This article has 3 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fimmu.2022.918476)

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[13. (Entsie2023The) Philomena Entsie, Ying Kang, Emmanuel Boadi Amoafo, Torsten Schöneberg, and Elisabetta Liverani. The signaling pathway of the adp receptor p2y12 in the immune system: recent discoveries and new challenges. International Journal of Molecular Sciences, 24(7):6709, April 2023. URL: http://dx.doi.org/10.3390/ijms24076709, doi:10.3390/ijms24076709. This article has 8 citations and is from a peer-reviewed journal.](https://doi.org/10.3390/ijms24076709)

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