Pathophysiological consequences of receptor mistraffic: Tales from the platelet P2Y 12 receptor

Cunningham, Margaret; Aungraheeta, Riyaad; Mundell, Stuart J

doi:10.1016/j.mce.2017.02.016

Cited by 7 publications

(4 citation statements)

References 87 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Pharmacological blockade of these receptors, including P2Y1 and P2Y12, can help to prevent arterial thrombosis. 19 Aspirin was effective in reducing the risk of unfavorable functional outcomes in patients in cluster 26 (Fig. 2i, j ).…”

Section: Resultsmentioning

confidence: 95%

Biomarker and genomic analyses reveal molecular signatures of non-cardioembolic ischemic stroke

Ding

Meng

et al. 2023

Sig Transduct Target Ther

View full text Add to dashboard Cite

Acute ischemic stroke (AIS) is a major cause of disability and mortality worldwide. Non-cardioembolic ischemic stroke (NCIS), which constitutes the majority of AIS cases, is highly heterogeneous, thus requiring precision medicine treatments. This study aimed to investigate the molecular mechanisms underlying NCIS heterogeneity. We integrated data from the Third China National Stroke Registry, including clinical phenotypes, biomarkers, and whole-genome sequencing data for 7695 patients with NCIS. We identified 30 molecular clusters based on 63 biomarkers and explored the comprehensive landscape of biological heterogeneity and subpopulations in NCIS. Dimensionality reduction revealed fine-scale subpopulation structures associated with specific biomarkers. The subpopulations with biomarkers for inflammation, abnormal liver and kidney function, homocysteine metabolism, lipid metabolism, and gut microbiota metabolism were associated with a high risk of unfavorable clinical outcomes, including stroke recurrence, disability, and mortality. Several genes encoding potential drug targets were identified as putative causal genes that drive the clusters, such as CDK10, ERCC3, and CHEK2. We comprehensively characterized the genetic architecture of these subpopulations, identified their molecular signatures, and revealed the potential of the polybiomarkers and polygenic prediction for assessing clinical outcomes. Our study demonstrates the power of large-scale molecular biomarkers and genomics to understand the underlying biological mechanisms of and advance precision medicine for NCIS.

show abstract

Section: Resultsmentioning

confidence: 95%

Biomarker and genomic analyses reveal molecular signatures of non-cardioembolic ischemic stroke

Ding

Meng

et al. 2023

Sig Transduct Target Ther

View full text Add to dashboard Cite

show abstract

“…The activities of the purinoceptors are rapidly and reversibly modulated in human platelets, with the underlying mechanism including receptor internalization and subsequent trafficking. The responsiveness of P2Y12 receptors in human platelets is rapidly desensitized when there is exposure to ADP and rapidly resensitized upon removal of ADP [ 66 ]. Activation of the P2Y12 receptors stimulates ADP ribosylation factor 6 (ARF6) activity, which facilitates dynamin-dependent fission of clathrin-coated vesicles, and there is subsequently internalization, which is an essential factor for platelet activation [ 67 ].…”

Section: Discussionmentioning

confidence: 99%

“…Activation of the P2Y12 receptors stimulates ADP ribosylation factor 6 (ARF6) activity, which facilitates dynamin-dependent fission of clathrin-coated vesicles, and there is subsequently internalization, which is an essential factor for platelet activation [ 67 ]. Blockade of receptor internalization or subsequent recycling by specific mutations will diminish receptor resensitization within the human platelets of individuals with bleeding disorders [ 66 ]. Our results have identified four SNPs (IQSEC1, WASHC3, PSD3, BTBD7) that are involved in the process of endocytosis.…”

Section: Discussionmentioning

confidence: 99%

Artificial-Intelligence-Assisted Discovery of Genetic Factors for Precision Medicine of Antiplatelet Therapy in Diabetic Peripheral Artery Disease

et al. 2022

View full text Add to dashboard Cite

An increased risk of cardiovascular events was identified in patients with peripheral artery disease (PAD). Clopidogrel is one of the most widely used antiplatelet medications. However, there are heterogeneous outcomes when clopidogrel is used to prevent cardiovascular events in PAD patients. Here, we use an artificial intelligence (AI)-assisted methodology to identify genetic factors potentially involved in the clopidogrel-resistant mechanism, which is currently unclear. Several discoveries can be pinpointed. Firstly, a high proportion (>50%) of clopidogrel resistance was found among diabetic PAD patients in Taiwan. Interestingly, our result suggests that platelet function test-guided antiplatelet therapy appears to reduce the post-interventional occurrence of major adverse cerebrovascular and cardiac events in diabetic PAD patients. Secondly, AI-assisted genome-wide association study of a single-nucleotide polymorphism (SNP) database identified a SNP signature composed of 20 SNPs, which are mapped into 9 protein-coding genes (SLC37A2, IQSEC1, WASHC3, PSD3, BTBD7, GLIS3, PRDM11, LRBA1, and CNR1). Finally, analysis of the protein connectivity map revealed that LRBA, GLIS3, BTBD7, IQSEC1, and PSD3 appear to form a protein interaction network. Intriguingly, the genetic factors seem to pinpoint a pathway related to endocytosis and recycling of P2Y12 receptor, which is the drug target of clopidogrel. Our findings reveal that a combination of AI-assisted discovery of SNP signatures and clinical parameters has the potential to develop an ethnic-specific precision medicine for antiplatelet therapy in diabetic PAD patients.

show abstract

“…The antiplatelet drugs in therapeutic use belong to different classes, each one acting through a distinct mechanism, such as COX inhibitors [4], phosphodiesterase inhibitors [5], thrombin inhibitors [6], and P2Y 12 receptor antagonists, which have received a great attention in recent decades. The P2Y 12 and P2Y 1 receptors, both members of the P2 purinergic G protein-coupled receptors or metabotropic P2 receptors, play an important pathogenic role in arterial thrombosis [7–9]. They cooperate to mediate platelet aggregation induced by adenosine 5′-diphosphate (ADP); the P2Y 1 receptor induces the mobilization of ionized calcium from internal stores and mediates shape change and a slight and rapidly reversible platelet aggregation, while the P2Y 12 receptor mediates a progressive and sustained aggregation not preceded by shape change.…”

Section: Introductionmentioning

confidence: 99%

Structure Activity Relationship of 4-Amino-2-thiopyrimidine Derivatives as Platelet Aggregation Inhibitors

Cacciari

Crepaldi

Cheng

et al. 2019

View full text Add to dashboard Cite

Background: Platelet aggregation plays a pathogenic role in the development of arterial thrombi, which are responsible for common diseases caused by thrombotic arterial occlusion, such as myocardial infarction and stroke. Much efforts are directed toward developing platelet aggregation inhibitors that act through several mechanisms: the main antiplatelet family of COX-inhibitors, phosphodiesterase inhibitors, and thrombin inhibitors. Recently, the important role in the platelet aggregation of adenosine diphosphate (ADP)-activated P2Y12 and P2Y1 receptors, G-protein coupled receptors of the P2 purinergic family, has emerged, and their inhibitors are explored as potential therapeutic antithrombotics. P2Y12 inhibitors, i.e. clopidogrel, prasugrel, ticagrelor, and cangrelor, are already used clinically to reduce coronary artery thrombosis risk and prevent acute coronary syndromes. The search for new P2Y12 inhibitors, with better risk-to-benefit profiles is still ongoing. Methods: Several years ago, our group prepared a series of 6-amino-2-thio-3H-pyrimidin-4-one derivatives that displayed an interesting platelet aggregation inhibiting activity. In order to probe the structure-activity relationships and improve their inhibitory effects of these compounds, we synthesized variously substituted 6-amino-2-thio-3H-pyrimidin-4-one derivatives and substituted 4-amino-2-thiopyrimidine-5-carboxylic acid analogues. All the synthesized compounds were tested by light trasmission aggregometry (LTA) as inducers or inhibitors of platelet aggregation in citrated platelet-rich plasma (PRP). Results: Among the 6-amino-2-thio-3H-pyrimidin-4-one derivatives, compounds 2c and 2h displayed marked inhibitory activity, with a capability to inhibit the ADP(10−6M)-induced platelet aggregation by 91% and 87% at 10−4M concentration, respectively. Selected 4-amino-2-thiopyrimidine-5-carboxylic acid derivatives were tested as P2Y12 and P2Y1 antagonists and found to display negligible activity. Conclusion: These negative findings demonstrated that this heterocyclic nucleus is not a useful common pharmacophore for developing P2Y-dependent inhibitors of platelet aggregation. Nevertheless, compounds 2c and 2h could represent a new chemotype to further develop inhibitors of platelet aggregation.

show abstract

Pathophysiological consequences of receptor mistraffic: Tales from the platelet P2Y 12 receptor

Cited by 7 publications

References 87 publications

Biomarker and genomic analyses reveal molecular signatures of non-cardioembolic ischemic stroke

Biomarker and genomic analyses reveal molecular signatures of non-cardioembolic ischemic stroke

Artificial-Intelligence-Assisted Discovery of Genetic Factors for Precision Medicine of Antiplatelet Therapy in Diabetic Peripheral Artery Disease

Structure Activity Relationship of 4-Amino-2-thiopyrimidine Derivatives as Platelet Aggregation Inhibitors

Contact Info

Product

Resources

About