ArticleMolecular pharmacology2014
The physical association of the P2Y12 receptor with PAR4 regulates arrestin-mediated Akt activation.
Article in Molecular pharmacology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 58 citations in OpenAlex.
- The Na/K-ATPase α1 subunit fine-tunes platelet P2Y12 function and mediates sex dimorphism-associated thrombosis.Blood advances · 2026Article
- From theory to platelets: unraveling the history and complexities of biased signaling.Blood vessels, thrombosis & hemostasis · 2025Review
- RNF144A suppresses ovarian cancer stem cell properties and tumor progression through regulation of LIN28B degradation via the ubiquitin-proteasome pathway.Cell biology and toxicology · 2022Article
- Diversification of PAR signaling through receptor crosstalk.Cellular & molecular biology letters · 2022Review
- Vascular Endothelial Cells Produce Coagulation Factors That Control Their Growth via Joint Protease-Activated Receptor and C5a Receptor 1 (CD88) Signaling.The American journal of pathology · 2022Article
- The Molecular Aspects of Disturbed Platelet Activation through ADP/P2YInternational journal of molecular sciences · 2021Article
- That was then, this is now: the development of our knowledge and understanding of P2 receptor subtypes.Purinergic signalling · 2021Article
- Protease-activated receptors: An illustrated review.Research and practice in thrombosis and haemostasis · 2021Review
- Lipid Receptor GPR31 (G-Protein-Coupled Receptor 31) Regulates Platelet Reactivity and Thrombosis Without Affecting Hemostasis.Arteriosclerosis, thrombosis, and vascular biology · 2021Article
- Article
- Molecular basis for activation and biased signaling at the thrombin-activated GPCR proteinase activated receptor-4 (PAR4).The Journal of biological chemistry · 2020Article
- Article
- Enhanced potency of prasugrel on protease-activated receptors following bivalirudin treatment for PCI as compared to clopidogrel.Thrombosis research · 2019Article
- The protease-activated receptor 4 Ala120Thr variant alters platelet responsiveness to low-dose thrombin and protease-activated receptor 4 desensitization, and is blocked by non-competitive P2YJournal of thrombosis and haemostasis : JTH · 2018Article
- G Protein-Coupled Receptor Signaling Through β-Arrestin-Dependent Mechanisms.Journal of cardiovascular pharmacology · 2017Review
- Protease-activated receptor-4 and purinergic receptor P2Y12 dimerize, co-internalize, and activate Akt signaling via endosomal recruitment of β-arrestin.The Journal of biological chemistry · 2017Article
- New Concepts and Mechanisms of Platelet Activation Signaling.Physiology (Bethesda, Md.) · 2017Review
- Protease-activated receptor 4: from structure to function and back again.British journal of pharmacology · 2016Review
- Protease-activated Receptor-4 Signaling and Trafficking Is Regulated by the Clathrin Adaptor Protein Complex-2 Independent of β-Arrestins.The Journal of biological chemistry · 2016Article
- Protease-activated receptors in hemostasis.Blood · 2016Review
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
Abstract
It is now well accepted that protease activated receptor (PAR) 1 and PAR4 have differential roles in platelet activation. PAR4, a low-affinity thrombin receptor in human platelets, participates in sustained platelet activation in a P2Y12-dependent manner; however, the mechanisms are not defined. Our previous studies demonstrated that thrombin induces the association of PAR4 with P2Y12, together with arrestin recruitment to the complex. Here we show that PAR4 and P2Y12 directly interact to coregulate Akt signaling after PAR4 activation. We observed direct and specific interaction of P2Y12 with PAR4 but not PAR1 by bioluminescent resonance energy transfer when the receptors were coexpressed in human embryonic kidney 293T cells. PAR4-P2Y12 dimerization was promoted by PAR4-AP and inhibited by P2Y12 antagonist. By using sequence comparison of the transmembrane domains of PAR1 and PAR4, we designed a mutant form of PAR4, "PAR4SFT," by replacing LGL194-196 at the base of transmembrane domain 4 with the corresponding aligned PAR1 residues SFT 220-222. PAR4SFT supported only 8.74% of PAR4-P2Y12 interaction, abolishing P2Y12-dependent arrestin recruitment to PAR4 and Akt activation. Nonetheless, PAR4SFT still supported homodimerization with PAR4. PAR4SFT failed to induce a calcium flux when expressed independently; however, coexpression of increasing concentrations of PAR4SFT, together with PAR4 potentiated PAR4-mediated calcium flux, suggested that PAR4 act as homodimers to signal to Gq-coupled calcium responses. In conclusion, PAR4 LGL (194-196) governs agonist-dependent association of PAR4 with P2Y12 and contributes to Gq-coupled calcium responses. PAR4-P2Y12 association supports arrestin-mediated sustained signaling to Akt. Hence, PAR4-P2Y12 dimerization is likely to be important for the PAR4-P2Y12 dependent stabilization of platelet thrombi.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.