ArticleThe Journal of biological chemistry2013
Protease-activated receptor 1 (PAR1) and PAR4 heterodimers are required for PAR1-enhanced cleavage of PAR4 by α-thrombin.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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Who cites it
47 citing papers in PubMed, 90 citations in OpenAlex.
- Differential regulation of cyclic adenosine monophosphate by phosphodiesterase 3A discriminates thrombin-induced protease activated receptor 1- and 4-dependent platelet activation.Journal of thrombosis and haemostasis : JTH · 2026Article
- PAR-1 in Alzheimer's Disease: Pathophysiological Insights and Mechanistic Perspectives.Current medical science · 2026Review
- Neutrophil cathepsin G potentiates biased signaling through protease-activated receptor 4.Blood advances · 2026Article
- Dabigatran Attenuates the Binding of Thrombin to Platelets-A Novel Mechanism of Action.Thrombosis and haemostasis · 2025Article
- PARInternational journal of molecular sciences · 2025Article
- The protease-activated receptors are expressed in glioblastoma and differentially modulate adherent versus stem-like growth of LN-18 GBM cells.Frontiers in oncology · 2025Article
- Acetaminophen Overdose Reveals PAR4 as a Low-Expressing but Potent Receptor on the Hepatic Endothelium in Mice.Arteriosclerosis, thrombosis, and vascular biology · 2025Article
- Endothelial protease-activated receptor 4: impotent or important?Frontiers in cardiovascular medicine · 2025Review
- Rivaroxaban attenuates neutrophil maturation in the bone marrow niche.Basic research in cardiology · 2023Article
- Thrombin-mediated activation of PAR1 enhances doxorubicin-induced cardiac injury in mice.Blood advances · 2023Article
- A comprehensive review of the ten main platelet receptors involved in platelet activity and cardiovascular disease.American journal of blood research · 2023Review
- Protease-activated receptors in health and disease.Physiological reviews · 2023Review
- Novel strategies in antithrombotic therapy: targeting thrombosis while preserving hemostasis.Frontiers in cardiovascular medicine · 2023Review
- Diversification of PAR signaling through receptor crosstalk.Cellular & molecular biology letters · 2022Review
- Parallel imaging of coagulation pathway proteases activated protein C, thrombin, and factor Xa in human plasma.Chemical science · 2022Article
- 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
- Histone 2B Facilitates Plasminogen-Enhanced Endothelial Migration through Protease-Activated Receptor 1 (PAR1) and Protease-Activated Receptor 2 (PAR2).Biomolecules · 2022Article
- Protease Activated Receptors and Arthritis.International journal of molecular sciences · 2021Review
- Bothrops lanceolatus snake (Fer-de-lance) venom triggers inflammatory mediators' storm in human blood.Archives of toxicology · 2021Article
- Protease-activated receptors: An illustrated review.Research and practice in thrombosis and haemostasis · 2021Review
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Thrombin is a potent platelet agonist that activates platelets and other cells of the cardiovascular system by cleaving its G-protein-coupled receptors, protease-activated receptor 1 (PAR1), PAR4, or both. We now show that cleaving PAR1 and PAR4 with α-thrombin induces heterodimer formation. PAR1-PAR4 heterodimers were not detected when unstimulated; however, when the cells were stimulated with 10 nm α-thrombin, we were able to detect a strong interaction between PAR1 and PAR4 by bioluminescence resonance energy transfer. In contrast, activating the receptors without cleavage using PAR1 and PAR4 agonist peptides (TFLLRN and AYPGKF, respectively) did not enhance heterodimer formation. Preventing PAR1 or PAR4 cleavage with point mutations or hirugen also prevented the induction of heterodimers. To further characterize the PAR1-PAR4 interactions, we mapped the heterodimer interface by introducing point mutations in transmembrane helix 4 of PAR1 or PAR4 that prevented heterodimer formation. Finally, we show that mutations in PAR1 or PAR4 at the heterodimer interface prevented PAR1-assisted cleavage of PAR4. These data demonstrate that PAR1 and PAR4 require allosteric changes induced via receptor cleavage by α-thrombin to mediate heterodimer formation, and we have determined the PAR1-PAR4 heterodimer interface. Our findings show that PAR1 and PAR4 have dynamic interactions on the cell surface that should be taken into account when developing and characterizing PAR antagonists.
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