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P2Y12 receptor constitutive activity as a new target for antiplatelet therapy
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Edité par CCSD -
International audience. Introduction: The platelet P2Y12 receptor (P2Y12-R) for adenosine diphosphate (ADP) plays a crucial role in platelet activation and thus constitutes one of the major drug targets to inhibit platelet aggregation in the treatment/prevention of arterial thrombosis. However, although effective, the clinical use of P2Y12-R antagonists faces some limitations, such as a delayed onset of action (clopidogrel) or adverse effects (ticagrelor, cangrelor), justifying the development of a new generation of P2Y12-R antagonists with a better clinical benefit-risk balance. Although the recent concept of biased agonism offers the possibility to alleviate undesirable adverse effects while preserving therapeutic outcomes by selecting a specific subset of signaling pathways associated with a GPCR, it has never been explored at P2Y12-R.Material and methods: In this study, using highly sensitive BRET-based probes, we sought to accurately decipher the pharmacological signature of P2Y12-R agonist (ADP) or antagonists (antiplatelet drugs) by screening the activation profile of G protein activation and downstream effectors in living HEK293T cells.Results: We found that at basal state, P2Y12-R exhibits high constitutive activity on Gi protein family and downstream adenylyl cyclase inhibition. Importantly, P2Y12-R constitutive activity is abolished by the R122C mutation that was associated with bleeding disorder, unveiling the critical importance of the P2Y12-R constitutive signaling in platelet aggregation. Moreover, we showed that similarly to ticagrelor, the P2Y12-R antagonist cangrelor acted as an inverse agonist at P2Y12-R but exhibited different pharmacological profiling on both G protein and cAMP signaling, indicating that cangrelor behaves as a biased inverse agonist relative to ticagrelor. This biased inverse agonist efficacy was further confirmed in human resting platelets.Discussion/Conclusion: Our study points out that constitutive P2Y12-R signaling is a normal feature of the receptor that might be essential for platelets to respond faster to a vessel injury. From a therapeutic standpoint, our data suggest that the beneficial advantages of antiplatelet drugs might be more related to inverse agonism at P2Y12-R than to antagonism of ADP-mediated signaling. In the future, deciphering P2Y12-R constitutive activity should allow the discovery of more selective biased P2Y12-R blockers demonstrating therapeutic advantages over classical antiplatelet drugs by improving therapeutic outcomes and concomitantly relieving undesirable adverse effects.
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