Stimulation of platelet P2Y 1 receptors by different endogenous nucleotides leads to functional selectivity via biased signalling.

Autor: Arkless KL; Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, London, UK., Pan D; Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, London, UK., Shankar-Hari M; School of Immunology and Microbial Sciences, King's College London, London, UK.; Centre for Inflammation Research, The University of Edinburgh, Edinburgh, UK., Amison RT; Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, London, UK., Page CP; Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, London, UK., Rahman KM; Chemical Biology Group, Institute of Pharmaceutical Science, King's College London, London, UK., Pitchford SC; Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, London, UK.
Jazyk: angličtina
Zdroj: British journal of pharmacology [Br J Pharmacol] 2024 Feb; Vol. 181 (4), pp. 564-579. Date of Electronic Publication: 2023 Feb 13.
DOI: 10.1111/bph.16039
Abstrakt: Background and Purpose: Platelet function during inflammation is dependent on activation by endogenous nucleotides. Non-canonical signalling via the P2Y 1 receptor is important for these non-thrombotic functions of platelets. However, apart from ADP, the role of other endogenous nucleotides acting as agonists at P2Y 1 receptors is unknown. This study compared the effects of ADP, Ap3A, NAD + , ADP-ribose, and Up4A on platelet functions contributing to inflammation or haemostasis.
Experimental Approach: Platelets obtained from healthy human volunteers were incubated with ADP, Ap3A, NAD + , ADP-ribose, or Up4A, with aggregation and fibrinogen binding measured (examples of function during haemostasis) or before exposure to fMLP to measure platelet chemotaxis (an inflammatory function). In silico molecular docking of these nucleotides to the binding pocket of P2Y 1 receptors was then assessed.
Key Results: Platelet aggregation and binding to fibrinogen induced by ADP was not mimicked by NAD + , ADP-ribose, and Up4A. However, these endogenous nucleotides induced P2Y 1 -dependent platelet chemotaxis, an effect that required RhoA and Rac-1 activity, but not canonical PLC activity. Analysis of molecular docking of the P2Y 1 receptor revealed distinct differences of amino acid interactions and depth of fit within the binding pocket for Ap3A, NAD + , ADP-ribose, or Up4A compared with ADP.
Conclusion and Implications: Platelet function (aggregation vs motility) can be differentially modulated by biased-agonist activation of P2Y 1 receptors. This may be due to the character of the ligand-binding pocket interaction. This has implications for future therapeutic strategies aimed to suppress platelet activation during inflammation without affecting haemostasis as is the requirement of current ant-platelet drugs.
Linked Articles: This article is part of a themed issue on Platelet purinergic receptor and non-thrombotic disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.4/issuetoc.
(© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
Databáze: MEDLINE
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