Faculty, Staff and Student Publications
Language
English
Publication Date
11-1-2024
Journal
British Journal of Pharmacology
DOI
10.1111/bph.16500
PMID
39014887
Abstract
Background and purpose: Although the amphiphilic nature of the widely used antithrombotic drug Ticagrelor is well known, it was never considered as a membranotropic agent capable of interacting with the lipid bilayer in a receptor-independent way. In this study, we investigated the influence of Ticagrelor on plasma membrane lipid order in platelets and if this modulates the potency of Ticagrelor at the P2Y12 receptor.
Experimental approach: We combined fluorescent in situ, in vitro and in silico approaches to probe the interactions between the plasma membrane of platelets and Ticagrelor. The influence of Ticagrelor on the lipid order of the platelet plasma membrane and large unilamellar vesicles was studied using the advanced fluorescent probe NR12S. Furthermore, the properties of model lipid bilayers in the presence of Ticagrelor were characterized by molecular dynamics simulations. Finally, the influence of an increased lipid order on the dose-response of platelets to Ticagrelor was studied.
Key results: Ticagrelor incorporates spontaneously into lipid bilayers and affects the lipid order of the membranes of model vesicles and isolated platelets, in a nontrivial composition and concentration-dependent manner. We showed that higher plasma membrane lipid order in platelets leads to a lower IC50 value for Ticagrelor. It is shown that membrane incorporation of Ticagrelor increases its potency at the P2Y12 receptor, by increasing the order of the platelet plasma membrane.
Conclusion and implications: A novel dual mechanism of Ticagrelor action is suggested that combines direct binding to P2Y12 receptor with simultaneous modulation of receptor-lipid microenvironment.
Keywords
Ticagrelor, Receptors, Purinergic P2Y12, Blood Platelets, Cell Membrane, Humans, Membrane Lipids, Lipid Bilayers, Molecular Dynamics Simulation, Purinergic P2Y Receptor Antagonists, P2Y12, antiplatelet drug, lipid order, plasma membrane, platelet
Published Open-Access
yes
Recommended Citation
Pyrshev, Kyrylo; Allemand, Florentin; Rabani, Vahideh; et al., "Ticagrelor Increases Its Own Potency at the P2Y12 Receptor by Directly Changing the Plasma Membrane Lipid Order in Platelets" (2024). Faculty, Staff and Student Publications. 3491.
https://digitalcommons.library.tmc.edu/uthmed_docs/3491