Ticagrelor increases its own potency at the P2Y12 receptor by directly changing the plasma membrane lipid order in platelets

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F24%3A00587986" target="_blank" >RIV/61388963:_____/24:00587986 - isvavai.cz</a>

Alternative codes found

RIV/61989592:15310/24:73627546

Result on the web

<a href="https://doi.org/10.1111/bph.16500" target="_blank" >https://doi.org/10.1111/bph.16500</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1111/bph.16500" target="_blank" >10.1111/bph.16500</a>

Result language

angličtina

Original language name

Ticagrelor increases its own potency at the P2Y12 receptor by directly changing the plasma membrane lipid order in platelets

Original language description

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.

Czech name

—

Czech description

—

Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

10403 - Physical chemistry

Project

—

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2024

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

British Journal of Pharmacology

ISSN

0007-1188

e-ISSN

1476-5381

Volume of the periodical

181

Issue of the periodical within the volume

21

Country of publishing house

US - UNITED STATES

Number of pages

12

Pages from-to

4369-4380

UT code for WoS article

001268597400001

EID of the result in the Scopus database

2-s2.0-85198737143