Abstract
Ticagrelor is a potent antagonist of the P2Y12 receptor (P2Y12R)
and consequently an inhibitor of platelet activity effective in the
treatment of atherothrombosis. Here, we sought to further characterise
its molecular mechanism of action. Initial studies showed that
ticagrelor promoted a greater inhibition of ADP-induced Ca2+ release in washed platelets versus other P2Y12R antagonists. This additional effect of ticagrelor beyond P2Y12R
antagonism was in part as a consequence of ticagrelor inhibiting the
equilibrative nucleoside transporter 1 (ENT1) on platelets, leading to
accumulation of extracellular adenosine and activation of Gs-coupled adenosine A2A
receptors. This contributed to an increase in basal cAMP and VASP
phosphorylation. In addition, ticagrelor increased platelet cAMP and
VASP phosphorylation in the absence of ADP in an adenosine
receptor-independent manner. We hypothesised that this increase
originated from a direct effect on basal agonist-independent P2Y12R signalling, and this was validated in 1321N1 cells stably transfected with human P2Y12R. In these cells, ticagrelor blocked the constitutive agonist-independent activity of the P2Y12R, limiting basal Gi-coupled
signalling and thereby increasing cAMP levels. These data suggest that
ticagrelor has the pharmacological profile of an inverse agonist. Based
on our results showing insurmountable inhibition of ADP-induced Ca2+
release and forskolin-induced cAMP, the mode of antagonism of
ticagrelor also appears non-competitive, at least functionally. In
summary, our studies describe two novel modes of action of ticagrelor,
inhibition of platelet ENT1 and inverse agonism at the P2Y12R that contribute to its effective inhibition of platelet activation.
Original language | English |
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Pages (from-to) | 2717-2728 |
Number of pages | 12 |
Journal | Blood |
Volume | 128 |
Issue number | 23 |
Early online date | 30 Sept 2016 |
DOIs | |
Publication status | Published - 8 Dec 2016 |
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Dive into the research topics of 'Inverse agonism at the P2Y12 receptor and ENT1 transporter blockade contribute to platelet inhibition by ticagrelor'. Together they form a unique fingerprint.Profiles
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Professor Eamonn P Kelly
- School of Physiology, Pharmacology & Neuroscience - Professor of Molecular Pharmacology
Person: Academic
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Professor Stuart J Mundell
- School of Physiology, Pharmacology & Neuroscience - Professor in Cellular Pharmacology
- Dynamic Cell Biology
Person: Academic , Member