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Publication - Professor Eamonn Kelly

    Inverse agonism at the P2Y12 receptor and ENT1 transporter blockade contribute to platelet inhibition by ticagrelor

    Citation

    Aungraheeta, R, Conibear, A, Butler, M, Kelly, E, Nylander, S, Mumford, A & Mundell, S, 2017, ‘Inverse agonism at the P2Y12 receptor and ENT1 transporter blockade contribute to platelet inhibition by ticagrelor’. Blood, vol 128., pp. 2717-2728

    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.

    Full details in the University publications repository