Structural insights in platelet receptor synergism-antiplatelet therapy in post-ischemic cerebrovascular events

Synergy between agonists of platelet aggregation, namely, ADP and epinephrine, has been studied in patients having a history of cerebrovascular ischemic event. There is a significant variability of responsiveness among individuals towards clopidogrel, which is a specific inhibitor of the low-affinity human purinergic receptor (P2Y12). For responders of clopidogrel, simultaneous application of ADP and epinephrine at sub-threshold concentrations (i.e., concentration below the threshold concentration at which aggregation occurs) leads to platelet aggregation, which is followed by deaggregation. For non-responders of the drug, the synergism seems to be stronger, showing no deaggregatory pattern. The inhibition of synergism by yohimbine hydrochloride (YH), a blocker of alpha2A-adrenoreceptors is more pronounced in non-responders. A simple structural model based on receptor-receptor interaction is proposed to explain the synergism. The model explains synergy in terms of cooperative interaction between the low-affinity ADP receptor P2Y12 (Swiss Prot:Q9H244) and the alpha2A-adrenoreceptor (Swiss Prot:P08913). It follows that the synergistic effect can be achieved in only one of the two 3D structures for the alpha2A-adrenoreceptor P08913 permitted by homology modeling, as there is a better docking interface with the Q9H244. The synergism itself and the observed dichotomous phenomenon in relation to inhibition of synergism among responders and non-responders can be accounted for, if the interacting receptors on the dynamic membrane interface compete with the clopidogrel binding.