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.
Lahiri
Prabir
P
Institute of Haematology and Transfusion Medicine, Medical College, Kolkata, India.
Chaudhuri
Utpal
U
Chattopadhyay
Arnab
A
Chakraborty
Prantar
P
Mandal
Dipes
D
Dasgupta
Anjan Kr
AK
D000244:Adenosine Diphosphate / Q000494:pharmacology; D058669:Adrenergic alpha-2 Receptor Antagonists; D002545:Brain Ischemia / Q000188:drug therapy; D000077144:Clopidogrel; D004351:Drug Resistance; D004357:Drug Synergism; D004837:Epinephrine / Q000494:pharmacology; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D008958:Models, Molecular; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D058919:Purinergic P2 Receptor Antagonists; D020239:Receptor Cross-Talk; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058925:Receptors, Purinergic P2Y12; D020521:Stroke / Q000188:drug therapy*; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000627:therapeutic use
C547768:ADRA2A protein, human; D058669:Adrenergic alpha-2 Receptor Antagonists; D008565:Membrane Proteins; C548576:P2RY12 protein, human; D010975:Platelet Aggregation Inhibitors; D058919:Purinergic P2 Receptor Antagonists; D018341:Receptors, Adrenergic, alpha-2; D018048:Receptors, Purinergic P2; D058925:Receptors, Purinergic P2Y12; D000244:Adenosine Diphosphate; D000077144:Clopidogrel; D013988:Ticlopidine; D004837:Epinephrine