Purinoceptors on blood platelets: further pharmacological and clinical evidence to suggest the presence of two ADP receptors.
Platelet aggregation by ADP plays a major role in the development and extension of arterial thrombosis. The antithrombotic thienopyridine compounds ticlopidine and clopidogrel have proved useful tools to investigate the mechanisms of ADP-induced platelet activation. In essence, although clopidogrel has been shown to completely and selectively block ADP-induced platelet aggregation, G protein activation and inhibition of adenylyl cyclase, this drug does not affect shape change and Ca2+ influx. Binding studies, using the non-hydrolysable ligand [33P]2MeSADP, have shown that human platelets contain about 600 high-affinity binding sites for 2MeSADP (Kd approximately 5 nM). These sites present pharmacological characteristics of a P2T receptor. Clopidogrel treatment reduces the number of sites by 70% on rat platelets (from 1200 to 450) and leaves the residual binding sites resistant to clopidogrel. Moreover, patients with congenital impairment of ADP-induced platelet aggregation but normal shape change display very low levels of [33P]2MeSADP binding sites. The current data thus strongly suggest the presence of two ADP receptors, one responsible for shape change and rapid Ca2+ influx and the other a Gi protein-coupled receptor responsible for Ca2+ mobilization from internal stores, inhibition of adenylyl cyclase and platelet aggregation.
INSERM U.311, Etablissement de Transfusion Sanguine de Strasbourg, France.
C
C
Gachet
M
M
Cattaneo
P
P
Ohlmann
B
B
Hechler
A
A
Lecchi
J
J
Chevalier
D
D
Cassel
P M
PM
Mannucci
J P
JP
Cazenave
D000244:Adenosine Diphosphate / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D000077144:Clopidogrel; D005260:Female; D006801:Humans; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D013873:Thionucleotides / Q000378:metabolism*; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology
D010975:Platelet Aggregation Inhibitors; D018048:Receptors, Purinergic P2; D013873:Thionucleotides; C002480:methylthio-ADP; D000244:Adenosine Diphosphate; D000077144:Clopidogrel; D013988:Ticlopidine