Role of P2Y1 purinoceptor in ADP-induced platelet activation

• Published in: FEBS letters Vol. 422; no. 3; pp. 291 - 295
• Main Authors: Savi, P, Beauverger, P, Labouret, C, Delfaud, M, Salel, V, Kaghad, M, Herbert, J.M
• Format: Journal Article
• Language: English
• Published: England Elsevier B.V 06.02.1998
• Subjects: Adenosine diphosphate; Adenosine Diphosphate - physiology; Animals; Calcium - metabolism; Clopidogrel; Humans; In Vitro Techniques; P2Y1 purinoceptor; Platelet Activation - drug effects; Platelet Activation - physiology; Platelet aggregation; Platelet Aggregation Inhibitors - pharmacology; Polymerase Chain Reaction; Rabbits; Receptors, Purinergic P2 - drug effects; Receptors, Purinergic P2 - physiology; Receptors, Purinergic P2Y1; Ticlopidine - analogs & derivatives; Ticlopidine - pharmacology; Adenosine diphosphate; Platelet aggregation; P2Y1 purinoceptor
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/S0014-5793(98)00025-8

ADP acts as an agonist of platelet aggregation via specific receptors which are still to be characterised. Amplification by PCR of a human platelet cDNA library confirmed the presence of mRNA of the P2Y1 receptor in platelets. In order to determine if these P2Y1 receptors were involved in ADP-induced platelet activation, we determined the effects of A3P5PS, an antagonist of the P2Y1 receptor, on the binding of [ 33P]2-MeS-ADP, a potent analogue of ADP. We found that A3P5PS displaced about 27% of [ 33P]2-MeS-ADP binding, a receptor population which has been shown to be resistant to treatment with clopidogrel, a selective anti-ADP agent. A3P5PS specifically inhibited 2-MeS-ADP-induced shape change and calcium increase but did not affect adenylyl cyclase down-regulation. 2-MeS-ADP-induced platelet aggregation was also inhibited by A3P5PS but was restored when platelets were further activated by serotonin, a non-aggregating compound, therefore suggesting that P2Y1-mediated stimulation is an absolute prerequisite for ADP to induce platelet aggregation and a key event for platelet activation and aggregation to occur. These results therefore show that ADP-induced aggregation cannot be attributed to activation of P2Y1 alone, but must be attributed to the simultaneous activation of the high affinity receptor (P2Y1) and a low affinity receptor of ADP (still to be discovered), each of them essential, but neither able to trigger aggregation alone.