Defective platelet aggregation and increased resistance to thrombosis in purinergic P2Y1 receptor–null mice
Open Access
- 15 December 1999
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 104 (12), 1731-1737
- https://doi.org/10.1172/jci8399
Abstract
ADP is a key agonist in hemostasis and thrombosis. ADP-induced platelet activation involves the purinergic P2Y1 receptor, which is responsible for shape change through intracellular calcium mobilization. This process also depends on an unidentified P2 receptor (P2cyc) that leads to adenylyl cyclase inhibition and promotes the completion and amplification of the platelet response. P2Y1-null mice were generated to define the role of the P2Y1 receptor and to determine whether the unidentified P2cyc receptor is distinct from P2Y1. These mice are viable with no apparent abnormalities affecting their development, survival, reproduction, or the morphology of their platelets, and the platelet count in these animals is identical to that of wild-type mice. However, platelets from P2Y1-deficient mice are unable to aggregate in response to usual concentrations of ADP and display impaired aggregation to other agonists, while high concentrations of ADP induce platelet aggregation without shape change. In addition, ADP-induced inhibition of adenylyl cyclase still occurs, demonstrating the existence of an ADP receptor distinct from P2Y1. P2Y1-null mice have no spontaneous bleeding tendency but are resistant to thromboembolism induced by intravenous injection of ADP or collagen and adrenaline. Hence, the P2Y1 receptor plays an essential role in thrombotic states and represents a potential target for antithrombotic drugs. J. Clin. Invest.104:1731–1737 (1999).Keywords
This publication has 44 references indexed in Scilit:
- Specific Impairment of Human Platelet P2Y AC ADP Receptor–Mediated Signaling by the Antiplatelet Drug ClopidogrelArteriosclerosis, Thrombosis, and Vascular Biology, 1999
- Restenosis after coronary angioplastyCurrent Problems in Cardiology, 1997
- Loss of ATP Diphosphohydrolase Activity with Endothelial Cell ActivationThe Journal of Experimental Medicine, 1997
- Activation of Receptor-operated Cation Channels via P2X1 Not P2T Purinoceptors in Human PlateletsPublished by Elsevier BV ,1996
- Cloning of Rat and Mouse P2Y PurinoceptorsBiochemical and Biophysical Research Communications, 1995
- An inherited bleeding disorder linked to a defective interaction between ADP and its receptor on platelets. Its influence on glycoprotein IIb-IIIa complex function.JCI Insight, 1995
- Cloning and functional expression of a brain G‐protein‐coupled ATP receptorFEBS Letters, 1993
- Disruption of the Hox-1.6 homeobox gene results in defects in a region corresponding to its rostral domain of expressionCell, 1991
- Aggregation of Blood Platelets by Adenosine Diphosphate and its ReversalNature, 1962
- Adenosine Diphosphate in Red Cells as a Factor in the Adhesiveness of Human Blood PlateletsNature, 1961