title: Decreased platelet aggregation, increased bleeding time and resistance to thromboembolism in P2Y1-deficient mice.
abstract: Platelet activation is characterized by shape change, induction of fibrinogen receptor expression and release of granular contents, leading to aggregation and plug formation. While this response is essential for hemostasis, it is also important in the pathogenesis of a broad spectrum of diseases, including myocardial infarction, stroke and unstable angina. Adenosine 5'-diphosphate (ADP) induces platelet aggregation, but the mechanism for this has not been established, and the relative contribution of ADP in hemostasis and the development of arterial thrombosis is poorly understood. We show here that the purinoceptor P2Y1 is required for platelet shape change in response to ADP and is also a principal receptor mediating ADP-induced platelet aggregation. Activation of P2Y1 resulted in increased intracellular calcium but no alteration in cyclic adenosine monophosphate (cAMP) levels. P2Y1-deficient platelets partially aggregated at higher ADP concentrations, and the lack of P2Y1 did not alter the ability of ADP to inhibit cAMP, indicating that platelets express at least one additional ADP receptor. In vivo, the lack of P2Y1 expression increased bleeding time and protected from collagen- and ADP-induced thromboembolism. These findings support the hypothesis that the ATP receptor P2Y1 is a principal receptor mediating both physiologic and pathological ADP-induced processes in platelets.
authors.affiliation: Department of Medicine, University of North Carolina, CB# 7248, Chapel Hill, Thurston Bowles Bld, Durham, North Carolina, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Fabre
authors.forename: M
authors.initials: M
authors.lastname: Nguyen
authors.forename: A
authors.initials: A
authors.lastname: Latour
authors.forename: J A
authors.initials: JA
authors.lastname: Keifer
authors.forename: L P
authors.initials: LP
authors.lastname: Audoly
authors.forename: T M
authors.initials: TM
authors.lastname: Coffman
authors.forename: B H
authors.initials: BH
authors.lastname: Koller
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology*; D000818:Animals; D001760:Bleeding Time; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects; D048429:Cell Size; D000242:Cyclic AMP; D007113:Immunity, Innate; D051379:Mice; D008817:Mice, Mutant Strains; D008954:Models, Biological; D016296:Mutagenesis; D010974:Platelet Aggregation / Q000502:physiology*; D018048:Receptors, Purinergic P2 / Q000172:deficiency* / Q000235:genetics; D058472:Receptors, Purinergic P2Y1; D013923:Thromboembolism / Q000209:etiology*
chemical_list: C546383:P2ry1 protein, mouse; D018048:Receptors, Purinergic P2; D058472:Receptors, Purinergic P2Y1; D000244:Adenosine Diphosphate; D000242:Cyclic AMP