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ORIGINAL ARTICLE

Differential Regulation and Relocalization of the Platelet P2Y Receptors after Activation: A Way to Avoid Loss of Hemostatic Properties?

Laboratoire de Biologie et de Pharmacologie de l'Hémostase et de la Thrombose, Institut National de la Santé et de la Recherche Médicale U.311, Etablissement Français du Sang-Alsace, Strasbourg Cedex, France (A.B., A.E., B.H., G.K., J.-P.C., C.L., C.G.); and Département Récepteurs et Protéines Membranaires, Unité Propre de Recherche Centre National de la Recherche Scientifique 9050, Institut Fédératif Gilbert Laustriat, l'Institut Fédératif de Recherches 85, Ecole Supérieure de Biotechnologie de Strasbourg, Illkirch, France (J.-L.G.)

Abstract

In the present study, we investigated the desensitization and trafficking of the P2Y₁ and P2Y₁₂ receptors after agonist-induced stimulation of platelets or astrocytoma cells transfected with the P2Y₁ or P2Y₁₂ receptors fused to green fluorescent protein. In platelets and in transfected cells, exposure to 10 µM ADP caused desensitization of the P2Y₁ receptor-driven calcium signal, whereas the P2Y₁₂ receptor-mediated inhibition of cAMP formation was not affected. Plasma membranes from ADP-stimulated platelets also retained P2Y₁₂ activity. Agonist-induced P2Y₁ receptor desensitization was accompanied by its internalization in platelets and transfected cells. In contrast, although a substantial fraction of P2Y₁₂ receptors was rapidly and transiently internalized, most of the P2Y₁₂ receptors remained at the plasma membrane. Activated P2Y₁ receptors were internalized through a clathrin-dependent pathway in cells and platelets, whereas the P2Y₁₂ receptors seemed to use a distinct, clathrin-independent pathway. Together, these data indicate that the P2Y₁ and P2Y₁₂ receptors are differentially regulated upon activation. The absence of desensitization of the Gi protein-coupled P2Y₁₂ receptor-dependent responses could represent a mechanism to preserve the hemostatic properties of otherwise unresponsive platelets.

Address correspondence to: Dr. Christian Gachet, Laboratoire de Biologie et de Pharmacologie de l'Hémostase et de la Thrombose, INSERM U.311, Etablissement Français du Sang-Alsace, 10 rue Spielmann, BP 36, 67065 Strasbourg Cedex, France. E-mail:christian.gachet{at}efs-alsace.fr

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