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First published on December 15, 2004; DOI: 10.1124/mol.104.004846

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Received for publication July 9, 2004.
Revised December 13, 2004.
Accepted for publication December 14, 2004.

Differential regulation and relocalization of the platelet P2Y receptors following activation : a way to avoid loss of hemostatic properties?

Anthony Baurand 1, Anita Eckly 1, Beatrice Hechler 1, Gilles Kauffenstein 1, Jean-Luc Galzi 2, Jean-Pierre Cazenave 3, Catherine Leon 3, Christian Gachet 3*

1 the Laboratoire de Biologie et de Pharmacologie de l'Hemostase et de la Thrombose, INSERM U.311, Eta 2 Departement Recepteurs et Proteines Membranaires, UPR CNRS 9050, Institut Federatif Gilbert Laustria 3 Laboratoire de Biologie et de Pharmacologie de l'Hemostase et de la Thrombose, INSERM U.311, Etablis

* Address correspondence to: E-mail: christian.gachet{at}efs-alsace.fr

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 (GFP). Both in platelets and transfected cells, exposure to 10 µM ADP caused desensitization of the P2Y1 receptor-driven calcium signal while 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 appeared to utilize a distinct, clathrin-independent pathway. Altogether, 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.


Key words: Purinergic, Gi family, Gq/11 family, cAMP, Calcium (G Protein Coupled Signals), Desensitization/uncoupling, Sequestration/Internalization, Platelets


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