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Blood, 1 May 2005, Vol. 105, No. 9, pp. 3552-3560. Prepublished online as a Blood First Edition Paper on January 21, 2005; DOI 10.1182/blood-2004-07-2893. This Article Full Text (PDF) All Versions of this Article: 2004-07-2893v1 105/9/3552    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Hardy, A. R Articles by Mundell, S. J Search for Related Content PubMed PubMed Citation Articles by Hardy, A. R Articles by Mundell, S. J Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 27, 2004 Accepted December 21, 2004 P2Y1 and P2Y12 receptors for ADP desensitize by distinct kinase-dependent mechanisms Adam R Hardy, Pamela B Conley, Jiansong Luo, Jeffrey L Benovic, Alastair W Poole, and Stuart J Mundell* Department of Pharmacology, School of Medical Sciences, University Walk, University of Bristol, Bristol, United Kingdom Portola Pharmaceuticals Inc., San Francisco, CA, USA Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA * Corresponding author; email: s.j.mundell{at}bris.ac.uk. ADP plays a central role in regulating platelet function by the activation of the G protein-coupled receptors P2Y1 and P2Y12. Although it is well established that aggregation responses of platelets to ADP desensitize, the underlying mechanisms involved remain unclear. In this study we demonstrate that both P2Y1- and P2Y12- mediated platelet responses desensitize rapidly. Furthermore, we have established that these receptors desensitize by different kinase-dependent mechanisms. GRK2 and GRK6 are both endogenously expressed in platelets. Transient over-expression of dominant negative mutants of these kinases or reductions in endogenous GRK expression by the use of specific siRNAs in 1321N1 cells showed that P2Y12, but not P2Y1, desensitization is mediated by GRKs. In contrast, desensitization of P2Y1, but not P2Y12, is largely dependent upon protein kinase C activity. This study is therefore the first to show that both P2Y1 and P2Y12 desensitize in human platelets and reveals ways in which their sensitivity to ADP may be differentially and independently altered. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. Reiner, N. Ziegler, C. Leon, K. Lorenz, K. von Hayn, C. 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