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Blood, 15 November 2003, Vol. 102, No. 10, pp. 3466-3467. This Article Full Text (PDF) 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 Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Rosa, J.-P. Search for Related Content PubMed Articles by Rosa, J.-P. Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  P2X1: definitely not an ADP receptor The story of platelets and purine nucleotides is one of the longest and most exciting in the biology and pathology of hemostasis. It began in the 1960s with the discovery of the role of adenosine diphosphate (ADP) as an important platelet agonist; like a good novel this story follows large avenues, but also dead ends, and turnabouts. Among the large avenues was the use of cloning technology, production, and analysis of knock-out and/or transgenic mice, along with the careful clinical, biologic, and molecular genetic analysis of patients suffering from ADP-dependent platelet defects, which led to the identification of the 3 purine receptors P2X1, P2Y1, and P2Y12 in platelets. The combination of all 3 receptors appears to correspond to the formerly termed P2T receptor. P2Y1 and P2Y12 are both G-protein-coupled receptors (GPCRs) specific for ADP. Acting in concert, P2Y1 mediates Ca2+ mobilization through a Gq pathway, while P2Y12 elicits a Gi-dependent pathway, both acting concurrently to activate integrin IIb3 and initiate platelet aggregation.1 One specific feature of P2X1 is that it is not a GPCR, but a purine-dependent ligand-gated ion channel (hence, X in the P2 subfamily of purine receptors). P2X1 appears to trigger a rapid initial extracellular Ca2+ intake by platelets, necessary for P2Y1 and P2Y12 to promote platelet aggregation.1 A second surprise is that P2X1 was shown to bind adenosine triphosphate (ATP) instead of ADP, which is contrary to what was originally thought. The role of ATP in hemostasis is a long-standing controversial issue, but consensus has been reached on the fact that it is an antagonist of ADP for P2Y1 and an agonist for P2X1. However, the issue of ADP versus ATP as a P2X1-specific ligand was recently reactivated by the identification of an alternate P2X1 receptor termed P2X1del, which is deleted of 17 amino acids within the cytoplasmic tail. P2X1del was found to mediate ADP-evoked inward Ca2+ currents and to be present in cell lines of the megakaryocytic lineage, as well as in platelets.2 Strong controversy was raised by this work,3 and the issue has remained unsettled. In a new study, Vial and colleagues (page 3646) provide clear and definitive evidence that P2X1del is not surface expressed when transfected alone, but that it can be surface expressed only as an heteromeric P2X1/P2X1del receptor, which then mediates ATP- and not ADP-evoked inward currents. Finally, these authors show that in platelets the level of total P2X1del is most likely too low to account for a physiologic response, and that ATP but not ADP has potential to evoke the P2X1-specific rapid Ca2+ rise in platelets in conditions where P2Y1 response is blunted. These authors therefore conclude that ATP is the sole P2X1 agonist and reinforce the idea that this purine nucleotide is probably an important physiologic platelet activator. Jean-Philippe Rosa INSERM U348, Paris References Kunapuli SP, Dorsam RT, Kim S, Quinton TM. Platelet purinergic receptors. Curr Opin Pharmacol. 2003;3: 175-180.[CrossRef][Medline] [Order article via Infotrieve] Greco NJ, Tonon G, Chen W, Luo X, Dalal R, Jamieson GA. Novel structurally altered P(2X1) receptor is preferentially activated by adenosine diphosphate in platelets and megakaryocytic cells. Blood. 2001;98: 100-107.[Abstract/Free Full Text] Oury C, Toth-Zsamboki E, Vermylen J, Hoylaerts MF. Does the P(2X1del) variant lacking 17 amino acids in its extracellular domain represent a relevant functional ion channel in platelets? Blood. 2002;99: 2275-2277.[Free Full Text] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This Article Full Text (PDF) 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 Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Rosa, J.-P. Search for Related Content PubMed Articles by Rosa, J.-P. Social Bookmarking                   What's this?

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