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Blood, 1 December 2004, Vol. 104, No. 12, pp. 3603-3610. Prepublished online as a Blood First Edition Paper on August 5, 2004; DOI 10.1182/blood-2003-12-4330. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-12-4330v1 104/12/3603    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Jedlitschky, G. Articles by Kroemer, H. K. Search for Related Content PubMed PubMed Citation Articles by Jedlitschky, G. Articles by Kroemer, H. K. Related Collections Hemostasis, Thrombosis, and Vascular Biology Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY The nucleotide transporter MRP4 (ABCC4) is highly expressed in human platelets and present in dense granules, indicating a role in mediator storage Gabriele Jedlitschky, Konstanze Tirschmann, Lena E. Lubenow, Hendrik K. Nieuwenhuis, Jan W. N. Akkerman, Andreas Greinacher, and Heyo K. Kroemer From the Department of Pharmacology, Peter Holtz Research Center of Pharmacology and Experimental Therapeutics, Greifswald, Germany; the Department of Immunology and Transfusion Medicine, Ernst-Moritz-Arndt-University, Greifswald, Germany; and the Department of Haematology, University Medical Centre Utrecht, Utrecht, the Netherlands. Platelet aggregation is initiated by the release of mediators as adenosine diphosphate (ADP) stored in platelet granules. Possible candidates for transport proteins mediating accumulation of these mediators in granules include multidrug resistance protein 4 (MRP4, ABCC4), a transport pump for cyclic nucleotides and nucleotide analogs. We investigated the expression of MRP4 in human platelets by immunoblotting, detecting a strong signal at 170 kDa. Immunofluorescence microscopy using 2 MRP4-specific antibodies revealed staining mainly in intracellular structures, which largely colocalized with the accumulation of mepacrine as marker for delta-granules and to a lower extent at the plasma membrane. Furthermore, an altered distribution of MRP4 was observed in platelets from a patient with Hermansky-Pudlak syndrome with defective delta-granules. Adenosine triphosphate (ATP)–dependent cyclic guanosine monophosphate (cGMP) transport codistributed with MRP4 detection in subcellular fractions, with highest activities in the dense granule and plasma membrane fractions. This transport was inhibited by dipyramidole, indomethacin, and MK571 with median inhibitory concentration (IC50) values of 12, 22, and 43 µM, and by ibuprofen. Transport studies with [3H]ADP indicated the presence of an orthovanadate-sensitive ADP transporting system, inhibited by dipyramidole, MK571, and cyclic nucleotides. The results indicate a function of MRP4 in platelet mediator storage and inhibition of MRP4 may represent a novel mechanism for inhibition of platelet function by some anti-inflammatory drugs. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: R. van de Ven, R. Oerlemans, J. W. van der Heijden, G. L. Scheffer, T. D. de Gruijl, G. Jansen, and R. J. Scheper ABC drug transporters and immunity: novel therapeutic targets in autoimmunity and cancer J. Leukoc. Biol., November 1, 2009; 86(5): 1075 - 1087. [Abstract] [Full Text] [PDF] J. Niessen, G. Jedlitschky, M. Grube, S. Bien, H. 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