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Blood, 1 September 2004, Vol. 104, No. 5, pp. 1335-1343. Prepublished online as a Blood First Edition Paper on May 13, 2004; DOI 10.1182/blood-2004-01-0069. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-01-0069v1 104/5/1335    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 Shankar, H. Articles by Kunapuli, S. P. Search for Related Content PubMed PubMed Citation Articles by Shankar, H. Articles by Kunapuli, S. P. Related Collections Hemostasis, Thrombosis, and Vascular Biology Cell Adhesion and Motility Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Role of G protein–gated inwardly rectifying potassium channels in P2Y12 receptor–mediated platelet functional responses Haripriya Shankar, Swaminathan Murugappan, Soochong Kim, Jianguo Jin, Zhongren Ding, Kevin Wickman, and Satya P. Kunapuli From the Department of Physiology, the Department of Pharmacology, and the Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA; and the Department of Pharmacology, University of Minnesota, Minneapolis. The role of the Gi-coupled platelet P2Y12 receptor in platelet function has been well established. However, the functional effector or effectors contributing directly to IIb3 activation in human platelets has not been delineated. As the P2Y12 receptor has been shown to activate G protein–gated, inwardly rectifying potassium (GIRK) channels, we investigated whether GIRK channels mediate any of the functional responses of the platelet P2Y12 receptor. Western blot analysis revealed that platelets express GIRK1, GIRK2, and GIRK4. In aspirin-treated and washed human platelets, 2 structurally distinct GIRK inhibitors, SCH23390(R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride) and U50488H (trans-(±)-3,4-dichloro-N-methyl-N-[2-(pyrrolidinyl)cyclohexyl] benzeneacetamide methanesulfonate), inhibited adenosine diphosphate (ADP)–, 2-methylthioADP (2-MeSADP)–, U46619-, and low-dose thrombin–mediated platelet aggregation. However, the GIRK channel inhibitors did not affect platelet aggregation induced by high concentrations of thrombin, AYPGKF, or convulxin. Furthermore, the GIRK channel inhibitors reversed SFLLRN-induced platelet aggregation, inhibited the P2Y12-mediated potentiation of dense granule secretion and Akt phosphorylation, and did not affect the agonist-induced Gq-mediated platelet shape change and intracellular calcium mobilization. Unlike AR-C 69931MX, a P2Y12 receptor–selective antagonist, the GIRK channel blockers did not affect the ADP-induced adenlylyl cyclase inhibition, indicating that they do not directly antagonize the P2Y12 receptor. We conclude that GIRK channels are important functional effectors of the P2Y12 receptor in human platelets. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: E. Mintert, L. I. Bosche, A. Rinne, M. Timpert, M.-C. Kienitz, L. Pott, and K. Bender Generation of a constitutive Na+-dependent inward-rectifier current in rat adult atrial myocytes by overexpression of Kir3.4 J. Physiol., November 15, 2007; 585(1): 3 - 13. [Abstract] [Full Text] [PDF] S. M. Schoenwaelder, A. Ono, S. Sturgeon, S. M. Chan, P. Mangin, M. J. Maxwell, S. Turnbull, M. Mulchandani, K. Anderson, G. Kauffenstein, et al. Identification of a Unique Co-operative Phosphoinositide 3-Kinase Signaling Mechanism Regulating Integrin {alpha}IIbbeta3 Adhesive Function in Platelets J. Biol. Chem., September 28, 2007; 282(39): 28648 - 28658. [Abstract] [Full Text] [PDF] H. Shankar, B. N. Kahner, J. Prabhakar, P. Lakhani, S. Kim, and S. P. Kunapuli G-protein-gated inwardly rectifying potassium channels regulate ADP-induced cPLA2 activity in platelets through Src family kinases Blood, November 1, 2006; 108(9): 3027 - 3034. [Abstract] [Full Text] [PDF] R. S. Scotland, M. Cohen, P. Foster, M. Lovell, A. Mathur, A. Ahluwalia, and A. J. Hobbs C-type natriuretic peptide inhibits leukocyte recruitment and platelet-leukocyte interactions via suppression of P-selectin expression PNAS, October 4, 2005; 102(40): 14452 - 14457. [Abstract] [Full Text] [PDF] G. Tolhurst, C. Vial, C. Leon, C. Gachet, R. J. Evans, and M. P. Mahaut-Smith Interplay between P2Y1, P2Y12, and P2X1 receptors in the activation of megakaryocyte cation influx currents by ADP: evidence that the primary megakaryocyte represents a fully functional model of platelet P2 receptor signaling Blood, September 1, 2005; 106(5): 1644 - 1651. [Abstract] [Full Text] [PDF] R. T. Dorsam, S. Kim, S. Murugappan, S. Rachoor, H. Shankar, J. Jin, and S. P. Kunapuli Differential requirements for calcium and Src family kinases in platelet GPIIb/IIIa activation and thromboxane generation downstream of different G-protein pathways Blood, April 1, 2005; 105(7): 2749 - 2756. [Abstract] [Full Text] [PDF]

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