SEARCH:   Advanced

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 (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 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 Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted January 14, 2004 Accepted April 7, 2004 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* Physiology, Temple University Medical School, Philadelphia, PA, USA Physiology, Temple University Medical School, Philadelphia, PA, USA; Sol Sherry Thrombosis Research Center, Temple University Medical School, Philadelphia, PA, USA Pharmacology, University of Minnesota, Minneapolis, MN, USA Physiology, Temple University Medical School, Philadelphia, PA, USA; Pharmacology, Temple University Medical School, Philadelphia, PA, USA; Sol Sherry Thrombosis Research Center, Temple University Medical School, Philadelphia, PA, USA * Corresponding author; email: spk{at}temple.edu. The role of the Gi-coupled platelet P2Y12 receptor in platelet aggregation, potentiation of dense granule release, and thromboxane A2 production has been well-established. However, the functional effector(s) contributing directly to IIb3 activation in human platelets have not been delineated. As the rat brain P2Y12 receptor has been shown to activate G protein-gated inwardly-rectifying potassium (GIRK) channels, we investigated whether GIRK channels mediate any or all of the functional responses of the platelet P2Y12 receptor. Western blot analysis revealed that platelets express three different GIRK subunits (GIRK1, GIRK2, and GIRK4). We analyzed platelet functional responses using two structurally-distinct GIRK inhibitors, SCH23390 and U50488H. In aspirin-treated and washed human platelets, both SCH23390 and U50488H inhibited ADP-, 2-MeSADP-, U46619-, and low dose thrombin-mediated platelet aggregation in a concentration-dependent manner. However, the GIRK channel inhibitors did not affect platelet aggregation induced by high concentrations of thrombin or AYPGKF, which occurs independently of the P2Y12 receptor activation. Furthermore, the GIRK channel inhibitors reversed SFLLRN-induced platelet aggregation and inhibited the P2Y12-mediated potentiation of dense granule secretion and Akt phosphorylation, but 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. Based on these results, we conclude that GIRK channels play an important role in the functional responses mediated by P2Y12 receptor activation 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]

	Copyright © 2004 by American Society of Hematology         Online ISSN: 1528-0020