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Related Collections Hemostasis, Thrombosis, and Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, Vol. 92 No. 10 (November 15), 1998: pp. 3675-3683 Association Between Ligand-Induced Conformational Changes of Integrin IIb3 and IIb3-Mediated Intracellular Ca2+ Signaling Shigenori Honda, Yoshiaki Tomiyama, Toshiaki Aoki, Masamichi Shiraga, Yoshiyuki Kurata, Jiro Seki, and Yuji Matsuzawa From The Second Department of Internal Medicine, Osaka University Medical School, Osaka, Japan; the New Drug Research Laboratory, Fujisawa Pharmaceutical Co, Ltd, Osaka, Japan; and the Department of Blood Transfusion, Osaka University Hospital, Osaka, Japan. Platelet IIb3 is a prototypic integrin and plays a critical role in platelet aggregation. Occupancy of IIb3 with multivalent RGD ligands, such as fibrinogen, induces both expression of ligand-induced binding sites (LIBS) and IIb3 clustering, which are thought to be necessary for outside-in signaling. However, the association between LIBS expression and outside-in signaling remains elusive. In this study, we used various IIb3-specific peptidomimetic compounds as a monovalent ligand instead of fibrinogen and examined the association between LIBS expression and outside-in signaling such as IIb3-mediated intracellular Ca2+ signaling. Using a set of monoclonal antibodies (MoAbs) against LIBS, we showed that antagonists can be divided into two groups. In group I, antagonists can induce LIBS on both IIb and 3 subunits. In group II, antagonists can induce LIBS on the IIb subunit, but not on the 3 subunit. Inhibition studies suggested that group I and group II antagonists interact with distinct but mutually exclusive sites on IIb3. Neither group I nor group II antagonist increased intracellular Ca2+ concentrations ([Ca2+]i) in nonactivated platelets. All antagonists at nanomolar concentrations abolished the increase in [Ca2+]i in 0.03 U/mL thrombin-stimulated platelets, which is dependent on both fibrinogen-binding to IIb3 and platelet-aggregation. However, only group I antagonists at higher concentrations dose-dependently augmented the [Ca2+]i increase, which is due to aggregation-independent thromboxane A2 production. This increase in [Ca2+]i was not observed in thrombasthenic platelets, which express no detectable IIb3. Thus, only the group I antagonists, albeit a monovalent ligand, can initiate IIb3-mediated intracellular Ca2+ signaling in the presence of thrombin stimulation. Our findings strongly suggest the association between 3 LIBS expression and IIb3-mediated intracellular Ca2+ signaling in platelets. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? 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