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0026-895X/97/020227-10$3.00/0
Copyright © by The American Society for Pharmacology and Experimental Therapeutics
All rights of reproduction in any form reserved.
MOLECULAR PHARMACOLOGY 52:227-236 (1997).

Arginine-Glycine-Aspartic Acid Mimics Can Identify a Transitional Activation State of Recombinant alpha IIbbeta 3 in Human Embryonic Kidney 293 Cells

Dicky G. Abraham, Elka M. Nutt, Rodney A. Bednar, Bohumil Bednar, Robert J. Gould, and Le T. Duong

Departments of Pharmacology (D.G.A., R.A.B., B.B., R.J.G.) and Bone Biology and Osteoporosis (E.M.N., L.T.D.), Merck Research Laboratories, West Point, Pennsylvania 19486

The platelet-specific integrin alpha IIbbeta 3 achieves a high affinity binding state in response to extracellular agonists such as thrombin, ADP, or collagen. During this activation, the receptor undergoes a number of conformational changes. To characterize the different conformations of alpha IIbbeta 3, we expressed recombinant alpha IIbbeta 3 in human embryonic kidney (HEK) 293 cells. Antigenic and peptide recognition specificities of the full-length recombinant receptor resembled those of the native receptor in platelets. We used an array of peptidic and nonpeptidic arginine-glycine-aspartic acid (RGD) mimics that specifically bind to human platelet alpha IIbbeta 3 to determine the affinity state of the receptor. Some of these RGD mimics were previously shown to clearly discriminate between resting and activated alpha IIbbeta 3. Solution-phase binding of these RGD mimics to the recombinant cells suggested that in HEK 293 cells the full-length alpha IIbbeta 3 is expressed in a "transitional" activation state. This observation was confirmed by the binding of the activation-specific, monoclonal anti-alpha IIbbeta 3 antibody PAC1 to cells expressing the full-length recombinant alpha IIbbeta 3. Deletion of the entire cytoplasmic domain of the beta  subunit was sufficient to convert the receptor in HEK 293 cells to a fully active form, as found in activated platelets. In addition, the full-length receptor was capable of mediating agonist-independent aggregation of cells in the presence of fibrinogen. Thus, by using RGD mimics, we have identified a functional transitional activation state of alpha IIbbeta 3 that is capable of mediating fibrinogen-dependent cell aggregation.

Copyright © by The American Society for Pharmacology and Experimental Therapeutics


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