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(Received for publication, September 10, 1996, and in revised form, November 27, 1996)
From the Platelet responses to thrombin are at least
partly mediated by a G-protein-coupled receptor whose NH2
terminus is a substrate for thrombin. In the present studies we have
examined the location of thrombin receptors in resting platelets and
followed their redistribution during platelet activation. The results
reveal several new aspects of thrombin receptor biology. 1) On resting platelets, approximately two-thirds of the receptors were located in
the plasma membrane. The remainder were present in the membranes of the
surface connecting system. 2) When platelets were activated by ADP or a
thromboxane analog, thrombin receptors that were initially in the
surface connecting system were exposed on the platelet surface,
increasing the number of detectable receptors by 40% and presumably
making them available for subsequent activation by thrombin. 3)
Platelet activation by thrombin rapidly abolished the binding of the
antibodies whose epitopes are sensitive to receptor cleavage and left
the platelets in a state refractory to both thrombin and the agonist
peptide, SFLLRN. This was accompanied by a 60% decrease in the binding
of receptor antibodies directed COOH-terminal to the cleavage site
irrespective of whether the receptors were activated proteolytically by
thrombin or nonproteolytically by SFLLRN. 4) The loss of antibody
binding sites caused by thrombin was due in part to receptor
internalization and in part to the shedding of thrombin receptors into
membrane microparticles, especially under conditions in which
aggregation was allowed to occur. However, at least 40% of the cleaved
receptors remained on the platelet surface. 5) Lacking the ability to
synthesize new receptors and lacking an intracellular reserve of
preformed receptors comparable to that found in endothelial cells,
platelets were unable to repopulate their surface with intact receptors
following exposure to thrombin. This difference underlies the ability
of endothelial cells to recover responsiveness to thrombin rapidly
while platelets do not, despite the presence on both of the same
receptor for thrombin.
Volume 272, Number 9,
Issue of February 28, 1997
pp. 6011-6017
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
INITIAL LOCALIZATION AND SUBSEQUENT REDISTRIBUTION DURING
PLATELET ACTIVATION
§
,
,
,
Departments of Medicine and Pathology and
the Center for Experimental Therapeutics of the University of
Pennsylvania, Philadelphia, Pennsylvania 19104, the
§ Istituto di Ricerche Farmacologiche Mario Negri, Consorzio
Mario Negri Sud, Santa Maria Imbaro 66030, Italy, the
Department of Pathology,
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