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(Received for publication, December 4, 1996, and in revised form, February 10, 1997)
from the Human endothelial cells express thrombin
receptors and PAR-2, the two known members of the family of
protease-activated G protein-coupled receptors. Because previous
studies have shown that the biology of the human thrombin receptor
varies according to the cell in which it is expressed, we have taken
advantage of the presence of both receptors in endothelial cells to
examine the enabling and disabling interactions with candidate
proteases likely to be encountered in and around the vascular space to
compare the responses elicited by the two receptors when they are
present in the same cell and to compare the mechanisms of thrombin
receptor and PAR-2 clearance and replacement in a common cellular
environment. Of the proteases that were tested, only trypsin activated
both receptors. Cathepsin G, which disables thrombin receptors, had no
effect on PAR-2, while urokinase, kallikrein, and coagulation factors
IXa, Xa, XIa, and XIIa neither substantially activated nor noticeably
disabled either receptor. Like thrombin receptors, activation of PAR-2
caused pertussis toxin-sensitive phospholipase C activation as well as
activation of phospholipase A2, leading to the
release of PGI2. Concurrent activation of both receptors caused a greater response than activation of either alone. It also
abolished a subsequent response to the PAR-2 agonist peptide, SLIGRL,
while only partially inhibiting the response to the agonist peptide,
SFLLRN, which activates both receptors. After proteolytic or
nonproteolytic activation, PAR-2, like thrombin receptors, was cleared
from the endothelial cell surface and then rapidly replaced with new
receptors by a process that does not require protein synthesis.
Selective activation of either receptor had no effect on the clearance
of the other. These results suggest that the expression of both
thrombin receptors and PAR-2 on endothelial cells serves more to extend
the range of proteases to which the cells can respond than it does to
extend the range of potential responses. The results also show that
proteases that can disable these receptors can distinguish between
them, just as do most of the proteases that activate them. Finally, the
residual response to SFLLRN after activation of thrombin receptors and
PAR-2 raises the possibility that a third, as yet unidentified member
of this family is expressed on endothelial cells, one that is activated by neither thrombin nor trypsin.
Volume 272, Number 17,
Issue of April 25, 1997
pp. 11133-11141
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
TWO PROTEASE-ACTIVATED RECEPTORS LOCATED IN A SINGLE CELLULAR
ENVIRONMENT
§
,
,
,
,
and
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, 66030 Santa Maria Imbaro, Italy, the 
Department
of Physiology, Thomas Jefferson University, Philadelphia, Pennsylvania
19107, and the ** R. W. Johnson Pharmaceutical Research Institute,
Spring House, Pennsylvania 19477
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