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Vol. 281, Issue 2, 957-964, 1997
Isoform
(TP
) Functionally Couples to the G Proteins
Gq and G11 In Vivo and is Activated
by the Isoprostane 8-epi Prostaglandin F21
Department of Biochemistry (B.T.K.), University College Dublin,
Dublin, Ireland;
Elan Corporation Research Institute (D.J.OM.),
Trinity College, Dublin, Ireland;
Centre for Cardiovascular Science,
Department of Medicine and Experimental Therapeutics (D.J.OM.),
University College Dublin, Mater Hospital, Dublin, Ireland and
Center
for Experimental Therapeutics (G.A.F.), University of
Pennsylvania, Philadelphia, Pennsylvania
To establish whether the thromboxane A2 (TXA2)
receptor (TP) functionally couples to the Gq family of
heterotrimeric G proteins in vivo, we have coexpressed the
cDNAs coding for the human platelet/placental TP alpha isoform
(TP
) and the 
subunits of Gq or
G11 in human embryonic kidney (HEK) 293 cells. TP
activation in response to ligand stimulation was monitored by analyzing
mobilization of intracellular calcium (Ca++i)
in FURA2/AM-loaded transfected HEK 293 and in platelets. Second, we
wished to examine the possible interaction of the isoprostane 8-epi
prostaglandin F2 with the TP, in
transfected HEK 293 cells and with the TPs expressed in platelets. Thus
both the prostaglandin endoperoxide/TXA2 analog (U46619)
and the 8-epi PGF2 were utilized as ligand probes of
TP activation. The results demonstrate that each ligand
induced elevations of Ca++i levels in HEK 293 cells, cotransfected with either the TP and
Gq or the TP and G11, and
also in platelets. Initial stimulation of these cells with U46619 or
8-epi PGF2 desensitized a subsequent rise in
[Ca++]i in response to U46619 or 8-epi
PGF2, respectively. Moreover, prestimulation with U46619
desensitized a subsequent rise in Ca++i
concentration in response to 8-epi PGF2, and vice
versa. These responses were blocked by the TP antagonist SQ29,548
in both cell types. In contrast, prestimulation of the transfected HEK
293 cells or platelets with thrombin did not desensitize a subsequent
rise in [Ca++]i in response to U46619 or
8-epi PGF2. After stimulation with either U46619 or
8-epi PGF2, no significant rise in Ca++i levels was observed in HEK 293 cells
transfected with the TP receptor only or in control
cells transfected with the vector pCMV5. These results demonstrate that
the TP isoform functionally couples with either
Gq or G11 in vivo, whether activated
by a PG/TXA2 analog or by the F2 isoprostane
8-epi PGF2.
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