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Vol. 283, Issue 1, 207-215, 1997
Division of Nephrology, Department of Medicine, Duke University and
Durham VA Medical Centers, Durham, North Carolina
To investigate regulatory domains of the thromboxane A2
(TxA2) receptor, we constructed a truncated form of the
mouse TxA2 receptor and expressed it in a mesangial cell
line. The mutant receptor lacked 22 amino acids in the C-terminus
including four potential phosphorylation sites. Ligand binding of
mutant receptors was identical with the wild type. Stimulation with
TxA2 agonist induced increases in inositol trisphosphate
(IP3) generation and [Ca++]i by both
wild-type and mutant receptors. However, the initial increase in IP3
generation by the mutant receptor was only 
50% of that seen in the
wild type. Exposure of wild-type receptors to TxA2 agonist
caused desensitization of IP3 and calcium responses. Pretreatment with
TxA2 agonist caused some desensitization of mutant
receptors, but the extent of desensitization was reduced compared with
the wild type. The protein kinase C inhibitor staurosporine attenuated
TxA2-induced desensitization of wild-type receptors, but
had little effect on TxA2-induced desensitization of mutant receptors. Pretreatment with low concentrations of the phorbol ester,
phorbol 12,13-dibutyrate (100 nM), reduced subsequent responsiveness of
wild-type but not mutant TxA2 receptors. In contrast,
high-dose phorbol 12,13-dibutyrate (1 µM) produced a similar degree
of desensitization of both receptor types. These data suggest that: 1)
the C-terminus participates in coupling of the TxA2
receptor to its effector systems; 2) the C-terminus contributes to
agonist-specific desensitization of the TxA2 receptor; and
3) protein kinase C-induced desensitization of the TxA2
receptor is complex and depends, in part, on C-terminal domains of the
TxA2 receptor.
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