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Department of Pharmacology (M.B., B.A.) and
Sol Sherry Thrombosis
Research Center (B.A.), Temple University School of Medicine,
Philadelphia, Pennsylvania 19140
The 488-amino acid human prostaglandin E2 receptor
EP4 subtype, which couples to stimulation of adenylyl
cyclase, shares the major structural features of G protein-coupled
receptors, having seven putative transmembrane domains, an
extracellular amino terminus, and a cytoplasmic carboxyl terminus. The
latter is composed of 156 amino acids and contains 38 serine and
threonine residues, which are potential phosphorylation sites. The
carboxyl terminus may be important in receptor function; in some
receptors, truncation of the cytoplasmic tail abolishes
desensitization. In others, truncation leads to constitutive activity,
and in other receptors, truncation has no effect on receptor function.
To investigate the role of the long cytoplasmic tail of the
EP4 receptor, we constructed a mutant EP4 that
lacks the last 138 amino acids at the carboxyl terminus, including 36 serine and threonine residues. The truncated EP4 receptor
was stably expressed in Chinese hamster ovary cells at levels
comparable to that of the wild-type receptor and exhibited a
Kd value for
[3H]PGE2 binding similar to that of the
wild-type receptor. PGE2-mediated adenylyl cyclase activity
as a function of PGE2 concentration was similar in cells
expressing the wild-type and truncated EP4 receptors.
Neither the wild-type receptor nor the truncated form showed any
constitutive activity. However, the wild-type EP4 receptor underwent PGE2-induced desensitization fully within 15-20
min, whereas the truncated EP4 receptor, lacking 36 of the
38 carboxyl-terminal serines and threonines, displayed a sustained
activation. Despite the continuous presence of PGE2, the
rate of cAMP synthesis via stimulation of the truncated receptor
remained constant over 
20 min. These findings suggest that the
cytoplasmic tail of EP4 plays an important role in
agonist-induced desensitization.
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