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B in
Transfected Chinese Hamster Ovary Cells
Departments of
Pharmacology (D.S.C., P.B.M., D.R.M.) and
Psychiatry
(D.S.C.), University of Pennsylvania School of Medicine, Philadelphia,
Pennsylvania
The regulation in expression of human 5-hydroxytryptamine1A
(5-HT1A) receptors by agonists and antagonists was studied
in a stable transfected Chinese hamster ovary cell line expressing the
human 5-HT1A receptor. Receptor density and affinity were measured with
[125I]4-(2
-methoxyphenyl)-1-[2-[N-(2-pyridinyl)-p-iodobenzamido]ethyl]piperazine ([125I]p-MPPI), a selective antagonist of
5-HT1A receptors. Treatment of Chinese hamster ovary cells
with serotonin or the selective agonist
(±)-8-hydroxy-N,N-dipropyl-2-aminotetralin
stimulated a 2.5-fold increase in receptor density. The antagonists
4-(2-methoxyphenyl)-1-[2-[N-(2-pyridinyl)-p-iodobenzamidoethyl]piperazine, (
)-(S)-pindolol, and spiperone also stimulated
up-regulation of receptor expression. Agonist- and
antagonist-stimulated up-regulations of receptor expression were
mechanistically different. The effect of agonists was inhibited by
pertussis toxin, actinomycin D, and cycloheximide.
Antagonist-stimulated up-regulation was inhibited by cycloheximide,
only partially inhibited by actinomycin D, and not inhibited by
pertussis toxin. In the course of identifying potential pathways for
coupling of the receptor to activation of transcription, we
demonstrated that agonists activate the transcription regulatory factor
nuclear factor-
B (NF-B). Agonists were found to stimulate
degradation of the inhibitory subunit, IB
, and to increase the
activity of a NF-B-dependent CAT reporter gene. In contrast, the
antagonist
4-(2-methoxyphenyl)-1-[2-[N-(2-pyridinyl)-p-iodobenzamidoethyl]piperazine neither elicited degradation of I-B nor increased reporter
activity. Our data suggest that expression of 5-HT1A
receptors can be regulated by both agonists and antagonists and that
the agonist but not antagonist stimulation occurs concomitantly with
activation of NF-B.
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