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Vol. 55, Issue 5, 863-872, May 1999
Department of Pharmacology (K.A.B., B.D.S., J.D.C., W.P.C.),
University of Texas Health Science Center, San Antonio, Texas; and
Department of Anesthesiology (S.M.), Mount Sinai School of Medicine,
City University of New York, New York, New York
In cell systems where ligand-independent receptor activity is optimized
(such as when receptors are overexpressed or mutated), acute treatment
with inverse agonists reduces basal effector activity whereas prolonged
exposure leads to sensitization of receptor systems and receptor
up-regulation. Few studies, however, have reported effects of inverse
agonists in systems where nonmutated receptors are expressed at
relatively low density. Here, we investigated the effects of inverse
agonists at human serotonin (5-HT)2C receptors expressed
stably in Chinese hamster ovary cells (
250 fmol/mg protein).
In these cells, there is no receptor reserve for 5-HT and
5-HT2C inverse agonists did not reduce basal inositol
phosphate (IP) accumulation nor arachidonic acid (AA) release but
behaved as simple competitive antagonists, suggesting that these
receptors are not overexpressed. Prolonged treatment (24 h) with
inverse agonists enhanced selectively 5-HT2C-mediated IP
accumulation but not AA release. The enhancing effect occurred within
4 h of treatment, reversed within 3 to 4 h (after 24-h
treatment), and could be blocked with neutral antagonists or weak
positive agonists. The enhanced responsiveness was not due to receptor
up-regulation but may involve changes in the expression of the G
protein, G
q/11 and possibly G12 and
G13. Interestingly, 24-h exposure to inverse agonists
acting at 5-HT2C receptors also selectively enhanced IP
accumulation, but not AA release, elicited by activation of endogenous
purinergic receptors. These data suggest that actions of inverse
agonists may be mediated through effects on receptor systems that are
not direct targets for these drugs.
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