TY - JOUR
T1 - Novel actions of inverse agonists on 5-HT(2C) receptor systems
AU - Berg, Kelly A.
AU - Stout, Brian D.
AU - Cropper, Jodie D.
AU - Maayani, Saul
AU - Clarke, William P.
PY - 1999
Y1 - 1999
N2 - 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-HT(2C) 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-HT(2C)-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(αq/11) and possibly G(α12) and G(α13). Interestingly, 24-h exposure to inverse agonists acting at 5-HT(2C) 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.
AB - 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-HT(2C) 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-HT(2C)-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(αq/11) and possibly G(α12) and G(α13). Interestingly, 24-h exposure to inverse agonists acting at 5-HT(2C) 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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M3 - Article
C2 - 10220565
AN - SCOPUS:0032907370
SN - 0026-895X
VL - 55
SP - 863
EP - 872
JO - Molecular pharmacology
JF - Molecular pharmacology
IS - 5
ER -