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Vol. 285, Issue 1, 119-126, April 1998
-Thio]Triphosphate-[35S] Binding
Department of Molecular Pharmacology, Preclinical R & D, Astra
Arcus AB, S-151 85 Södertälje, Sweden
In this study, the ligand-receptor-G protein interactions of the
dopamine D3 receptor expressed in Chinese hamster ovary
cells were investigated using guanosine
5'-[
-thio]triphosphate-[35S]
([35S]GTPS) and receptor binding experiments. Dopamine
stimulated the [35S]GTPS binding in a guanine
nucleotide, magnesium and sodium-dependent manner. Dopamine and
quinpirole produced maximal stimulation of the
[35S]GTPS binding whereas (+)-7-OH-DPAT and (-)-3-PPP
were partial agonists. Interestingly, several compounds previously
classified as D2 receptor antagonists behaved as inverse
agonists at the D3 receptor, i.e., they
inhibited the basal [35S]GTPS binding in a dose
dependent fashion. Haloperidol, (+)-UH-232, (+)-AJ-76 and raclopride
were full inverse agonists but clozapine was a partial inverse agonist.
Pertussis toxin treatment abolished the D3
receptor-mediated agonist as well as inverse agonist responses, indicating the involvement of Gi/Go proteins in
both processes. According to the ternary complex model, agonists should
bind with higher affinity to the G protein coupled receptor (RG) and
thereby shift the equilibrium from free receptor (R) toward RG, which produces a biological response. However, an inverse agonist should bind
with higher affinity to R than to RG and thereby inhibit the basal
activity of the cell. We found that the high affinity agonist binding
site (RG) was abolished by pertussis toxin treatment of the cells.
However, the inverse agonists bound with the same affinity to untreated
and pertussis toxin treated D3 receptor membranes. Thus, we
found no evidence for the hypothesis that inverse agonists would shift
the equilibrium from RG toward R by binding with higher affinity to R
than to RG.
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