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Vol. 290, Issue 2, 908-916, August 1999
Departments of Biochemical Pharmacology (J.F.M.V., B.J.B.F.,
J.E.L.) and Functional Genomics (W.H.M.L.L.), Janssen Research
Foundation, Beerse, Belgium; and Heymans Institute, University of Gent,
Gent, Belgium (N.F.)
Human dopamine D2 (hD2) and
D3 (hD3) receptors were expressed at similar,
high expression levels in Chinese hamster ovary (CHO) cells, and their
coupling to G proteins and further signal transduction pathways were
compared. In competition radioligand-binding experiments,
guanosine-5'-O-(3-thio)triphosphate (GTP
S) treatment of hD2S- or hD3-CHO cell membranes induced a
rightward shift and steeping of the dopamine inhibition curve. This
effect was pronounced for hD2 receptors and small for
hD3 receptors. Activation of G proteins was investigated in
[35S]GTPS-binding assays. Dopamine stimulated
[35S]GTPS binding 330 and 70% over basal levels on
hD2-CHO and hD3-CHO cell membranes,
respectively. (+)-7-(Dipropylamino)-5,6,7,8-tetrahydro-2-naphthalenol and PD128907 were partial agonists for both receptors. Haloperidol, risperidone, raclopride, and nemonapride inhibited dopamine-stimulated [35S]GTPS binding with potencies comparable to their
binding affinities for hD2 and hD3 receptors in
CHO cell membranes; inverse agonism could not be detected with this
assay. Receptor stimulation by dopamine inhibited forskolin-induced
cyclic AMP formation in hD2-CHO and hD3-CHO
cells by 70%. Furthermore, the extracellular acidification rate
increased when hD2-CHO and hD3-CHO cells were
stimulated by dopamine; this effect was abolished by pertussis toxin
pretreatment. In this study, we could demonstrate clear functional
effects at different levels of the signaling cascade of hD2
and hD3 receptors in CHO cells when expressed at high
levels. High-affinity agonist binding to hD2 and
hD3 receptors was still present, but effects of receptor-G
protein uncoupling at hD3 receptors were small, indicating
that hD3 receptors maintain relatively high-affinity agonist binding in the absence of G proteins.
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