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Vol. 55, Issue 3, 564-574, March 1999
Department of Psychopharmacology, Institut de Recherches Servier,
Croissy-sur-Seine (Paris), France
Despite extensive study, the G protein coupling of dopamine
D3 receptors is poorly understood. In this study, we used
guanosine-5'-O-(3-[35S]thio)-triphosphate
([35S]-GTP
S) binding to investigate the activation of
G proteins coupled to human (h) D3 receptors stably
expressed in Chinese hamster ovary (CHO) cells. Although the receptor
expression level was high (15 pmol/mg), dopamine only stimulated G
protein activation by 1.6-fold. This was despite the presence of marked
receptor reserve for dopamine, as revealed by Furchgott analysis after irreversible hD3 receptor inactivation with the alkylating
agent, EEDQ
(N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline).
Thus, half-maximal stimulation of [35S]-GTPS binding
required only 11.8% receptor occupation of hD3 sites. In
contrast, although the hD2(short) receptor expression level
in another CHO cell line was 11-fold lower, stimulation by dopamine was
higher (2.5-fold). G protein activation was increased at
hD3 and, less potently, at hD2 receptors by the
preferential D3 agonists, PD 128,907 [(+)-(4aR,10bR)-3,4,4a,10b-tetrahydro-4-propyl-2H,5H- [1]benzopyrano[4,3-b]-1,4-oxazin-9-ol] and (+)-7-OH-DPAT
(7-hydroxy-2-(di-n-propylamino)tetralin). Furthermore,
the selective D3 antagonists, S 14297 ((+)-[7-(N, N-dipropylamino)-5,6,7,8-tetrahydro-naphtho(2,3b)dihydro-2,3-furane]) and GR 218,231 (2(R,S)-(dipropylamino)-6-(4-methoxyphenylsulfonylmethyl)-1,2,3,4- tetrahydronaphtalene), blocked dopamine-stimulated
[35S]GTPS binding more potently at hD3
than at hD2 sites. Antibodies against
G
i/o reduced dopamine-induced G protein
activation at both CHO-hD3 and -hD2 membranes,
whereas GS antibodies had no effect at either site. In
contrast, incubation with anti-Gq/11 antibodies, which did not affect dopamine-induced G protein activation at hD2 receptors, attenuated hD3-induced G
protein activation. These data suggest that hD3 receptors
may couple to Gq/11 and would be
consistent with the observation that pertussis toxin pretreatment,
which inactivates only Gi/o proteins, only submaximally (80%) blocked dopamine-stimulated [35S]GTPS binding
in CHO-hD3 cells. Taken together, the present data indicate
that 1) hD3 receptors functionally couple to G protein activation in CHO cells, 2) hD3 receptors activate G
proteins less effectively than hD2 receptors, and 3)
hD3 receptors may couple to different G protein subtypes
than hD2 receptors, including nonpertussis sensitive
Gq/11 proteins.
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