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Vol. 62, Issue 3, 578-589, September 2002
Institut de Recherches Servier, Psychopharmacology Department,
chemin de Ronde, Croissy/Seine, Paris, France
As determined by a guanosine
5'-O-(3-[35S]thio)triphosphate
([35S]GTP
S) binding assay, which does not
distinguish G protein subtypes, 5-hydroxytryptamine (5-HT) and
2(S)- 1-(6-chloro-5-fluoro-1H-indol-1-yl)-2-propanamine fumarate (Ro600175) behaved as full agonists at human
5-HT2C (h5-HT2C) receptors (VSV isoform) stably
expressed in Chinese hamster ovary (CHO) cells, whereas
1-2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI),
d-lysergic acid diethylamide (LSD), and lisuride
exhibited partial agonist properties. After treatment with pertussis
toxin to uncouple 5-HT2C receptors from Gi/Go but not
Gq/11, DOI and LSD were as efficacious as 5-HT and Ro600175 in
stimulating [35S]GTPS binding, whereas lisuride still
exhibited low efficacy (40%). Correspondingly, in a scintillation
proximity assay employing specific antibodies against Gq/11, 5-HT,
Ro600175, DOI, and LSD behaved as high-efficacy agonists, whereas
lisuride showed efficacy of 36%. In contrast, when employing a
specific antibody recognizing Gi3, DOI and LSD were less
efficacious (80 and 30%, respectively) than 5-HT and Ro600175, and
lisuride was inactive. Agonist actions were specifically mediated by
h5-HT2C receptors inasmuch as the selective
5-HT2C antagonist SB242,084 blocked
[35S]GTPS binding at both Gq/11 and Gi3.
Agonist potency for stimulation of Gi3 was ~6- to 8-fold
less than for Gq/11, indicating that the latter was preferentially
engaged by h5-HT2C receptors. Inactivation of
h5-HT2C receptors with the alkylating agent
N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline did not
modify the efficacy of 5-HT, Ro600175, and DOI at Gq/11, whereas their
efficacies were substantially reduced at Gi3, indicating a
greater receptor reserve for the former. Finally, the preferential activation of Gq/11 versus Gi3 by DOI, LSD, and lisuride
was diminished in the presence of lower receptor number. In conclusion,
h5-HT2C receptors couple to both Gq/11 and Gi3
in CHO cells, and efficacy for G protein subtype activation is both
ligand- and receptor reserve-dependent.
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