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Vol. 280, Issue 2, 576-583, 1997
Departments of Biochemistry and Psychiatry, Case Western Reserve
University School of Medicine, Cleveland, Ohio
In this study, the relationship between high-affinity agonist binding
and second messenger production was examined at native and mutant
5-hydroxytryptamine2A receptors. At native
5-hydroxytryptamine2A receptors all agonists, with the
exception of quipazine, discriminated between high- and low-affinity
states of the receptor, as determined by analysis of competition
binding assays. There was no correlation between the ability of
selected agonists to label the high-affinity agonist state and to
augment phosphoinositide hydrolysis. Quipazine, which did not
discriminate between the affinity states of the receptor, behaved as a
full agonist. Similar results were obtained when a point mutation
(F340L) of a highly conserved phenylalanine located in transmembrane
domain VI was examined. With the F340L mutant, most of the agonists
tested labeled significantly fewer high-affinity sites, compared with
the native receptor. There was no significant relationship between
high-affinity agonist binding and second messenger production.
Bufotenine and 4-iodo-3,5-dimethoxyphenylisopropylamine labeled similar
percentages of high-affinity agonist binding sites (22%
vs. 26%), but 4-iodo-3,5-dimethoxyphenylisopropylamine
behaved as a full agonist, whereas bufotenine was devoid of detectable agonist activity. The inability of selected agonists to activate phosphoinositide hydrolysis was not due solely to lower agonist affinity for the mutant receptor, because the binding affinity of
quipazine was unchanged by the F340L mutation but quipazine had no
detectable agonist activity at the mutant receptor. Our results
demonstrate that the ability of an agonist to promote the
high-affinity state of the 5-hydroxytryptamine2A receptor is not correlated with its ability to augment second messenger production. These results are consistent with recent models of G
protein-receptor functioning (e.g., modified ternary
complex model) that predict that additional transition states of the
receptor-ligand complex are essential for agonist efficacy.
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