ALLOSTERIC INTERACTIONS AMONG AGONISTS AND ANTAGONISTS AT 5-HYDROXYTRYPTAMINE(3) RECEPTORS

Cooperation in the action of agonists suggests that there are multiple binding sites on 5-hydroxytryptamine(3) (5-HT3) receptors. The purpos e of this study was to characterize these binding sites and their inte ractions on both native and cloned 5-HT3 receptors. The affinities of competitive 5-HT3 receptor antagonists were similar regardless of whet her the receptors were labeled with [H-3]RS-42358, [H-3]granisetron, o r 1-(m-[H-3]chlorophenyl)biguanide ([H-3]mCPG). By contrast, the affin ities of the agonists 5-HT, mCPG, and phenylbiguanide were approximate ly 10-fold higher when the receptors were labeled with [H-3]mCPG. The dissociation of [H-3]mCPG, [H-3]RS-42358, and [H-3]RS-25259, but not [ H-3]-granisetron, from both cloned and native 5-HT3 receptors was mark edly slower in the presence of 5-HT or 2-methyl-5-HT than in the prese nce of antagonists such as RS42358. This suggests that the binding of these agonists to unoccupied sites on the receptor can increase the re ceptor's affinity for prebound ligands and thereby slow their dissocia tion. These data support previous indications of positive cooperation among multiple binding sites on both native and cloned 5-HT3 receptors , and they extend this idea by demonstrating that agonists can modify the interaction of some, but not all, antagonists with the receptor.