The cholecystokininB receptor is coupled to two effector pathways through pertussis toxin-sensitive and -insensitive...

Previous binding studies have suggested the existence of two affinity states for type B cholecystokinin receptors (CCK(B)R), which could correspond to different coupling states of the receptor to G proteins. To test this hypothesis, we have further investigated signal transduction pathways coupled to rat CCK(B)R stably transfected in Chinese hamster ovary cells. We show that CCK(B)R are coupled to two distinct transduction pathways involving two different G proteins, a pertussis toxin-insensitive/phospholipase C pathway leading to the production of inositol phosphate and arachidonic acid, and a pertussis toxin-sensitive/phospholipase A2 pathway leading to the release of arachidonic acid. We further demonstrate that the relative degree of activation of each effector pathway by different specific CCK(B)R agonists is the same, and that a specific CCK(B)R antagonist, RB213, can differentially antagonize the two signal transduction pathways elicited by these agonists. Taken all together, these data could be explained by the recently proposed theory assuming that the receptor can exist in a three-state model in which two active conformations corresponding to the complex formed by the receptor with two different G proteins coexist. According to this model, agonists or antagonists could recognize preferentially either conformation of the activated receptor, leading to variable behavior in a system containing a single receptor type.