The cholecystokinin(B) receptor is coupled to two effector pathways through pertussis toxin-sensitive and -insensitive G proteins

Previous binding studies have suggested the existence of two affinity state s for type B cholecystokinin receptors (CCKBR), which could correspond to d ifferent coupling states of the receptor to G proteins, To test this hypoth esis, we have further investigated signal transduction pathways coupled to rat CCKBR stably transfected in Chinese hamster ovary cells. We show that C CKBR are coupled to two distinct transduction pathways involving two differ ent G proteins, a pertussis toxin-insensitive/ phospholipase C pathway lead ing to the production of inositol phosphate and arachidonic acid, and a per tussis toxin-sensitive/phospholipase A(2) pathway leading to the release of arachidonic acid. We further demonstrate that the relative degree of activ ation of each effector pathway by different specific CCKBR agonists is the same, and that a specific CCKBR antagonist, RB213, can differentially antag onize the two signal transduction pathways elicited by these agonists. Take n all together, these data could be explained by the recently proposed theo ry assuming that the receptor can exist in a three-state model in which two active conformations corresponding to the complex formed by the receptor w ith two different G proteins coexist. According to this model, agonists or antagonists could recognize preferentially either conformation of the activ ated receptor, leading to variable behavior in a system containing a single receptor type.