The stability of the agonist beta2-adrenergic receptor-Gs complex: evidence for agonist-specific states.

Abstract

A restricted version of the ternary complex model for receptor-G protein complex formation has recently been proposed. Known as the two-state model, this model proposes that in the context of agonist and G protein interactions, only two thermodynamic states exist for the receptor: active (R*) and inactive (R). One form of this model suggests that only the R* state of the receptor is capable of interacting with and subsequently activating G proteins. We directly tested the kinetic aspects of a strict two-state receptor model in a cell line containing the native beta2-adrenergic receptor that is capable of inducing Gs expression. We examined adenylyl cyclase activity in the presence of limiting GTP levels and concluded that there exists a different rate of heterotrimer dissociation (i.e., HR*G yields HR* + G*) for different beta2-agonists. This finding is inconsistent with a strict two-state model in which R* is a characteristic of the receptor that is independent of the identity of the agonist. It implies that agonist activation of adenylyl cyclase is more complicated than a simple two-state model.