Do recent operational studies indicate that a single state model is no longer applicable to G protein-coupled receptors?

Recent evidence suggests that unliganded G protein-coupled receptors exist in at least two states, an inactive conformation and an active conformation possessing affinity for the G protein even in the absence of agonist. The data accumulated so far for wild-type receptors imply that this is true for receptors for several hormones and receptor subtypes, and theoretically for all G protein-coupled receptors. The data now consist of studies implicating not only spontaneous receptor-G protein coupling, but also effector mechanisms and, in the case of transgenic mice over-expressing the human beta 2-adrenoceptor, physiologic responses at the level of the isolated tissue and in vivo. Furthermore, there appear to be ligands (inverse agonists) that can decrease the level of the constitutively active conformation of the receptor, and neutral antagonists can not only block classical agonist responses, but also inhibit the response of inverse agonists.