Update on current concepts of the molecular basis of beta2-adrenergic receptor signaling.

Abstract

The proposed manner by which beta(2)-adrenergic receptors signal has dramatically changed from earlier concepts that centered on a lock-and-key mechanism in which the receptor acts as a simple switch. We now know that beta(2)-adrenergic receptors spontaneously toggle to an activated state (R*) and that the equilibrium between R (the inactive state) and R* can be altered by ligands. In addition, the R* conformation is likely to consist of multiple subspecies that may favor certain signaling pathways or regulatory events. Changes in agonist structure alter the abundance of certain subspecies of R*. Indeed, multifunctional coupling is common with many G-protein-coupled receptors and can be modulated pharmacologically to attain specific outcomes. In addition to providing the basis for development of new beta-agonists for unique signaling, these properties can be extended such that beta(2)-adrenergic receptors, or highly modified "designer" receptors, can be used for gene therapy with highly specific effects.