The β₂ Adrenergic Receptor as a Model for G-Protein-Coupled Receptor Structure and Activation by Diffusible Hormones

G-protein-coupled receptors (GPCRs) represent the largest family of membrane proteins in the human genome. Structurally, all GPCRs are characterized by the presence of seven membrane-spanning α-helical segments. Many GPCR signaling systems are complex and tightly regulated, involving multiple G-protein subtypes and desensitization pathways. The β2 adrenergic receptor (β2AR) is among the most extensively characterized family A GPCRs. The β2AR is activated by epinephrine and norepinephrine, and plays key regulatory roles in cardiovascular and pulmonary physiology through mediation of sympathetic neurotransmission. Due to the importance of the β2AR and other adrenergic receptors in cardiovascular and pulmonary diseases, many drugs have been developed that target these GPCRs. The combination of high-resolution structure and in vitro biophysical data makes the β2AR unique among GPCRs recognizing diffusible ligands. This chapter provides an understanding of the β2 adrenergic receptor as a model for the G-protein-coupled receptor, focusing on its structure and function. It begins by reviewing the biochemical properties of the β2AR, in particular the evidence for multiple conformational states of the receptor. Following this, it describes various features of the recently published β2AR crystal structures. Finally, it discusses potential molecular mechanisms for β2AR activation, based on the structures as well as the existing biochemical and biophysical data on β2AR conformational changes.