G protein-coupled receptors: from radioligand binding to cellular signaling

G protein-coupled receptors (GPCRs) represent by far the largest, most versatile, and ubiquitous class of cellular receptors, comprising more than 800 distinct receptors. They represent the largest class of targets for therapeutic drugs, comprising almost one-third of all FDA-approved agents, amounting to some 700 different drugs. Yet when one of us (Lefkowitz) began his career, there was no concrete evidence that drug and hormone receptors actually existed as independent molecular entities. And moreover, the tools did not exist to prove their existence and study their properties. All this changed in the early 1970s with the development of radioligand-binding techniques (1), which permitted the identification and study of receptors such as the [3-adrenergic receptor ([3AR) (2). Work on the [3-2 adrenergic receptor ([32AR) would become the prototype for studies of this large receptor family. Strategies that advanced the study of GPCRs Initial development of ligands for the [3AR was done in model systems, such as frog and turkey erythrocyte membranes, which are rich sources of [3ARs, which are coupled to the enzyme adenylate cyclase to catalyze formation of the second messenger cyclic AMP. But very quickly thereafter, experiments were devised to determine whether these powerful methods could be extended to human material, which would enable clinically relevant investigations of receptor signaling and regulatory mechanisms. Two of the earliest such studies were [...]