Abstract

In contrast to earlier concepts, it seems that distinct ligands acting on the same receptor may elicit qualitative different response patterns, a phenomenon given many names, including “functional selectivity,” “agonist-directed trafficking,” “biased agonism,” “protean agonism,” or “ligand-directed signaling.” In this issue of Molecular Pharmacology, Sato et al. (p. 1359) extend this concept to β₃-adrenergic receptors and report that distinct ligands can activate a single distal response via different signaling pathways. Moreover, they demonstrate that expression density can affect how distinct ligands acting on the same receptor differentially induce cellular responses. We discuss the underlying concepts for such findings and their implications for drug discovery.