Seeking ligand bias: assessing GPCR coupling to β-arrestins for drug discovery

G-protein-coupled receptors (GPCR) are the major sites of action for endogenous hormones and neurotransmitters. Early drug discovery efforts focused on determining whether ligands could engage G protein coupling and subsequently activate or inhibit cognate ‘second messengers.’ Gone are those simple days as we now realize that receptors can also couple β-arrestins. As we delve into the complexity of ligand-directed signaling and receptosome scaffolds, we are faced with what may seem like endless possibilities triggered by receptor–ligand-mediated events.