Biased signalling: from simple switches to allosteric microprocessors

Key Points G protein-coupled receptors (GPCRs) adopt multiple conformational states that can activate or block distinct intracellular signalling pathways, such as those regulated by heterotrimeric G proteins or β-arrestins. Different agonists for the same receptor can stabilize distinct GPCR conformational states. Agonists that preferentially activate certain intracellular pathways relative to others are referred to as biased agonists. Structural studies support a model in which GPCRs act as allosteric microprocessors that integrate diverse extracellular and intracellular stimuli to generate distinct conformations that result in varied intracellular responses. In addition to biased agonists, biased signalling may be encoded by the receptor ('receptor bias') or by the relative expression levels of transducers ('system bias'). Biased signalling is also observed in other receptor families, such as nuclear hormone receptors and receptor tyrosine kinases. Recent preclinical and clinical work suggests that by more selectively targeting signalling pathways of interest, biased agonists have the potential to increase clinical efficacy while reducing undesirable side effects. A given G protein-coupled receptor can signal through a range of downstream transducers depending on the stimulating ligand, enabling biased signalling towards different biological outcomes. Lefkowitz and colleagues describe the latest advances in the field, including efforts to harness biased signalling for improved therapeutic outcomes. G protein-coupled receptors (GPCRs) are the largest class of receptors in the human genome and some of the most common drug targets. It is now well established that GPCRs can signal through multiple transducers, including heterotrimeric G proteins, GPCR kinases and β-arrestins. While these signalling pathways can be activated or blocked by 'balanced' agonists or antagonists, they can also be selectively activated in a 'biased' response. Biased responses can be induced by biased ligands, biased receptors or system bias, any of which can result in preferential signalling through G proteins or β-arrestins. At many GPCRs, signalling events mediated by G proteins and β-arrestins have been shown to have distinct biochemical and physiological actions from one another, and an accurate evaluation of biased signalling from pharmacology through physiology is crucial for preclinical drug development. Recent structural studies have provided snapshots of GPCR–transducer com