Biased signalling: from simple switches to allosteric microprocessors

Abstract

<p class="first" id="P1">G protein-coupled receptors (GPCRs) are the largest class of receptors in the human genome and one of the most common drug targets. It is now well-established that GPCRs can signal through multiple transducers, including heterotrimeric G proteins, G protein receptor kinases and βarrestins. While these signaling 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 signaling through G proteins or βarrestins. At many GPCRs, G protein- and βarrestin-mediated signaling have been shown to have distinct biochemical and physiological actions from one another and an accurate evaluation of biased signaling from pharmacology through physiology is critical for preclinical drug development. Recent structural studies have provided snapshots of GPCR-transducer complexes, which should aid in the structure-based design of novel biased therapies. Our understanding of GPCRs from two-state, on-and-off switches has evolved to that of multistate allosteric microprocessors, in which biased ligands transmit distinct structural information that is processed into distinct biological outputs. The development of biased ligands as therapeutics heralds an era of increased drug efficacy with reduced drug side effects. </p>