Biased signaling of G protein coupled receptors (GPCRs): Molecular determinants of GPCR/transducer selectivity and therapeutic potential

Abstract G protein coupled receptors (GPCRs) convey signals across membranes via interaction with G proteins. Originally, an individual GPCR was thought to signal through one G protein family, comprising cognate G proteins that mediate canonical receptor signaling. However, several deviations from canonical signaling pathways for GPCRs have been described. It is now clear that GPCRs can engage with multiple G proteins and the line between cognate and non-cognate signaling is increasingly blurred. Furthermore, GPCRs couple to non-G protein transducers, including β-arrestins or other scaffold proteins, to initiate additional signaling cascades. Receptor/transducer selectivity is dictated by agonist-induced receptor conformations as well as by collateral factors. In particular, ligands stabilize distinct receptor conformations to preferentially activate certain pathways, designated ‘biased signaling’. In this regard, receptor sequence alignment and mutagenesis have helped to identify key receptor domains for receptor/transducer specificity. Furthermore, molecular structures of GPCRs bound to different ligands or transducers have provided detailed insights into mechanisms of coupling selectivity. However, receptor dimerization, compartmentalization, and trafficking, receptor-transducer-effector stoichiometry, and ligand residence and exposure times can each affect GPCR coupling. Extrinsic factors including cell type or assay conditions can also influence receptor signaling. Understanding these factors may lead to the development of improved biased ligands with the potential to enhance therapeutic benefit, while minimizing adverse effects. In this review, evidence for ligand-specific GPCR signaling toward different transducers or pathways is elaborated. Furthermore, molecular determinants of biased signaling toward these pathways and relevant examples of the potential clinical benefits and pitfalls of biased ligands are discussed.