Functional consequences of spatial, temporal and ligand bias of G protein-coupled receptors

G protein-coupled receptors (GPCRs) regulate every aspect of kidney function by mediating the effects of various endogenous and exogenous substances. A key concept in GPCR function is biased signalling, whereby certain ligands may selectively activate specific pathways within the receptor’s signalling repertoire. For example, different agonists may induce biased signalling by stabilizing distinct active receptor conformations — a concept that is supported by advances in structural biology. However, the processes underlying functional selectivity in receptor signalling are extremely complex, involving differences in subcellular compartmentalization and signalling dynamics. Importantly, the molecular mechanisms of spatiotemporal bias, particularly its connection to ligand binding kinetics, have been detailed for GPCRs critical to kidney function, such as the AT 1 angiotensin receptor (AT 1 R), V 2 vasopressin receptor (V 2 R) and the parathyroid hormone 1 receptor (PTH 1 R). This expanding insight into the multifaceted nature of biased signalling paves the way for innovative strategies for targeting GPCR functions; the development of novel biased agonists may represent advanced pharmacotherapeutic approaches to the treatment of kidney diseases and related systemic conditions, such as hypertension, diabetes and heart failure. G protein-coupled receptors (GPCRs) elicit cellular responses to an array of stimuli to regulate the function of virtually all organs. The diverse functions of GPCRs are determined by their expression profiles and their ability to adopt different active and inactive conformations, resulting in functional selectivity or biased signalling. This Review describes the mechanisms and consequences of biased GPCR signalling with a focus on GPCRs of relevance to the kidney. Key points G protein-coupled receptors (GPCRs) are abundantly expressed in cells of the kidney and represent important pharmacological targets; of note, the ligands and functions of numerous GPCRs are unknown. GPCRs can be targeted by orthosteric and allosteric ligands; ligand binding can stabilize distinct active or inactive receptor conformations to promote receptor signalling. In addition to canonical signal transmission from the plasma membrane, GPCRs can also signal from intracellular organelles, contributing to the complex spatiotemporal organization of GPCR signalling. Functionally selective ligands have the potential to selectively activate or inhibit certain GPCR-medi