Abstract
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 AT1 angiotensin receptor (AT1R), V2 vasopressin receptor (V2R) and the parathyroid hormone 1 receptor (PTH1R). 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.
Key points
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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.
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GPCRs can be targeted by orthosteric and allosteric ligands; ligand binding can stabilize distinct active or inactive receptor conformations to promote receptor signalling.
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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.
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Functionally selective ligands have the potential to selectively activate or inhibit certain GPCR-mediated signalling pathways, providing promising drug candidates with greater effectiveness and better safety profiles than currently available therapeutics.
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Biased signalling can result from multiple mechanisms, including biased receptor conformations, variations of signalling kinetics or location-specific actions of certain compounds.
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Preclinical studies with biased drugs have demonstrated promising results; success in clinical trials has so far been limited, although progress in biased therapeutics is anticipated in the near future.
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Acknowledgements
L.H. and G.T. are supported by the Hungarian National Research, Development and Innovation Fund (NVKP_16-1-2016-0039, NKFI K 139231, NKFI FK 138862), L.H. is supported by the Ministry for National Economy (Competitive Central Hungary Operational Programme VEKOP-2.3.2-16-2016-00002). G.T. is supported by the János Bolyai Research Scholarship and János Bolyai Research Scholarship Plus of the Hungarian Academy of Sciences BO/00807/21. The authors used ChatGPT to assist with grammar and language of the initial draft of the manuscript prior to submission; however, it was not used for generating text content.
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G.T. and L.H. serve as scientific advisers and research collaborators of Gedeon Richter Plc., on topics not directly related to the content of this manuscript. A.D.T. declares no competing interests.
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Biased Signalling Atlas: https://BiasedSignalingAtlas.org
CellxGene: https://cellxgene.cziscience.com/
Ensembl: https://ensembl.org/
GPCRdb: https://gpcrdb.org/
Therapeutic Target Database: https://db.idrblab.net/ttd/
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Tóth, A.D., Turu, G. & Hunyady, L. Functional consequences of spatial, temporal and ligand bias of G protein-coupled receptors. Nat Rev Nephrol (2024). https://doi.org/10.1038/s41581-024-00869-3
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DOI: https://doi.org/10.1038/s41581-024-00869-3
