A multi-dimensional view of context-dependent G protein-coupled receptor function

Abstract

G protein-coupled receptor (GPCR) family members can sense an extraordinary variety of biomolecules to activate intracellular signalling cascades that modulate key aspects of cell physiology. Apart from their crucial role in maintaining cell homeostasis, these critical sensory and modulatory properties have made GPCRs the most successful drug target class to date. However, establishing direct links between receptor activation of specific intracellular partners and individual physiological outcomes is still an ongoing challenge. By studying this receptor signalling complexity at increasing resolution through the development of novel biosensors and high-throughput techniques, a growing number of studies are revealing how receptor function can be diversified in a spatial, temporal or cell-specific manner. This mini-review will introduce recent examples of this context-dependent receptor signalling and discuss how it can impact our understanding of receptor function in health and disease, and contribute to the search of more selective, efficacious and safer GPCR drug candidates.

Deciphering Complex Interactions in Bioactive Lipid Signaling

“…It is remarkable that almost all receptors of bioactive lipids are G protein-coupled receptors (GPCRs), the exceptions being the ECB-binding TRPV1 channels and PPARα/γ/δ nuclear receptors ( Figure 1 , Figure 2 and Figure 3 ). GPCRs are one of the most important classes of membrane receptors, able to sense an extraordinary variety of biomolecules in order to activate multiple intracellular signaling cascades [ 65 ]. An unresolved issue about GPCRs is signal bias (also known as biased signaling, biased agonism or functional selectivity), whereby a ligand-dependent selectivity exists for certain signal transduction pathways compared to a reference ligand (often the endogenous agonist) at the same receptor.…”

Exploring human rare disease variants from a multidimensional perspective illuminates receptor – G protein coupling diversity

“…On the other, systematic analyses of the functional coupling preferences of hundreds of receptors towards different G protein types have started uncovering the pairing rules governing GPCR signalling (3)(4)(5). Importantly, parallel developments in RNA sequencing and proteomics now allow us to assess how different signalling partners combine in specific cells, tissues or organisms (6), thus giving rise to context-specific responses to the same stimulus (7). Taken together, all these insights have boosted our knowledge of GPCR function and offer the opportunity to address new holistic questions on receptor signalling such as: how does structural variation at the receptor or G protein level translate into phenotypic variability?…”