Research Topic

Recent Advances in G Protein-Coupled Receptor Signalling: Impact of Intracellular Location, Environment and Biased Agonism

About this Research Topic

G protein-coupled receptors (GPCRs), the largest family of cell surface receptors, are targeted by approximately 35% of approved drugs that treat a wide variety of diseases including those of the cardiovascular, respiratory, metabolic and reproductive systems and of the central and peripheral nervous system. Currently the great majority of approved drugs interact with orthosteric binding sites on the receptor as agonists, partial agonists, antagonists or inverse agonists. Of some 800 GPCRs only about 12% have been utilized therapeutically with the remainder being either olfactory or orphan receptors with many having poorly understood signalling mechanisms.

Drug development involving GPCRs often utilizes recombinant systems in the early stages that tend to assume that cellular environment has little influence on response. However recent work suggests that membrane phospholipids, sphingolipids, glycolipids and sterols, and in particular cholesterol, influence membrane fluidity and GPCR function. Regions of the plasma membrane that are enriched in combinations of these substituents form microdomains containing not only receptors but other signalling proteins. The plasma membrane organisation of particular cells can therefore have a profound effect on GPCR function and regulation. Another paradigm that is being challenged is that GPCRs are cell surface receptors; many studies now show that GPCRs, their cognisant G-proteins and second messengers, are present and functional at a number of intracellular sites such as the endoplasmic reticulum where they are synthesized, folded, modified and assembled but also in nuclear membranes, vesicles, mitochondria, and in the nucleoplasm.

There continues to be great interest in exploiting novel drug binding sites as identified by allostery, oligomerization and biased agonism as paradigms for novel drug discovery. These approaches potentially allow the production of the therapeutic effect without on-target adverse effects. Allosteric ligands recognize a topographically distinct site that may be conformationally linked to the orthosteric binding site. Oligomerization of GPCRs may create new druggable surfaces that discriminate oligomerized receptors from monomeric receptors. Biased agonists may interact with the orthosteric binding site to produce subtly different receptor conformations that differentially affect signalling pathways. These new paradigms are altering approaches to drug development and have the potential to produce more efficacious drugs with novel modes of action and reduced unwanted effects.

This Research Topic is an opportunity to present original results, Reviews, Commentaries and Opinion pieces on new approaches to drug design targeting GPCRs.


Image demonstrating the importance of cellular location of G protein coupled receptor signalling. This image was produced from Dr Aylin Hanyaloglu's laboratory.


Keywords: GPCR, cell signalling, drug discovery


Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

G protein-coupled receptors (GPCRs), the largest family of cell surface receptors, are targeted by approximately 35% of approved drugs that treat a wide variety of diseases including those of the cardiovascular, respiratory, metabolic and reproductive systems and of the central and peripheral nervous system. Currently the great majority of approved drugs interact with orthosteric binding sites on the receptor as agonists, partial agonists, antagonists or inverse agonists. Of some 800 GPCRs only about 12% have been utilized therapeutically with the remainder being either olfactory or orphan receptors with many having poorly understood signalling mechanisms.

Drug development involving GPCRs often utilizes recombinant systems in the early stages that tend to assume that cellular environment has little influence on response. However recent work suggests that membrane phospholipids, sphingolipids, glycolipids and sterols, and in particular cholesterol, influence membrane fluidity and GPCR function. Regions of the plasma membrane that are enriched in combinations of these substituents form microdomains containing not only receptors but other signalling proteins. The plasma membrane organisation of particular cells can therefore have a profound effect on GPCR function and regulation. Another paradigm that is being challenged is that GPCRs are cell surface receptors; many studies now show that GPCRs, their cognisant G-proteins and second messengers, are present and functional at a number of intracellular sites such as the endoplasmic reticulum where they are synthesized, folded, modified and assembled but also in nuclear membranes, vesicles, mitochondria, and in the nucleoplasm.

There continues to be great interest in exploiting novel drug binding sites as identified by allostery, oligomerization and biased agonism as paradigms for novel drug discovery. These approaches potentially allow the production of the therapeutic effect without on-target adverse effects. Allosteric ligands recognize a topographically distinct site that may be conformationally linked to the orthosteric binding site. Oligomerization of GPCRs may create new druggable surfaces that discriminate oligomerized receptors from monomeric receptors. Biased agonists may interact with the orthosteric binding site to produce subtly different receptor conformations that differentially affect signalling pathways. These new paradigms are altering approaches to drug development and have the potential to produce more efficacious drugs with novel modes of action and reduced unwanted effects.

This Research Topic is an opportunity to present original results, Reviews, Commentaries and Opinion pieces on new approaches to drug design targeting GPCRs.


Image demonstrating the importance of cellular location of G protein coupled receptor signalling. This image was produced from Dr Aylin Hanyaloglu's laboratory.


Keywords: GPCR, cell signalling, drug discovery


Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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Submission Deadlines

02 August 2020 Manuscript

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Manuscripts can be submitted to this Research Topic via the following journals:

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Topic Editors

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Submission Deadlines

02 August 2020 Manuscript

Participating Journals

Manuscripts can be submitted to this Research Topic via the following journals:

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