Davenport, Anthony P

Halls, Michelle L

Summers, Roger J

English

PubMed

Apollo (Cambridge)

Editorial: Recent Advances in GProtein-Coupled Receptor Signalling:Impact of Intracellular Location,Environment and Biased AgonismMichelle L. Halls1, Anthony P. Davenport2 and Roger J. Summers1*1Drug Discovery Biology Theme, Faculty of Pharmacy and Pharmaceutical Sciences, Monash Institute of PharmaceuticalSciences, Monash University, Parkville, VIC, Australia, 2Experimental Medicine and Immunotherapeutics, Addenbrooke’s Centrefor Clinical Investigation, University of Cambridge, Cambridge, United KingdomKeywords: GPCR, cell signalling, drug discovery, allosteric action, biased signallingEditorial on the Research TopicRecent Advances in G Protein-Coupled Receptor Signalling: Impact of Intracellular Location,Environment and Biased AgonismG protein-coupled receptors (GPCRs), the largest family of cell surface receptors, are targeted byapproximately 35% of approved drugs that treat a wide variety of diseases including those of thecardiovascular, respiratory, metabolic, and reproductive systems, and of the central, andperipheral nervous system. Currently the great majority of approved drugs interact withorthosteric binding sites on the receptor as agonists, partial agonists, antagonists or inverseagonists. Of some 800 GPCRs only about 12% have been utilised therapeutically with theremainder being either olfactory or orphan receptors with many having poorly understoodsignalling mechanisms.Drug development involving GPCRs in the early stages often utilises recombinant systems thattend to assume that cellular environment has little influence on response. However recent worksuggests that membrane phospholipids, sphingolipids, glycolipids and sterols, and in particularcholesterol, influence membrane fluidity and GPCR function. Regions of the plasma membranethat are enriched in combinations of these substituents form microdomains containing not onlyreceptors but other signalling proteins. The plasma membrane organisation of particular cells cantherefore have a profound effect on GPCR function and regulation. Another paradigm that is beingchallenged is that GPCRs are cell surface receptors; many studies now show that GPCRs, theircognant G-proteins, and second messengers, are present, and functional at a number ofintracellular sites such as the endoplasmic reticulum where they are synthesised, folded, modified,and assembled but they are also found in nuclear membranes, vesicles, mitochondria, and in thenucleoplasm.There continues to be great interest in exploiting novel drug binding sites as identified by allostery,oligomerisation, and biased agonism as paradigms for novel drug discovery. Allosteric ligandsrecognise a topographically distinct site that may be conformationally linked to the orthostericbinding site. Oligomerisation of GPCRs may create new druggable surfaces that discriminateoligomerised receptors from monomeric receptors. Biased agonists may interact with theorthosteric binding site to produce subtly different receptor conformations that differentially affectsignalling pathways. Targeting novel drug binding sites has application for studies of orphan GPCRs,for known target receptors where selectivity has not been achieved by conventional approaches, and forreceptor targets currently exploited therapeutically but where side effects are a significant problem.Edited and reviewed by:Salvatore Salomone,University of Catania, Italy*Correspondence:Roger J. Summersroger.summers@monash.eduReceived: 10 May 2021Accepted: 12 May 2021Published: 28 May 2021Citation:Halls ML, Davenport AP andSummers RJ (2021) Editorial: RecentAdvances in G Protein-CoupledReceptor Signalling: Impact ofIntracellular Location, Environment andBiased Agonism.Front. Pharmacol. 12:707393.doi: 10.3389/fphar.2021.707393Frontiers in Pharmacology | www.frontiersin.org May 2021 | Volume 12 | Article 7073931EDITORIALpublished: 28 May 2021doi: 10.3389/fphar.2021.707393These new paradigms are altering approaches to drugdevelopment, and have the potential to produce moreefficacious drugs with novel modes of action, and reducedunwanted effects.The studies described in this issue explore many of theseconcepts. In “Fine tuning muscarinic acetylcholine receptorsignalling through allostery and bias”, van der Westhuizenet al. provide an excellent example of known drug targets, theM1 and M4 muscarinic acetylcholine (mACh) receptors, thathave been difficult to target selectively using the orthostericligand binding site for acetylcholine that is well conservedacross mACh receptor subtypes. Their findings suggest that inaddition to an allosteric mode of action, drug candidates mayhave to exhibit a particular bias profile in order to displaytherapeutic efficacy while minimising on-target side effects.The concept is continued in two studies that examine theutility of allosteric agonists at the Follicle Stimulating Hormone(FSH) receptor. In “Pharmacological programming of endosomalsignaling activated by small molecule ligands of the folliclestimulating hormone receptor”, Sposini et al. examine theproperties of two low MWt allosteric agonists of the FSHreceptor and show that the compounds possessed differentabilities to alter receptor endosomal trafficking and cAMPsignalling suggesting that these functions can be selected forpharmacologically. In “Discovery and preclinical development oforally active small molecules that exhibit highly selective folliclestimulating hormone receptor agonism”, Nataraja et al. describe thedevelopment of orally active FSH receptor allosteric agonists withclinical potential for the treatment of infertility. They show that thesecompounds mimic the biological activity of recombinant humanFSH in preclinical studies, and cause folliculogenesis, andsuperovulation in rats, and mice. Importantly, the compoundshave properties that make them suitable for oral administration,that would avoid the current limitation in the clinic of usingrecombinant FSH that has to be injected.The concept of biased agonism is explored in “The G proteinbiased smallmolecule apelin agonist CMF-019 is diseasemodifyingin endothelial cell apoptosis in vitro and induces vasodilatationwithout desensitisation in vivo” by Read et al. that describes a studyon the apelin receptor, a target for the treatment of pulmonaryarterial hypertension. The endogenous peptide agonists areunsuitable therapeutics due to poor bioavailability, rapiddesensitisation, and rapid inactivation. In contrast, the smallmolecule agonist CMF-019 not only retains the vasodilatorproperties of the peptides without receptor desensitisation butprotects endothelial cells from apoptosis. Such biased agonismcould form the basis for new therapeutic agents. The study on“The effect of cell surface expression and linker sequence onthe recruitment of arrestin to the GIP receptor”, by Al-Sabahet al. examines one of the problems associated with thedemonstration of bias, that is the choice, and configuration ofthe assays used. They show that replacement of the native signalpeptide in the GIP receptor with a HA signal peptide influences theexperimental result probably by increasing receptor cell surfaceexpression. The linker between the receptor and fluorescentprotein was also shown to be important and could result in theinclusion of phosphorylation sites that produced false positiveresults. In another study that points to the care that must beFIGURE 1 | Factors affecting signalling in response to activation of GPCRs. Glycolipids (blue hexagons), phospholipids (green rectangles), and sterols (yellow) caninfluence ligand binding at orthosteric, and allosteric sites. Ligands can produce different receptor conformations leading to different signalling patterns and degrees ofinteraction with β-arrestins, internalisation, and desensitisation. Ligands with differing physicochemical properties can result in altered spatial and temporal signalintegration, and affect the relative degree of cell surface/intracellular signal transduction as well as influencing receptor recycling or lysosomal degradation.Frontiers in Pharmacology | www.frontiersin.org May 2021 | Volume 12 | Article 7073932Halls et al. Advances in GPCR Signalingexercised with the use of tool compounds to examine GPCRsignalling, Chen and Sabatini caution on “The kinase specificityof protein kinase inhibitor peptide (PKI)” showing in a study of 55mouse kinases that in addition to inhibition of PKA, PKI alsocan activate multiple isoforms of PKC. This may suggest re-evaluation of some studies using PKI as a specific inhibitorof PKA.In “G protein-coupled receptors in taste physiology andpharmacology” Ahmad and Dalziel examine the interestingproperties of GPCR taste receptors that not only respond toa wide variety of ligands including orthosteric agonists, andantagonists but also positive, and negative allosteric modulators.While initially identified as taste receptors, it is now recognisedthat these receptors control other physiological processes inaddition to taste, with expression of mRNA, and receptorprotein identified in range of tissues in humans (HumanProtein Atlas https://www.proteinatlas.org/). They outline thevalue of potential structural studies but emphasise thechallenges associated with these studies and taste receptorsand indicate how these may be overcome. The paper byMouat et al. “Deletion of orphan G protein-coupled receptorGPR37L1 in mice alters cardiovascular homeostasis in a sex-specific manner” provides more evidence that the orphan GPCRGPR37L1 is involved in maintaining sympathetic vasomotortone. The authors were also able to demonstrate genderdifferences between responses with female GPR37L1-/- miceshowing an attenuation of cardiovascular reactivity to aversivebut not appetitive stimuli. The study draws attention to genderdifferences in physiological responses and how these can affectdrug action. Substantial progress has been made inunderstanding the physiological role of GPR37L1 by usinggene deletion and identifying a potential drug target withoutknowing the identity of the endogenous ligand. The strategydescribed has wider applicability to the remaining orphanGPCRs that have not yet been exploited.In their paper “Inhibition of the proliferation of human lungfibroblasts by prostacyclin receptor agonists is linked to a sustainedcAMP signal in the nucleus” Roberts et al. (2021), examine factorsunderlying the anti-fibrotic effects of GPCR agonists acting toincrease cAMP. They show that the anti-fibrotic effects of a Gαs-coupled prostacyclin receptor requires sustained increases incAMP in the nucleus to inhibit PDGF driven nuclear ERK1/2and fibroblast proliferation indicating that both location andduration of the signal are key factors.The studies included in this themed issue describe some of theconcepts influencing current GPCR research with approachessuch as the targeting of allosteric sites and development of biasedagonists likely to produce new therapeutics that either act atknown targets with fewer side effects or at targets for which thereare no drugs currently available. Some studies also point todeficiencies in current assay tools that can be used to improvedrug development.AUTHOR CONTRIBUTIONSRS, MH, and AD contributed to the writing of the manuscript, itsrevision, and have read, and approved the submitted version.REFERENCESRoberts, M. J., May, L. T., Keen, A. C., Liu, B., Lam, T., Charlton, S. J., et al.(2021). Inhibition of the Proliferation of Human Lung Fibroblasts byProstacyclin Receptor Agonists Is Linked to a Sustained cAMP Signalin the Nucleus. Front. Pharmacol. 12, 1–14. doi:10.3389/fphar.2021.669227Conflict of Interest: The authors declare that the research was conducted in theabsence of any commercial or financial relationships that could be construed as apotential conflict of interest.Copyright © 2021 Halls, Davenport and Summers. This is an open-access articledistributed under the terms of the Creative Commons Attribution License (CC BY).The use, distribution or reproduction in other forums is permitted, provided theoriginal author(s) and the copyright owner(s) are credited and that the originalpublication in this journal is cited, in accordance with accepted academic practice. Nouse, distribution or reproduction is permitted which does not comply with these terms.Frontiers in Pharmacology | www.frontiersin.org May 2021 | Volume 12 | Article 7073933Halls et al. Advances in GPCR Signaling

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

Halls, Michelle L.

Davenport, Anthony P.

Summers, Roger J.

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

http://dx.doi.org/10.3389/fphar.2021.707393

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

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