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Biased Agonism in GPCRs: An Opportunity for Drug Discovery

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 16786

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Prof. Dr. Jesús Giraldo

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Laboratory of Molecular Neuropharmacology and Bioinformatics, Institut de Neurociències and Unitat de Bioestadística, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
Interests: GPCR; opioid receptors; dopamine signaling; agonist efficacy; biased agonism; receptor oligomerization; allosteric modulation; molecular modeling; molecular dynamics; mathematical modeling

Special Issue Information

Dear Colleagues,

G protein-coupled receptors (GPCRs) are membrane proteins responsible for signal transduction from the outside of the cell to the inside. They are activated by a variety of agonists, amongst them neurotransmitters, hormones, ions and light. GPCRs are involved in numerous physiological functions. Therefore, their malfunction is the cause of many diseases, including neurologic, neurodegenerative and psychiatric disorders. Because of this, GPCRs are the targets of about a third of all currently marketed medicines.

GPCRs are complex signaling machines. The conformational plasticity inherent to their structure allows these receptors to signal through various signaling pathways. GPCRs, either free or bound by their endogenous agonists, may recognize G proteins and β-arrestin transducer proteins with differential affinity, which leads to distinct signaling propensities. Alteration of the normal signaling propensity of GPCRs may have pathological consequences. Moreover, because signaling pathways may have their own therapeutic or pathophysiological effect, interest has arisen in the design of drugs directed towards specific signaling pathways. Thus, the classic drug discovery paradigm has recently changed: from receptor specific to signaling-pathway specific. These pharmacological and medicinal chemistry aspects of GPCR signaling encompass the concept of functional selectivity or biased agonism.

Biased agonism is at the center of current pharmacological research. The topic is under debate because of contradictory results between pharmacological assays and between laboratories. Further work, with integrative and complementary approaches at both experimental and computational levels, is needed to draw a complete picture that mechanistically explains the functional connection between the many pieces of this complex biological puzzle. This themed Special Issue is aimed at providing a step forward towards this goal.

Prof. Dr. Jesús Giraldo
Guest Editor

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Keywords

GPCR
functional selectivity
biased agonism
G protein
beta-arrestin
transducer proteins
signaling pathway
signal transduction
therapeutic window
side effects

Published Papers (6 papers)

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Research

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13 pages, 2298 KiB

Open AccessArticle

The P2Y₂ Receptor C-Terminal Tail Modulates but Is Dispensable for β-Arrestin Recruitment

by Eline Pottie, Jolien Storme and Christophe P. Stove

Int. J. Mol. Sci. 2022, 23(7), 3460; https://doi.org/10.3390/ijms23073460 - 22 Mar 2022

Cited by 1 | Viewed by 2051

Abstract

The P2Y₂ receptor (P2Y₂R) is a G protein-coupled receptor that is activated by extracellular ATP and UTP, to a similar extent. This allows it to play roles in the cell’s response to the (increased) release of these nucleotides, e.g., in response to stress situations, including mechanical stress and oxygen deprivation. However, despite its involvement in important (patho)physiological processes, the intracellular signaling induced by the P2Y₂R remains incompletely described. Therefore, this study implemented a NanoBiT^® functional complementation assay to shed more light on the recruitment of β-arrestins (βarr1 and βarr2) upon receptor activation. More specifically, upon determination of the optimal configuration in this assay system, the effect of different (receptor) residues/regions on βarr recruitment to the receptor in response to ATP or UTP was estimated. To this end, the linker was shortened, the C-terminal tail was truncated, and phosphorylatable residues in the third intracellular loop of the receptor were mutated, in either singly or multiply adapted constructs. The results showed that none of the introduced adaptations entirely abolished the recruitment of either βarr, although EC₅₀ values differed and time-luminescence profiles appeared to be qualitatively altered. The results hint at the C-terminal tail modulating the interaction with βarr, while not being indispensable. Full article

(This article belongs to the Special Issue Biased Agonism in GPCRs: An Opportunity for Drug Discovery)

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17 pages, 1951 KiB

Open AccessArticle

BRET-Based Biosensors to Measure Agonist Efficacies in Histamine H₁ Receptor-Mediated G Protein Activation, Signaling and Interactions with GRKs and β-Arrestins

by Eléonore W. E. Verweij, Reggie Bosma, Meichun Gao, Jelle van den Bor, Betty Al Araaj, Sabrina M. de Munnik, Xiaoyuan Ma, Rob Leurs and Henry F. Vischer

Int. J. Mol. Sci. 2022, 23(6), 3184; https://doi.org/10.3390/ijms23063184 - 16 Mar 2022

Cited by 12 | Viewed by 2849

Abstract

The histamine H₁ receptor (H₁R) is a G protein-coupled receptor (GPCR) and plays a key role in allergic reactions upon activation by histamine which is locally released from mast cells and basophils. Consequently, H₁R is a well-established therapeutic target for antihistamines that relieve allergy symptoms. H₁R signals via heterotrimeric G_q proteins and is phosphorylated by GPCR kinase (GRK) subtypes 2, 5, and 6, consequently facilitating the subsequent recruitment of β-arrestin1 and/or 2. Stimulation of a GPCR with structurally different agonists can result in preferential engagement of one or more of these intracellular signaling molecules. To evaluate this so-called biased agonism for H₁R, bioluminescence resonance energy transfer (BRET)-based biosensors were applied to measure H₁R signaling through heterotrimeric G_q proteins, second messengers (inositol 1,4,5-triphosphate and Ca²⁺), and receptor-protein interactions (GRKs and β-arrestins) in response to histamine, 2-phenylhistamines, and histaprodifens in a similar cellular background. Although differences in efficacy were observed for these agonists between some functional readouts as compared to reference agonist histamine, subsequent data analysis using an operational model of agonism revealed only signaling bias of the agonist Br-phHA-HA in recruiting β-arrestin2 to H₁R over G_q biosensor activation. Full article

(This article belongs to the Special Issue Biased Agonism in GPCRs: An Opportunity for Drug Discovery)

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15 pages, 1782 KiB

Open AccessArticle

Targeting Oxidative Stress: Novel Coumarin-Based Inverse Agonists of GPR55

by Matthias Apweiler, Soraya Wilke Saliba, Jana Streyczek, Thomas Hurrle, Simone Gräßle, Stefan Bräse and Bernd L. Fiebich

Int. J. Mol. Sci. 2021, 22(21), 11665; https://doi.org/10.3390/ijms222111665 - 28 Oct 2021

Cited by 9 | Viewed by 1942

Abstract

Oxidative stress is associated with different neurological and psychiatric diseases. Therefore, development of new pharmaceuticals targeting oxidative dysregulation might be a promising approach to treat these diseases. The G-protein coupled receptor 55 (GPR55) is broadly expressed in central nervous tissues and cells and is involved in the regulation of inflammatory and oxidative cell homeostasis. We have recently shown that coumarin-based compounds enfold inverse agonistic activities at GPR55 resulting in the inhibition of prostaglandin E₂. However, the antioxidative effects mediated by GPR55 were not evaluated yet. Therefore, we investigated the antioxidative effects of two novel synthesized coumarin-based compounds, KIT C and KIT H, in primary mouse microglial and human neuronal SK-N-SK cells. KIT C and KIT H show antioxidative properties in SK-N-SH cells as well as in primary microglia. In GPR55-knockout SK-N-SH cells, the antioxidative effects are abolished, suggesting a GPR55-dependent antioxidative mechanism. Since inverse agonistic GPR55 activation in the brain seems to be associated with decreased oxidative stress, KIT C and KIT H possibly act as inverse agonists of GPR55 eliciting promising therapeutic options for oxidative stress related diseases. Full article

(This article belongs to the Special Issue Biased Agonism in GPCRs: An Opportunity for Drug Discovery)

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Review

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10 pages, 2560 KiB

Open AccessReview

In Silico Study of Allosteric Communication Networks in GPCR Signaling Bias

by Adrian Morales-Pastor, Francho Nerín-Fonz, David Aranda-García, Miguel Dieguez-Eceolaza, Brian Medel-Lacruz, Mariona Torrens-Fontanals, Alejandro Peralta-García and Jana Selent

Int. J. Mol. Sci. 2022, 23(14), 7809; https://doi.org/10.3390/ijms23147809 - 15 Jul 2022

Cited by 2 | Viewed by 2311

Abstract

Signaling bias is a promising characteristic of G protein-coupled receptors (GPCRs) as it provides the opportunity to develop more efficacious and safer drugs. This is because biased ligands can avoid the activation of pathways linked to side effects whilst still producing the desired therapeutic effect. In this respect, a deeper understanding of receptor dynamics and implicated allosteric communication networks in signaling bias can accelerate the research on novel biased drug candidates. In this review, we aim to provide an overview of computational methods and techniques for studying allosteric communication and signaling bias in GPCRs. This includes (i) the detection of allosteric communication networks and (ii) the application of network theory for extracting relevant information pipelines and highly communicated sites in GPCRs. We focus on the most recent research and highlight structural insights obtained based on the framework of allosteric communication networks and network theory for GPCR signaling bias. Full article

(This article belongs to the Special Issue Biased Agonism in GPCRs: An Opportunity for Drug Discovery)

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18 pages, 1083 KiB

Open AccessReview

Quantitative Systems Pharmacology and Biased Agonism at Opioid Receptors: A Potential Avenue for Improved Analgesics

by Andrea Bedini, Elisabetta Cuna, Monica Baiula and Santi Spampinato

Int. J. Mol. Sci. 2022, 23(9), 5114; https://doi.org/10.3390/ijms23095114 - 4 May 2022

Cited by 2 | Viewed by 2557

Abstract

Chronic pain is debilitating and represents a significant burden in terms of personal and socio-economic costs. Although opioid analgesics are widely used in chronic pain treatment, many patients report inadequate pain relief or relevant adverse effects, highlighting the need to develop analgesics with improved efficacy/safety. Multiple evidence suggests that G protein-dependent signaling triggers opioid-induced antinociception, whereas arrestin-mediated pathways are credited with modulating different opioid adverse effects, thus spurring extensive research for G protein-biased opioid agonists as analgesic candidates with improved pharmacology. Despite the increasing expectations of functional selectivity, translating G protein-biased opioid agonists into improved therapeutics is far from being fully achieved, due to the complex, multidimensional pharmacology of opioid receptors. The multifaceted network of signaling events and molecular processes underlying therapeutic and adverse effects induced by opioids is more complex than the mere dichotomy between G protein and arrestin and requires more comprehensive, integrated, network-centric approaches to be fully dissected. Quantitative Systems Pharmacology (QSP) models employing multidimensional assays associated with computational tools able to analyze large datasets may provide an intriguing approach to go beyond the greater complexity of opioid receptor pharmacology and the current limitations entailing the development of biased opioid agonists as improved analgesics. Full article

(This article belongs to the Special Issue Biased Agonism in GPCRs: An Opportunity for Drug Discovery)

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14 pages, 833 KiB

Open AccessReview

Functional Selectivity of Dopamine D₁ Receptor Signaling: Retrospect and Prospect

by Yang Yang

Int. J. Mol. Sci. 2021, 22(21), 11914; https://doi.org/10.3390/ijms222111914 - 3 Nov 2021

Cited by 8 | Viewed by 3725

Abstract

Research progress on dopamine D₁ receptors indicates that signaling no longer is limited to G protein-dependent cyclic adenosine monophosphate phosphorylation but also includes G protein-independent β-arrestin-related mitogen-activated protein kinase activation, regulation of ion channels, phospholipase C activation, and possibly more. This review summarizes recent studies revealing the complexity of D₁ signaling and its clinical implications, and suggests functional selectivity as a promising strategy for drug discovery to magnify the merit of D₁ signaling. Functional selectivity/biased receptor signaling has become a major research front because of its potential to improve therapeutics through precise targeting. Retrospective pharmacological review indicated that many D₁ ligands have some degree of mild functional selectivity, and novel compounds with extreme bias at D₁ signaling were reported recently. Behavioral and neurophysiological studies inspired new methods to investigate functional selectivity and gave insight into the biased signaling of several drugs. Results from recent clinical trials also supported D₁ functional selectivity signaling as a promising strategy for discovery and development of better therapeutics. Full article

(This article belongs to the Special Issue Biased Agonism in GPCRs: An Opportunity for Drug Discovery)

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