Recent updates on GPCR biased agonism

Pupo, André S.; Duarte, Diego A.; Lima, Vinícius; Teixeira, Larissa B.; Parreiras-e-Silva, Lucas T.; Costa-Neto, Cláudio M.

doi:10.1016/j.phrs.2016.01.031

Cited by 82 publications

(68 citation statements)

References 91 publications

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“…GPCRs can use different G proteins when binding different ligands or in the presence of allosteric modulators, termed biased agonism [15]. To address whether OGR1 might couple to cyclic AMP (cAMP) signaling pathways in a substrate-stiffness-dependent manner, hOGR1-HEK cells were seeded on high-and low-stiffness substrate.…”

Section: Ogr1 Does Not Display Stiffness-dependent G Protein Couplingmentioning

confidence: 99%

Coincidence Detection of Membrane Stretch and Extracellular pH by the Proton-Sensing Receptor OGR1 (GPR68)

et al. 2018

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Highlights d OGR1 (aka GPR68) requires cell stretch and extracellular protons to activate d Cell stretch and extracellular acidosis synergistically promote OGR1 signaling d Cell-stretch-mediated actin polymerization is crucial for OGR1 activity d Actin depolymerization limits how long OGR1 stays responsive after cell stretch SUMMARYThe physical environment critically affects cell shape, proliferation, differentiation, and survival by exerting mechanical forces on cells. These forces are sensed and transduced into intracellular signals and responses by cells. A number of different membrane and cytoplasmic proteins have been implicated in sensing mechanical forces, but the picture is far from complete, and the exact transduction pathways remain largely elusive. Furthermore, mechanosensation takes place alongside chemosensation, and cells need to integrate physical and chemical signals to respond appropriately and ensure normal tissue and organ development and function. Here, we report that ovarian cancer G protein coupled receptor 1 (OGR1) (aka GPR68) acts as coincidence detector of membrane stretch and its physiological ligand, extracellular H + . Using fluorescence imaging, substrates of different stiffness, microcontact printing methods, and cell-stretching techniques, we show that OGR1 only responds to extracellular acidification under conditions of membrane stretch and vice versa. The level of OGR1 activity mirrors the extent of membrane stretch and degree of extracellular acidification. Furthermore, actin polymerization in response to membrane stretch is critical for OGR1 activity, and its depolymerization limits how long OGR1 remains responsive following a stretch event, thus providing a ''memory'' for past stretch. Cells experience changes in membrane stretch and extracellular pH throughout their lifetime. Because OGR1 is a widely expressed receptor, it represents a unique yet widespread mechanism that enables cells to respond dynamically to mechanical and pH changes in their microenvironment by integrating these chemical and physical stimuli at the receptor level. Current Biology 28, 3815-3823, December 3, 2018 ª 2018 Elsevier Ltd. 3815 FIJI NIH https://fiji.sc/ Driver software for custom built stretch machine Zaber Console https://www.zaber.com/zaber-software e1 Current Biology 28, 3815-3823.e1-e4, December 3, 2018

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Section: Ogr1 Does Not Display Stiffness-dependent G Protein Couplingmentioning

confidence: 99%

Coincidence Detection of Membrane Stretch and Extracellular pH by the Proton-Sensing Receptor OGR1 (GPR68)

et al. 2018

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“…A critical assumption is that the heterogeneity of active receptor conformations spontaneously exists and the ligand stabilizes a particular conformational subset that fails to evoke some of the responses but may stimulate other signaling events of the receptor to which it binds (Kenakin, 2004;Rajagopal et al, 2010). This process of "stimulus trafficking" has also been referred to as biased agonism or functional selectivity, and it explains why a ligand causes differential activation of only some of the signaling pathways associated with a specific receptor (Pupo et al, 2016).…”

Section: Biased Signaling At H 1 and H 2 Histamine Receptorsmentioning

confidence: 99%

Current Knowledge and Perspectives on Histamine H₁and H₂Receptor Pharmacology: Functional Selectivity, Receptor Crosstalk, and Repositioning of Classic Histaminergic Ligands

Monczor

Fernández

2016

Mol Pharmacol

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H 1 and H 2 histamine receptor antagonists, although developed many decades ago, are still effective for the treatment of allergic and gastric acid-related conditions. This article focuses on novel aspects of the pharmacology and molecular mechanisms of histamine receptors that should be contemplated for optimizing current therapies, repositioning histaminergic ligands for new therapeutic uses, or even including agonists of the histaminergic system in the treatment of different pathologies such as leukemia or neurodegenerative disorders. In recent years, new signaling phenomena related to H 1 and H 2 receptors have been described that make them suitable for novel therapeutic approaches. Crosstalk between histamine receptors and other membrane or nuclear receptors can be envisaged as a way to modulate other signaling pathways and to potentiate the efficacy of drugs acting on different receptors. Likewise, biased signaling at histamine receptors seems to be a pharmacological feature that can be exploited to investigate nontraditional therapeutic uses for H 1 and H 2 biased agonists in malignancies such as acute myeloid leukemia and to avoid undesired side effects when used in standard treatments. It is hoped that the molecular mechanisms discussed in this review contribute to a better understanding of the different aspects involved in histamine receptor pharmacology, which in turn will contribute to increased drug efficacy, avoidance of adverse effects, or repositioning of histaminergic ligands.

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“…6). However, the subsequent steps in the signaling cascade are continuously being explored; for example, biased agonism [41], molecular dynamics through allosteric nanobodies [42], and possible short‐lived intermediates [43] are among those steps.…”

Section: Discussionmentioning

confidence: 99%

Aquaporin 8 is involved in H₂O₂‐mediated differential regulation of metabolic signaling by α₁‐ and β‐adrenoceptors in hepatocytes

Vilchis-Landeros¹,

Guinzberg²,

Riveros‐Rosas³

et al. 2020

FEBS Letters

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Reactive oxygen species participate in regulating intracellular signaling pathways. Herein, we investigated the reported opposite effects of hydrogen peroxide (H 2 O 2 ) on metabolic signaling mediated by activated a 1 -and b-adrenoceptors (ARs) in hepatocytes. In isolated rat hepatocytes, stimulation of a 1 -AR increases H 2 O 2 production via NADPH oxidase 2 (NOX2) activation. We find that the H 2 O 2 thus produced is essential for a 1 -AR-mediated activation of the classical hepatic glycogenolytic, gluconeogenic, and ureagenic responses. However, H 2 O 2 inhibits b-AR-mediated activation of these metabolic responses. We show that H 2 O 2 mediates its effects on a 1 -AR and b-AR by permeating cells through aquaporin 8 (AQP8) channels and promoting Ca 2+ mobilization. Thus, our findings reveal a novel NOX2-H 2 O 2 -AQP8-Ca 2+ signaling cascade acting downstream of a 1 -AR in hepatocytes, which, by negatively regulating b-AR signaling, establishes negative crosstalk between the two pathways.

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Recent updates on GPCR biased agonism

Cited by 82 publications

References 91 publications

Coincidence Detection of Membrane Stretch and Extracellular pH by the Proton-Sensing Receptor OGR1 (GPR68)

Coincidence Detection of Membrane Stretch and Extracellular pH by the Proton-Sensing Receptor OGR1 (GPR68)

Current Knowledge and Perspectives on Histamine H₁and H₂Receptor Pharmacology: Functional Selectivity, Receptor Crosstalk, and Repositioning of Classic Histaminergic Ligands

Aquaporin 8 is involved in H₂O₂‐mediated differential regulation of metabolic signaling by α₁‐ and β‐adrenoceptors in hepatocytes

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Recent updates on GPCR biased agonism

Cited by 82 publications

References 91 publications

Coincidence Detection of Membrane Stretch and Extracellular pH by the Proton-Sensing Receptor OGR1 (GPR68)

Coincidence Detection of Membrane Stretch and Extracellular pH by the Proton-Sensing Receptor OGR1 (GPR68)

Current Knowledge and Perspectives on Histamine H1and H2Receptor Pharmacology: Functional Selectivity, Receptor Crosstalk, and Repositioning of Classic Histaminergic Ligands

Aquaporin 8 is involved in H2O2‐mediated differential regulation of metabolic signaling by α1‐ and β‐adrenoceptors in hepatocytes

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Product

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Current Knowledge and Perspectives on Histamine H₁and H₂Receptor Pharmacology: Functional Selectivity, Receptor Crosstalk, and Repositioning of Classic Histaminergic Ligands

Aquaporin 8 is involved in H₂O₂‐mediated differential regulation of metabolic signaling by α₁‐ and β‐adrenoceptors in hepatocytes