Nuclear G-protein-coupled receptors as putative novel pharmacological targets

Ribeiro-Oliveira, Rita; Vojtek, Martin; Gonçalves-Monteiro, Salomé; Vieira-Rocha, Maria Sofia; Sousa, Joana Beatriz; Gonçalves, Jorge; Diniz, Carmen

doi:10.1016/j.drudis.2019.09.003

Cited by 22 publications

(44 citation statements)

References 84 publications

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“…To avoid the potential harms of prolonged agonist stimulation in the cell, GPCRs undergo a rapid internalization known as desensitization. Upon prolonged and/or repetitive agonist stimulation, GPCRs are internalized and trafficked inside the cell: They may be targeted to different organelles such as endoplasmic reticulum, Golgi body, mitochondria, or nucleus or recycled back to the plasma membrane or be degraded in lysosomes (Ribeiro-Oliveira et al, 2019).…”

Section: Receptor Traffickingmentioning

confidence: 99%

“…At that time, however, the existence of enzymatic activity in the nucleus could not be explained. Recent research has brought to light the existence of nuclear GPCRs with the capacity to initiate identical and/or different signaling pathways compared to their respective counterparts located on the cell surface (Ribeiro-Oliveira et al, 2019). Approximately 30 different types of GPCRs have been detected in the nuclear membrane of multiple cells (Gobeil et al, 2006;Zhu et al, 2006).…”

Section: Gpcrs In the Nucleusmentioning

confidence: 99%

“…The nucleus possesses all fundamental components involved in GPCRs signaling pathways such as G-proteins, second messengers, ion channels, and regulator molecules (Ribeiro-Oliveira et al, 2019). Nuclear GPCRs mainly regulate nuclear Ca 2+ , NO levels, or cAMP synthesis; however, others, such as IP3, cyclic guanosine monophosphate, and diacylglycerol have been described.…”

Section: Gpcrs In the Nucleusmentioning

confidence: 99%

“…The presence of nuclear GPCRs has been suggested to occur in at least three different ways: (1) agonist dependent or independent translocation from the cell membrane, (2) it might be synthesized in the endoplasmic reticulum and then traffic directly to the nucleus by lateral diffusion, (3) or be synthesized within the nucleus (Bhosle et al, 2019;Ribeiro-Oliveira et al, 2019). The involvement of small GTPases, importins, and sorting nexin proteins has been postulated in the process of translocation of nuclear GPCRs mediated by vesicles (Bhosle et al, 2019).…”

Section: Gpcrs In the Nucleusmentioning

confidence: 99%

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Angiotensin Receptors Heterodimerization and Trafficking: How Much Do They Influence Their Biological Function?

et al. 2020

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G-protein-coupled receptors (GPCRs) are targets for around one third of currently approved and clinical prescribed drugs and represent the largest and most structurally diverse family of transmembrane signaling proteins, with almost 1000 members identified in the human genome. Upon agonist stimulation, GPCRs are internalized and trafficked inside the cell: they may be targeted to different organelles, recycled back to the plasma membrane or be degraded. Once inside the cell, the receptors may initiate other signaling pathways leading to different biological responses. GPCRs' biological function may also be influenced by interaction with other receptors. Thus, the ultimate cellular response may depend not only on the activation of the receptor from the cell membrane, but also from receptor trafficking and/or the interaction with other receptors. This review is focused on angiotensin receptors and how their biological function is influenced by trafficking and interaction with others receptors.

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Section: Receptor Traffickingmentioning

confidence: 99%

Section: Gpcrs In the Nucleusmentioning

confidence: 99%

Section: Gpcrs In the Nucleusmentioning

confidence: 99%

Section: Gpcrs In the Nucleusmentioning

confidence: 99%

See 2 more Smart Citations

Angiotensin Receptors Heterodimerization and Trafficking: How Much Do They Influence Their Biological Function?

et al. 2020

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“…The molecular targets for about 50-60% of currently validated drugs are membrane proteins, such as G-protein coupled receptors (GPCRs); this class of proteins still features the main target in drug discovery programs (Hauser et al, 2017;Ribeiro-Oliveira et al, 2019). To this purpose, a range of chemical, biochemical and biophysical techniques are available for the characterization of ligand binding and for screening libraries of compounds searching for potential drug candidates.…”

Section: Introductionmentioning

confidence: 99%

Surface Plasmon Resonance as a Tool for Ligand Binding Investigation of Engineered GPR17 Receptor, a G Protein Coupled Receptor Involved in Myelination

et al. 2020

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The aim of this study was to investigate the potential of surface plasmon resonance (SPR) spectroscopy for the measurement of real-time ligand-binding affinities and kinetic parameters for GPR17, a G protein-coupled receptor (GPCR) of major interest in medicinal chemistry as potential target in demyelinating diseases. The receptor was directly captured, in a single-step, from solubilized membrane extracts on the sensor chip through a covalently bound anti-6x-His-antibody and retained its ligand binding activity for over 24 h. Furthermore, our experimental setup made possible, after a mild regeneration step, to remove the bound receptor without damaging the antibody, and thus to reuse many times the same chip. Two engineered variants of GPR17, designed for crystallographic studies, were expressed in insect cells, extracted from crude membranes and analyzed for their binding with two high affinity ligands: the antagonist Cangrelor and the agonist Asinex 1. The calculated kinetic parameters and binding constants of ligands were in good agreement with those reported from activity assays and highlighted a possible functional role of the N-terminal residues of the receptor in ligand recognition and binding. Validation of SPR results was obtained by docking and molecular dynamics of GPR17-ligands interactions and by functional in vitro studies. The latter allowed us to confirm that Asinex 1 behaves as GPR17 receptor agonist, inhibits forskolin-stimulated adenylyl cyclase pathway and promotes oligodendrocyte precursor cell maturation and myelinating ability.

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T2R bitter taste receptors regulate apoptosis and may be associated with survival in head and neck squamous cell carcinoma

et al. 2021

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Better management of head and neck squamous cell carcinomas (HNSCCs) requires a clearer understanding of tumor biology and disease risk. Bitter taste receptors (T2Rs) have been studied in several cancers, including thyroid, salivary, and GI, but their role in HNSCC has not been explored. We found that HNSCC patient samples and cell lines expressed functional T2Rs on both the cell and nuclear membranes. Bitter compounds, including bacterial metabolites, activated T2R‐mediated nuclear Ca2+ responses leading to mitochondrial depolarization, caspase activation, and ultimately apoptosis. Buffering nuclear Ca2+ elevation blocked caspase activation. Furthermore, increased expression of T2Rs in HNSCCs from The Cancer Genome Atlas is associated with improved overall survival. This work suggests that T2Rs are potential biomarkers to predict outcomes and guide treatment selection, may be leveraged as therapeutic targets to stimulate tumor apoptosis, and may mediate tumor‐microbiome crosstalk in HNSCC.

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Nuclear G-protein-coupled receptors as putative novel pharmacological targets

Cited by 22 publications

References 84 publications

Angiotensin Receptors Heterodimerization and Trafficking: How Much Do They Influence Their Biological Function?

Angiotensin Receptors Heterodimerization and Trafficking: How Much Do They Influence Their Biological Function?

Surface Plasmon Resonance as a Tool for Ligand Binding Investigation of Engineered GPR17 Receptor, a G Protein Coupled Receptor Involved in Myelination

T2R bitter taste receptors regulate apoptosis and may be associated with survival in head and neck squamous cell carcinoma

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