Proton-Sensing GPCR-YAP Signalling Promotes Cell Proliferation And
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Metabolite Sensing Gpcrs: Promising Therapeutic Targets for Cancer Treatment?
cells Review Metabolite Sensing GPCRs: Promising Therapeutic Targets for Cancer Treatment? Jesús Cosín-Roger 1,*, Dolores Ortiz-Masia 2 , Maria Dolores Barrachina 3 and Sara Calatayud 3 1 Hospital Dr. Peset, Fundación para la Investigación Sanitaria y Biomédica de la Comunitat Valenciana, FISABIO, 46017 Valencia, Spain 2 Departament of Medicine, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain; [email protected] 3 Departament of Pharmacology and CIBER, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain; [email protected] (M.D.B.); [email protected] (S.C.) * Correspondence: [email protected]; Tel.: +34-963851234 Received: 30 September 2020; Accepted: 21 October 2020; Published: 23 October 2020 Abstract: G-protein-coupled receptors constitute the most diverse and largest receptor family in the human genome, with approximately 800 different members identified. Given the well-known metabolic alterations in cancer development, we will focus specifically in the 19 G-protein-coupled receptors (GPCRs), which can be selectively activated by metabolites. These metabolite sensing GPCRs control crucial processes, such as cell proliferation, differentiation, migration, and survival after their activation. In the present review, we will describe the main functions of these metabolite sensing GPCRs and shed light on the benefits of their potential use as possible pharmacological targets for cancer treatment. Keywords: G-protein-coupled receptor; metabolite sensing GPCR; cancer 1. Introduction G-protein-coupled receptors (GPCRs) are characterized by a seven-transmembrane configuration, constitute the largest and most ubiquitous family of plasma membrane receptors, and regulate virtually all known physiological processes in humans [1,2]. This family includes almost one thousand genes that were initially classified on the basis of sequence homology into six classes (A–F), where classes D and E were not found in vertebrates [3]. -
The Proton-Activated G Protein Coupled Receptor OGR1 Acutely Regulates the Activity of Epithelial Proton Transport Proteins
Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2012 The proton-activated G protein coupled receptor OGR1 acutely regulates the activity of epithelial proton transport proteins Mohebbi, Nilufar ; Benabbas, Chahira ; Vidal, Solange ; Daryadel, Arezoo ; Bourgeois, Soline ; Velic, Ana ; Ludwig, Marie-Gabrielle ; Seuwen, Klaus ; Wagner, Carsten A Abstract: The Ovarian cancer G protein-coupled Receptor 1 (OGR1; GPR68) is proton-sensitive in the pH range of 6.8 - 7.8. However, its physiological function is not defined to date. OGR1 signals via inositol trisphosphate and intracellular calcium, albeit downstream events are unclear. To elucidate OGR1 function further, we transfected HEK293 cells with active OGR1 receptor or a mutant lacking 5 histidine residues (H5Phe-OGR1). An acute switch of extracellular pH from 8 to 7.1 (10 nmol/l vs 90 nmol/l protons) stimulated NHE and H(+)-ATPase activity in OGR1-transfected cells, but not in H5Phe-OGR1-transfected cells. ZnCl(2) and CuCl(2) that both inhibit OGR1 reduced the stimulatory effect. The activity was blocked by chelerythrine, whereas the ERK1/2 inhibitor PD 098059 hadno inhibitory effect. OGR1 activation increased intracellular calcium in transfected HEK293 cells. Wenext isolated proximal tubules from kidneys of wild-type and OGR1-deficient mice and measured the effect of extracellular pH on NHE activity in vitro. Deletion of OGR1 affected the pH-dependent proton extrusion, however, in the opposite direction as expected from cell culture experiments. Upregulated expression of the pH-sensitive kinase Pyk2 in OGR1 KO mouse proximal tubule cells may compensate for the loss of OGR1. -
G Protein-Coupled Receptors
S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2015/16: G protein-coupled receptors. British Journal of Pharmacology (2015) 172, 5744–5869 THE CONCISE GUIDE TO PHARMACOLOGY 2015/16: G protein-coupled receptors Stephen PH Alexander1, Anthony P Davenport2, Eamonn Kelly3, Neil Marrion3, John A Peters4, Helen E Benson5, Elena Faccenda5, Adam J Pawson5, Joanna L Sharman5, Christopher Southan5, Jamie A Davies5 and CGTP Collaborators 1School of Biomedical Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK, 2Clinical Pharmacology Unit, University of Cambridge, Cambridge, CB2 0QQ, UK, 3School of Physiology and Pharmacology, University of Bristol, Bristol, BS8 1TD, UK, 4Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK, 5Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XD, UK Abstract The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/ 10.1111/bph.13348/full. G protein-coupled receptors are one of the eight major pharmacological targets into which the Guide is divided, with the others being: ligand-gated ion channels, voltage-gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. -
Fentanyl-Related Designer Drugs W-18 and W-15 Lack Appreciable Opioid Activity in Vitro and in Vivo
RESEARCH ARTICLE Fentanyl-related designer drugs W-18 and W-15 lack appreciable opioid activity in vitro and in vivo Xi-Ping Huang,1,2 Tao Che,1 Thomas J. Mangano,1,2 Valerie Le Rouzic,3 Ying-Xian Pan,3 Susruta Majumdar,3 Michael D. Cameron,4 Michael H. Baumann,5 Gavril W. Pasternak,3 and Bryan L. Roth1,2 1Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA. 2National Institute of Mental Health Psychoactive Drug Screening Program, Chapel Hill, North Carolina, USA. 3Department of Neurology and Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA. 4Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida, USA. 5Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland, USA. W-18 (4-chloro-N-[1-[2-(4-nitrophenyl)ethyl]-2-piperidinylidene]-benzenesulfonamide) and W-15 (4-chloro-N-[1-(2-phenylethyl)-2-piperidinylidene]-benzenesulfonamide) represent two emerging drugs of abuse chemically related to the potent opioid agonist fentanyl (N-(1-(2-phenylethyl)-4- piperidinyl)-N-phenylpropanamide). Here, we describe the comprehensive pharmacological profiles of W-18 and W-15, as examination of their structural features predicted that they might lack opioid activity. We found W-18 and W-15 to be without detectible activity at μ, δ, κ, and nociception opioid receptors in a variety of assays. We also tested W-18 and W-15 for activity as allosteric modulators at opioid receptors and found them devoid of significant positive or negative allosteric modulatory activity. -
Multi-Functionality of Proteins Involved in GPCR and G Protein Signaling: Making Sense of Structure–Function Continuum with In
Cellular and Molecular Life Sciences (2019) 76:4461–4492 https://doi.org/10.1007/s00018-019-03276-1 Cellular andMolecular Life Sciences REVIEW Multi‑functionality of proteins involved in GPCR and G protein signaling: making sense of structure–function continuum with intrinsic disorder‑based proteoforms Alexander V. Fonin1 · April L. Darling2 · Irina M. Kuznetsova1 · Konstantin K. Turoverov1,3 · Vladimir N. Uversky2,4 Received: 5 August 2019 / Revised: 5 August 2019 / Accepted: 12 August 2019 / Published online: 19 August 2019 © Springer Nature Switzerland AG 2019 Abstract GPCR–G protein signaling system recognizes a multitude of extracellular ligands and triggers a variety of intracellular signal- ing cascades in response. In humans, this system includes more than 800 various GPCRs and a large set of heterotrimeric G proteins. Complexity of this system goes far beyond a multitude of pair-wise ligand–GPCR and GPCR–G protein interactions. In fact, one GPCR can recognize more than one extracellular signal and interact with more than one G protein. Furthermore, one ligand can activate more than one GPCR, and multiple GPCRs can couple to the same G protein. This defnes an intricate multifunctionality of this important signaling system. Here, we show that the multifunctionality of GPCR–G protein system represents an illustrative example of the protein structure–function continuum, where structures of the involved proteins represent a complex mosaic of diferently folded regions (foldons, non-foldons, unfoldons, semi-foldons, and inducible foldons). The functionality of resulting highly dynamic conformational ensembles is fne-tuned by various post-translational modifcations and alternative splicing, and such ensembles can undergo dramatic changes at interaction with their specifc partners. -
G Protein‐Coupled Receptors
S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2019/20: G protein-coupled receptors. British Journal of Pharmacology (2019) 176, S21–S141 THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: G protein-coupled receptors Stephen PH Alexander1 , Arthur Christopoulos2 , Anthony P Davenport3 , Eamonn Kelly4, Alistair Mathie5 , John A Peters6 , Emma L Veale5 ,JaneFArmstrong7 , Elena Faccenda7 ,SimonDHarding7 ,AdamJPawson7 , Joanna L Sharman7 , Christopher Southan7 , Jamie A Davies7 and CGTP Collaborators 1School of Life Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK 2Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria 3052, Australia 3Clinical Pharmacology Unit, University of Cambridge, Cambridge, CB2 0QQ, UK 4School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, BS8 1TD, UK 5Medway School of Pharmacy, The Universities of Greenwich and Kent at Medway, Anson Building, Central Avenue, Chatham Maritime, Chatham, Kent, ME4 4TB, UK 6Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK 7Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, EH8 9XD, UK Abstract The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website. -
Pharmacology of W-18 and W-15
bioRxiv preprint doi: https://doi.org/10.1101/065623; this version posted July 24, 2016. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. PHARMACOLOGY OF W-18 AND W-15 Xi-Ping Huang1,2, Tao Che1, Thomas J Mangano1,2, Valerie Le Rouzic,3 Ying- Xian Pan, Susruta Majumdar3, Michael Cameron4, Michael Baumann5, Gavril W. Pasternak3, and Bryan L Roth1,2,6 1Department of Pharmacology, University of North Carolina School of Medicine and 2NIMH Psychoactive Drug Screening Program, Chapel Hill, NC 27514 3Department of Neurology and Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065 4Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458 5Designer Drug Research Unit, National Institute on Drug Abuse Baltimore, MD 21224 6Correspondence to: Bryan L. Roth MD, PhD 4072 Genetic Medicine Building Department of Pharmacology UNC School of Medicine Chapel Hill, NC 27514 [email protected] 919-966-7535 (Office) 919-843-5788 (Fax) 1 bioRxiv preprint doi: https://doi.org/10.1101/065623; this version posted July 24, 2016. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. ABSTRACT W-18 (1-(4-Nitrophenylethyl)piperidylidene-2-(4-chlorophenyl)sulfonamide) and W-15 (4-chloro-N-[1-(2-phenylethyl)-2-piperidinylidene]-benzenesulfonamide) represent two emerging drugs of abuse chemically related to the potent opioid agonist fentanyl (N-(1-(2-phenylethyl)-4-piperidinyl)-N-phenylpropanamide). -
Acidic Tumor Microenvironment and Ph-Sensing G Protein-Coupled Receptors
CORE Metadata, citation and similar papers at core.ac.uk Provided by ScholarShip REVIEW ARTICLE published: 05 December 2013 doi: 10.3389/fphys.2013.00354 Acidic tumor microenvironment and pH-sensing G protein-coupled receptors Calvin R. Justus 1, Lixue Dong 1 and Li V. Yang 1,2,3* 1 Department of Oncology, Brody School of Medicine, East Carolina University, Greenville, NC, USA 2 Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, USA 3 Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, Greenville, NC, USA Edited by: The tumor microenvironment is acidic due to glycolytic cancer cell metabolism, hypoxia, Ebbe Boedtkjer, Aarhus University, and deficient blood perfusion. It is proposed that acidosis in the tumor microenvironment Denmark is an important stress factor and selection force for cancer cell somatic evolution. Acidic pH Reviewed by: has pleiotropic effects on the proliferation, migration, invasion, metastasis, and therapeutic Klaus Seuwen, Novartis Institutes for Biomedical Research, response of cancer cells and the function of immune cells, vascular cells, and other Switzerland stromal cells. However, the molecular mechanisms by which cancer cells and stromal cells Raymond B. Penn, Thomas sense and respond to acidic pH in the tumor microenvironment are poorly understood. In Jefferson University, USA this article the role of a family of pH-sensing G protein-coupled receptors (GPCRs) in tumor *Correspondence: biology is reviewed. Recent studies show that the pH-sensing GPCRs, including GPR4, Li V. Yang, Department of Oncology at Brody School of Medicine, East GPR65 (TDAG8), GPR68 (OGR1), and GPR132 (G2A), regulate cancer cell metastasis and Carolina University, 600 Moye Blvd., proliferation, immune cell function, inflammation, and blood vessel formation. -
The Functional Roles of Ph-Sensing G Protein
The Functional Roles of pH-sensing G protein-coupled receptors in Intestinal Inflammation by Edward Joseph Sanderlin November, 2018 Director of Dissertation: Li Yang, PhD Department: Internal Medicine The inflammatory microenvironment in inflammatory bowel disease (IBD) is complex, replete with microbial byproducts, complement, leukocytes, and resulting inflammatory cytokines. Parallel to these microenvironmental factors are protons, which are produced in excess due to altered metabolism of infiltrated leukocytes and local ischemia. Immune cells and intestinal microvasculature exist in the acidic, inflamed microenvironment and in turn alter their function in response to the acidic pH. Currently, only little is known how cells sense extracellular acidity and subsequently alter the inflammatory response. Recently, a class of proton-sensing G protein- coupled receptors (GPCRs) have emerged as functional pH-sensors, expressed in either leukocytes or vasculature, and are capable of altering immune cell inflammatory programs in response to acidic pH. These family members include GPR4, OGR1 (GPR68), TDAG8 (GPR65), and G2A (GPR132). Our group has uncovered a novel role for GPR4 in mediating endothelial cell (EC) inflammation in response to acidic pH. GPR4 activation in ECs have resulted in increased vascular adhesion molecule expression and functionally mediates leukocyte-EC interactions which are essential for the leukocyte extravasation process. Proton-sensors GPR65 and GPR68, however, are not expressed in ECs but are highly expressed in myeloid and lymphoid cells. GPR65 and GPR68, therefore, has been shown to mediate both pro- and anti-inflammatory responses in leukocytes in response to acidic pH. GPR132, however, has been described as a promiscuous GPCR, capable of responding to protons, bioactive lipids, and oxidized free fatty acids. -
Activation of the Orphan G Protein–Coupled Receptor GPR27 by Surrogate Ligands Promotes B-Arrestin 2 Recruitment S
Supplemental material to this article can be found at: http://molpharm.aspetjournals.org/content/suppl/2017/03/17/mol.116.107714.DC1 1521-0111/91/6/595–608$25.00 https://doi.org/10.1124/mol.116.107714 MOLECULAR PHARMACOLOGY Mol Pharmacol 91:595–608, June 2017 Copyright ª 2017 by The American Society for Pharmacology and Experimental Therapeutics Activation of the Orphan G Protein–Coupled Receptor GPR27 by Surrogate Ligands Promotes b-Arrestin 2 Recruitment s Nadine Dupuis, Céline Laschet, Delphine Franssen, Martyna Szpakowska, Julie Gilissen, Pierre Geubelle, Arvind Soni, Anne-Simone Parent, Bernard Pirotte, Andy Chevigné, Jean- Claude Twizere, and Julien Hanson Laboratory of Molecular Pharmacology, GIGA-Molecular Biology of Diseases (N.D., C.L., J.G., P.G., A.S., J.H.), Laboratory of Medicinal Chemistry, Center for Interdisciplinary Research on Medicines (N.D., B.P., J.H.), Neuroendocrinology Unit, GIGA- Neurosciences (D.F., A.-S.P.), Laboratory of Protein Signaling and Interactions, GIGA-Molecular Biology of Diseases (J.-C.T.), Downloaded from University of Liège, Liège, Belgium; and Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur- Alzette, Luxembourg (M.S., A.C.) Received December 6, 2016; accepted March 16, 2017 ABSTRACT molpharm.aspetjournals.org Gprotein–coupled receptors are the most important drug targets the presence of membrane-anchored G protein-coupled receptor for human diseases. An important number of them remain devoid kinase-2. Therefore, we optimized a firefly luciferase complemen- of confirmed ligands. GPR27 is one of these orphan receptors, tation assay to screen against this chimeric receptor. We identified characterized by a high level of conservation among vertebrates two compounds [N-[4-(anilinocarbonyl)phenyl]-2,4-dichloroben- and a predominant expression in the central nervous system. -
Harnessing Ion-Binding Sites for GPCR Pharmacology
1521-0081/71/4/571–595$35.00 https://doi.org/10.1124/pr.119.017863 PHARMACOLOGICAL REVIEWS Pharmacol Rev 71:571–595, October 2019 Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics ASSOCIATE EDITOR: ERIC L. BARKER Harnessing Ion-Binding Sites for GPCR Pharmacology Barbara Zarzycka, Saheem A. Zaidi, Bryan L. Roth, and Vsevolod Katritch Departments of Biological Sciences (B.Z., S.A.Z., V.K.) and Chemistry (V.K.), Bridge Institute, Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, California; and Department of Pharmacology (B.L.R.) and Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy (B.L.R.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina Abstract. ....................................................................................572 Significance Statement ......................................................................572 I. Historical Overview . ........................................................................572 II. Structural Data for Conserved and Nonconserved Ion Binding Sites in G-Protein-Coupled Receptors ...................................................................................576 A. Conserved Sodium Binding Site in Class A G-Protein-Coupled Receptors .................576 1. High-Resolution Structures of Sodium in the Conserved Site . .........................576 2. Sodium Ion Detection Criteria . ......................................................577 3. Lower Resolution -
Gas-Coupled Gpcrs GPR65 and GPR174. Downers for Immune Responses Remy Robert & Charles R Mackay
Immunology & Cell Biology 2018; 96: 341–343 www.wileyonlinelibrary.com/journal/icb NEWS AND COMMENTARY Gas-coupled GPCRs GPR65 and GPR174. Downers for immune responses Remy Robert & Charles R Mackay Infection and Immunity Program, Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia Immunology & Cell Biology 2018; 96: 341–343; doi: 10.1111/imcb.12027 There are about 1000 different GPCRs, emphasizing the importance of proton Gai ¼ Adenylate Cyclase inhibition many of them labeled GPR123 and so sensing for immune regulation. ¼ i forth, so perhaps, one wonders, why GPR174 on the other hand is a cAMP nhibition wastetimeontwoobscureones— receptor for a phosphatidylserine ¼ immune cell inciting ðthink GPR65 and GPR174? Well, these two metabolite, lysophosphatidylserine inflammatory chemokine receptors share a fascinating feature— (LysoPS). Not much is known about receptors, for exampleÞ: they are widely expressed by immune this metabolite and why its presence cells and appear to be important may be immuno-regulating. Wirasinha et al.4, in a paper recently regulators of immunity, i.e. anti- What connects GPR65 and published in Immunology & Cell inflammatory. Indeed, the brakes GPR174 is that they appear to be two Biology, found that GPR65 plays an applied to immune responses by these of the most widely expressed GPCRs important role in demyelinating two receptors put them up there with that signal through the G-protein, autoimmune disease. They used Treg cells, and metabolite-sensing Gas (see Figure 1). Signaling through the typical murine model of MS, 1 receptors such as GPR43, as Gas leads to cAMP production, experimental autoimmune encephalo- regulators of immunity.