DOCSLIB.ORG

Biased Signaling of G Protein Coupled Receptors (Gpcrs): Molecular Determinants of GPCR/Transducer Selectivity and Therapeutic Potential

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Biased Signaling of G Protein Coupled Receptors (Gpcrs): Molecular Determinants of GPCR/Transducer Selectivity and Therapeutic Potential Pharmacology & Therapeutics 200 (2019) 148–178 Contents lists available at ScienceDirect Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera Biased signaling of G protein coupled receptors (GPCRs): Molecular determinants of GPCR/transducer selectivity and therapeutic potential Mohammad Seyedabadi a,b, Mohammad Hossein Ghahremani c, Paul R. Albert d,⁎ a Department of Pharmacology, School of Medicine, Bushehr University of Medical Sciences, Iran b Education Development Center, Bushehr University of Medical Sciences, Iran c Department of Toxicology–Pharmacology, School of Pharmacy, Tehran University of Medical Sciences, Iran d Ottawa Hospital Research Institute, Neuroscience, University of Ottawa, Canada article info abstract Available online 8 May 2019 G protein coupled receptors (GPCRs) convey signals across membranes via interaction with G proteins. Origi- nally, an individual GPCR was thought to signal through one G protein family, comprising cognate G proteins Keywords: that mediate canonical receptor signaling. However, several deviations from canonical signaling pathways for GPCR GPCRs have been described. It is now clear that GPCRs can engage with multiple G proteins and the line between Gprotein cognate and non-cognate signaling is increasingly blurred. Furthermore, GPCRs couple to non-G protein trans- β-arrestin ducers, including β-arrestins or other scaffold proteins, to initiate additional signaling cascades. Selectivity Biased Signaling Receptor/transducer selectivity is dictated by agonist-induced receptor conformations as well as by collateral fac- Therapeutic Potential tors. In particular, ligands stabilize distinct receptor conformations to preferentially activate certain pathways, designated ‘biased signaling’. In this regard, receptor sequence alignment and mutagenesis have helped to iden- tify key receptor domains for receptor/transducer specificity. Furthermore, molecular structures of GPCRs bound to different ligands or transducers have provided detailed insights into mechanisms of coupling selectivity. How- ever, receptor dimerization, compartmentalization, and trafficking, receptor-transducer-effector stoichiometry, and ligand residence and exposure times can each affect GPCR coupling. Extrinsic factors including cell type or assay conditions can also influence receptor signaling. Understanding these factors may lead to the development of improved biased ligands with the potential to enhance therapeutic benefit, while minimizing adverse effects. In this review, evidence for ligand-specific GPCR signaling toward different transducers or pathways is elabo- rated. Furthermore, molecular determinants of biased signaling toward these pathways and relevant examples of the potential clinical benefits and pitfalls of biased ligands are discussed. © 2019 Elsevier Inc. All rights reserved. Abbreviations: 5-HT1BR, serotonin 1B receptor; 5-HT2BR, serotonin 2B receptor; 5-HT2CR, serotonin 2C receptor; 7TM, seven-transmembrane; A1R, adenosine A1 receptor; A2R, adenosine A2 receptor; A3R, adenosine A3 receptor; AHD, α-helical domain; AC, adenylyl cyclase; AGS, activators of G protein signaling; APJ, apelin receptor; AT1R, angiotensin II receptor type 1; β2AR, β2 adrenergic receptor; BRET, bioluminescence resonance energy transfer; cAMP, cyclic adenosine monophosphate; CaSR, calcium-sensing receptor; CB1R, cannabinoid receptor 1; CB2R, cannabinoid receptor 2; CHO, Chinese hamster ovary; CNS, central nervous system; CTX, cholera toxin; D1R, dopamine D1 receptor; D2R, dopamine D2 receptor; DAG, diacylglycerol; δOR, δ opioid receptor; ECL, extracellular loop; EP2R, prostaglandin E2 receptor 2; ERK1/2, extracellular signal-regulated kinase; FRET, fluorescence resonance energy transfer; FPR2, formyl peptide receptor 2; GEF, GTP exchange factor; Gi, inhibitory G protein; GnRH, gonadotropin releasing hormone; GLP1R, glucagon-like peptide 1 receptor; GPCR, G-protein-coupled receptor; GRK, GPCR kinase; Gs, stimulatory G protein; GTP, guanosine 5′-triphosphate; GTPγS, guanosine 5′-O-[γ-thio]-triphosphate; H1R, histamine H2 receptor; H4R, histamine H4 receptor; HEK293, human embryonic kidney 293; ICL, intracellular loop; IP1, inositol monophosphate; IP3, inositol 1,4,5-triphosphate; JAK, Janus kinase; JNK, c-Jun N-terminal kinase; mAChR, muscarinic acetylcholine receptor; MAPK, mitogen-activated protein kinase; MD, molecular dynamics; mGluR, metabotropic glutamate receptor; NF-κB, Nuclear factor-κB; μOR, μ opioid receptor; κOR, κ opioid receptor; NMR, nuclear magnetic resonance; NT1R, neurotensin receptor type 1; PGE2, prostaglandin E2; PGI2, prostaglandin I2; phosphatidylinositol, (PI); PI3K, phosphoinositide 3 kinase; PIP2, phosphatidylinositol (4,5)-bisphosphate; PKA, cAMP-dependent protein kinase; PKC, protein kinase C; PKD, protein kinase D; PLC, phospholipase C; PTH1R, parathyroid hormone 1 receptor; PTX, pertussis toxin; RGS, regulator of G protein signaling; RHD, Ras-homology domain; RTK, receptor tyrosine kinase; S1P1R, sphingosine 1-phosphate receptor 1; STAT, signal transducer and activator of transcription; TM, transmembrane; VFD, Venus flytrap domain. ⁎ Corresponding author at: Ottawa Hospital Research Institute, Neuro, UOttawa Brain and Mind Research Institute, 451 Smyth Road #2464, Ottawa, ON K1H-8M5, Canada. E-mail address: [email protected] (P.R. Albert). https://doi.org/10.1016/j.pharmthera.2019.05.006 0163-7258/© 2019 Elsevier Inc. All rights reserved. M. Seyedabadi et al. / Pharmacology & Therapeutics 200 (2019) 148–178 149 Contents 1. Introduction............................................... 149 2. Differentialstrengthofsignal,functionalselectivity,andbiasedsignaling................... 151 3. Quantificationofbias........................................... 152 4. Revisitingthereceptor/transducerinteraction............................... 154 5. GPCRbiasedsignalingpathways...................................... 155 6. Moleculardeterminantsoftransducerselectivityandbiasedsignaling.................... 161 7. Conclusion............................................... 167 Authorcontribution.............................................. 167 Conflictofintereststatement......................................... 167 Acknowledgments.............................................. 167 References.................................................. 167 1. Introduction followed by dissociation of G proteins from the receptor into activated α and βγ subunits, which can then interact with downstream effectors The superfamily of seven transmembrane receptors (7TMR) is (Park, Scheerer, Hofmann, Choe, & Ernst, 2008). characterized by having seven highly conserved transmembrane alpha Several deviations from the canonical pathway have been reported helices (TM). They are also referred to as G protein-coupled receptors over the years and comprise “non-canonical” signaling. Firstly, G pro- (GPCRs), because they convey signals across biological membranes via tein signaling is not confined to plasma membrane; rather, they can interaction with intracellular guanine nucleotide-binding proteins modulate an array of effector molecules from within endosomal mem- (G proteins). This superfamily comprises approximately 2% of all pro- branes. In this regard, the effector protein content of biological mem- teins encoded in the human genome, and is the target of a substantial branes significantly influences the signaling efficiency of GPCRs and G portion of current pharmaceuticals (Fredriksson, Lagerström, Lundin, proteins (Hewavitharana & Wedegaertner, 2012). Secondly, GPCRs & Schiöth, 2003). These receptors are classified according to their ligand may form functional dimers that can influence ligand binding, allo- binding, structure and physiology. The most frequently used A-F system stery, receptor trafficking, and transducer selectivity (Lane et al., (A: rhodopsin-like, B: secretin, C: metabotropic glutamate, D: fungal 2014; Ng, Lee, & Chow, 2012). Thirdly, GPCRs are capable of mating pheromone receptors, E: cyclic AMP receptors, and F: frizzled/ interacting directly with a number of effector proteins in a G smoothened receptors) is designed to cover all GPCRs, in both verte- protein-independent manner (Walther & Ferguson, 2015). Fourthly, brates and invertebrates. Meanwhile, recent phylogenic studies have re- GPCRs from all classes can couple to multiple G proteins (Flock vealed that most human GPCRs can be categorized into five major et al., 2017). For example, upon PKA-induced phosphorylation Gs- families; Glutamate, Rhodopsin, Adhesion, Frizzled/Taste2, and Secre- coupled beta-adrenergic receptors switch to couple to Gi proteins tin, forming the GRAFS classification system (Fredriksson et al., 2003). and in turn to β-arrestin recruitment (Daaka, Luttrell, & Lefkowitz, G proteins consist of monomeric small G proteins and heterotrimeric 1997; Luttrell et al., 1999). However, not all GPCRs can couple to all (Gαβγ) G proteins, and function as transducers to initiate multiple in- G proteins and in many cases the agonist potency is greater for canon- tracellular signaling pathways. They switch between inactive/active ical vs. non-canonical GPCR signaling (Kukkonen, Näsman, & states upon GDP/GTP exchange. While GTP exchange factors (GEF) Akerman, 2001). Thus, GPCR/G protein combinations that respond promote activation, GTP hydrolysis by the GTPase domain, existing in with lower agonist potency or only in some cell types are designated monomeric G proteins and Gα subunit of the heterotrimers, turns “non-cognate” and mediate non-canonical
Load more

Recommended publications
  • Characterisation of the Α1b-Adrenoceptor by Modeling, Dynamics and Virtual Screening Kapil Jain B.Pharm, M.S.(Pharm.)
    Characterisation of the α1B-Adrenoceptor by Modeling, Dynamics and Virtual Screening Kapil Jain B.Pharm, M.S.(Pharm.) A Thesis submitted for the degree of Master of Philosophy at The University of Queensland in 2018 Institute for Molecular Bioscience 0 Abstract G protein-coupled receptors (GPCRs) are the largest druggable class of proteins yet relatively little is known about the mechanism by which agonist binding induces the conformational changes necessary for G protein activation and intracellular signaling. Recently, the Kobilka group has shown that agonists, neutral antagonists and inverse agonists stabilise distinct extracellular surface (ECS) conformations of the β2-adrenergic receptor (AR) opening up new possibilities for allosteric drug targeting at GPCRs. The goal of this project is to extend these studies to define how the ECS conformation of the α1B-AR changes during agonist binding and develop an understanding of ligand entry and exit mechanisms that may help in the design of specific ligands with higher selectivity, efficacy and longer duration of action. Two parallel approaches were initiated to identify likely functional residues. The role of residues lining the primary binding site were predicted by online web server (Q-Site Finder) while secondary binding sites residues were predicted from molecular dynamics (MD) simulations. Predicted functionally significant residues were mutated and their function was established using FLIPR, radioligand and saturation binding assays. Despite the α1B-AR being pursued as a drug target for over last few decades, few specific agonists and antagonists are known to date. In an attempt to address this gap, we pursued ligand-based approach to find potential new leads.
    [Show full text]
  • Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model
    Downloaded from http://www.jimmunol.org/ by guest on September 25, 2021 T + is online at: average * The Journal of Immunology , 34 of which you can access for free at: 2016; 197:1477-1488; Prepublished online 1 July from submission to initial decision 4 weeks from acceptance to publication 2016; doi: 10.4049/jimmunol.1600589 http://www.jimmunol.org/content/197/4/1477 Molecular Profile of Tumor-Specific CD8 Cell Hypofunction in a Transplantable Murine Cancer Model Katherine A. Waugh, Sonia M. Leach, Brandon L. Moore, Tullia C. Bruno, Jonathan D. Buhrman and Jill E. Slansky J Immunol cites 95 articles Submit online. Every submission reviewed by practicing scientists ? is published twice each month by Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts http://jimmunol.org/subscription Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html http://www.jimmunol.org/content/suppl/2016/07/01/jimmunol.160058 9.DCSupplemental This article http://www.jimmunol.org/content/197/4/1477.full#ref-list-1 Information about subscribing to The JI No Triage! Fast Publication! Rapid Reviews! 30 days* Why • • • Material References Permissions Email Alerts Subscription Supplementary The Journal of Immunology The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. This information is current as of September 25, 2021. The Journal of Immunology Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model Katherine A.
    [Show full text]
  • Computational Methods for Prediction and Classification of G Protein-Coupled Receptors Khodeza Begum University of Texas at El Paso, [email protected]
    University of Texas at El Paso DigitalCommons@UTEP Open Access Theses & Dissertations 2017-01-01 Computational methods for prediction and classification of G protein-coupled receptors Khodeza Begum University of Texas at El Paso, [email protected] Follow this and additional works at: https://digitalcommons.utep.edu/open_etd Part of the Bioinformatics Commons, Computer Sciences Commons, and the Mathematics Commons Recommended Citation Begum, Khodeza, "Computational methods for prediction and classification of G protein-coupled receptors" (2017). Open Access Theses & Dissertations. 408. https://digitalcommons.utep.edu/open_etd/408 This is brought to you for free and open access by DigitalCommons@UTEP. It has been accepted for inclusion in Open Access Theses & Dissertations by an authorized administrator of DigitalCommons@UTEP. For more information, please contact [email protected]. COMPUTATIONAL METHODS FOR PREDICTION AND CLASSIFICATION OF G PROTEIN-COUPLED RECEPTORS KHODEZA BEGUM Master’s Program in Computational Science APPROVED: Ming-Ying Leung, Ph.D., Chair Rachid Skouta, Ph.D. Xiaogang Su, Ph.D. Charlotte M. Vines, Ph.D. Charles Ambler, Ph.D. Dean of the Graduate School Copyright © by Khodeza Begum 2017 COMPUTATIONAL METHODS FOR PREDICTION AND CLASSIFICATION OF G PROTEIN-COUPLED RECEPTORS by KHODEZA BEGUM, B.S. THESIS Presented to the Faculty of the Graduate School of The University of Texas at El Paso in Partial Fulfillment of the Requirements for the Degree of MASTER OF SCIENCE COMPUTATIONAL SCIENCE PROGRAM THE UNIVERSITY OF TEXAS AT EL PASO December 2017 Acknowledgements I would first like to thank my advisor Dr. Ming-Ying Leung for the continuous support and encouragement in my study and thesis.
    [Show full text]
  • Edinburgh Research Explorer
    Edinburgh Research Explorer International Union of Basic and Clinical Pharmacology. LXXXVIII. G protein-coupled receptor list Citation for published version: Davenport, AP, Alexander, SPH, Sharman, JL, Pawson, AJ, Benson, HE, Monaghan, AE, Liew, WC, Mpamhanga, CP, Bonner, TI, Neubig, RR, Pin, JP, Spedding, M & Harmar, AJ 2013, 'International Union of Basic and Clinical Pharmacology. LXXXVIII. G protein-coupled receptor list: recommendations for new pairings with cognate ligands', Pharmacological reviews, vol. 65, no. 3, pp. 967-86. https://doi.org/10.1124/pr.112.007179 Digital Object Identifier (DOI): 10.1124/pr.112.007179 Link: Link to publication record in Edinburgh Research Explorer Document Version: Publisher's PDF, also known as Version of record Published In: Pharmacological reviews Publisher Rights Statement: U.S. Government work not protected by U.S. copyright General rights Copyright for the publications made accessible via the Edinburgh Research Explorer is retained by the author(s) and / or other copyright owners and it is a condition of accessing these publications that users recognise and abide by the legal requirements associated with these rights. Take down policy The University of Edinburgh has made every reasonable effort to ensure that Edinburgh Research Explorer content complies with UK legislation. If you believe that the public display of this file breaches copyright please contact [email protected] providing details, and we will remove access to the work immediately and investigate your claim. Download date: 02. Oct. 2021 1521-0081/65/3/967–986$25.00 http://dx.doi.org/10.1124/pr.112.007179 PHARMACOLOGICAL REVIEWS Pharmacol Rev 65:967–986, July 2013 U.S.
    [Show full text]
  • General Discussion
    UvA-DARE (Digital Academic Repository) EGF-TM7 receptors: A diverse and still evolving family of receptors on the leukocyte surface Matmati, M. Publication date 2008 Link to publication Citation for published version (APA): Matmati, M. (2008). EGF-TM7 receptors: A diverse and still evolving family of receptors on the leukocyte surface. General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl) Download date:23 Sep 2021 Chapter 6 General Discussion GENERAL DISCUSSION Since their identification, starting about 15 years ago, a growing amount of data has accumulated about the structure, the expression, the ligands and, more recently, also the functional implications of EGF-TM7 receptors. Studies with antibody treatment and gene targeting in mice and antibody treatment of human cells in vitro, led to the implication of EGF-TM7 receptors in the trafficking of granulocytes, the generation of efferent antigen specific regulatory T cells and the potentiation of different granulocyte effector functions [1-4].
    [Show full text]
  • Molecular Markers of Serine Protease Evolution
    The EMBO Journal Vol. 20 No. 12 pp. 3036±3045, 2001 Molecular markers of serine protease evolution Maxwell M.Krem and Enrico Di Cera1 ment and specialization of the catalytic architecture should correspond to signi®cant evolutionary transitions in the Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, Box 8231, St Louis, history of protease clans. Evolutionary markers encoun- MO 63110-1093, USA tered in the sequences contributing to the catalytic apparatus would thus give an account of the history of 1Corresponding author e-mail: [email protected] an enzyme family or clan and provide for comparative analysis with other families and clans. Therefore, the use The evolutionary history of serine proteases can be of sequence markers associated with active site structure accounted for by highly conserved amino acids that generates a model for protease evolution with broad form crucial structural and chemical elements of applicability and potential for extension to other classes of the catalytic apparatus. These residues display non- enzymes. random dichotomies in either amino acid choice or The ®rst report of a sequence marker associated with serine codon usage and serve as discrete markers for active site chemistry was the observation that both AGY tracking changes in the active site environment and and TCN codons were used to encode active site serines in supporting structures. These markers categorize a variety of enzyme families (Brenner, 1988). Since serine proteases of the chymotrypsin-like, subtilisin- AGY®TCN interconversion is an uncommon event, it like and a/b-hydrolase fold clans according to phylo- was reasoned that enzymes within the same family genetic lineages, and indicate the relative ages and utilizing different active site codons belonged to different order of appearance of those lineages.
    [Show full text]
  • Calmodulin-Dependent Protein Kinase II–Protein Phosphatase 1 Switch Facilitates Specificity in Postsynaptic Calcium Signaling
    An ultrasensitive Ca2؉͞calmodulin-dependent protein kinase II–protein phosphatase 1 switch facilitates specificity in postsynaptic calcium signaling J. Michael Bradshaw*†‡, Yoshi Kubota*, Tobias Meyer†, and Howard Schulman* Departments of *Neurobiology and †Molecular Pharmacology, Stanford University School of Medicine, Stanford, CA 94305 Edited by Roger A. Nicoll, University of California, San Francisco, CA, and approved July 21, 2003 (received for review May 7, 2003) The strength of hippocampal synapses can be persistently in- hence would provide a distinct Ca2ϩ activation region for creased by signals that activate Ca2؉͞calmodulin-dependent pro- CaMKII compared with other Ca2ϩ-activated enzymes at the tein kinase II (CaMKII). This CaMKII-dependent long-term potenti- synapse. In fact, it has been hypothesized that the signaling ation is important for hippocampal learning and memory. In this network controlling CaMKII autophosphorylation is a bistable work we show that CaMKII exhibits an intriguing switch-like type of switch that allows CaMKII to remain autophosphory- activation that likely is important for changes in synaptic strength. lated long after Ca2ϩ returns to a basal level (16). We found that autophosphorylation of CaMKII by itself showed a In this work we demonstrate experimentally that CaMKII 2؉ Ϸ ϩ steep dependence on Ca concentration [Hill coefficient (nH) 5]. responds in a switch-like fashion to Ca2 : CaMKII transitions 2؉ Ϸ However, an even steeper Ca dependence (nH 8) was observed rapidly from little to near-total autophosphorylation over a when autophosphorylation is balanced by the dephosphorylation narrow range of Ca2ϩ. Interestingly, this switch-like response was activity of protein phosphatase 1 (PP1).
    [Show full text]
  • Recent Advances in Drug Discovery of GPCR Allosteric Modulators
    Recent Advances in Drug Discovery of GPCR Allosteric Modulators ADDEX Pharma S.A., Head of Core Chemistry Chemin Des Aulx 12, 1228 Plan-les-Ouates, Geneva, Switzerland Jean-Philippe Rocher, PhD results in a number of differentiating factors. In fact, most Introduction allosteric modulators have little or no effect on receptor function until the active site is bound by an orthosteric The importance of the allosteric regulation of cellular ligand. Allosteric modulators therefore have multiple functions has been known for decades and even the word potential advantages compared to small molecule and “allosterome,” which describes the endogenous alloste- biologic orthosteric drugs. In particular, they offer new ric regulator molecules of a cell, has been proposed 1. chemistry possibilities allowing access to well known tar- Although best described as modulators of enzymes, gets that have been considered intractable to historical advances in molecular biology and robotic HTS technolo- small molecule approaches. For example, allosteric mod- gies recently allowed the discovery of small molecule allo- ulators may soon be developed for targets which hereto- steric modulators of various biological systems, including fore have been only successfully targeted with proteins GPCR and non-GPCR targets. Today, allosteric modula- and peptides. In other words, allosteric drugs with all the tors appear to be an emerging class of orally available advantages of small molecules － brain penetration, eas- therapeutic agents that can offer a competitive advantage ier manufacturing, distribution and oral administration over classical “orthosteric” drugs. This potential stems - may soon be viewed as the best life cycle management from their ability to offer greater selectivity and differ- strategy for protein therapeutics 2.
    [Show full text]
  • (PDE 1 B 1) Correlates with Brain Regions Having Extensive Dopaminergic Innervation
    The Journal of Neuroscience, March 1994, 14(3): 1251-l 261 Expression of a Calmodulin-dependent Phosphodiesterase lsoform (PDE 1 B 1) Correlates with Brain Regions Having Extensive Dopaminergic Innervation Joseph W. Polli and Randall L. Kincaid Section on Immunology, Laboratory of Molecular and Cellular Neurobiology, National Institute on Alcohol Abuse and Alcoholism, Rockville, Maryland 20852 Cyclic nucleotide-dependent protein phosphorylation plays PDE implies an important physiological role for Ca2+-regu- a central role in neuronal signal transduction. Neurotrans- lated attenuation of CAMP-dependent signaling pathways mitter-elicited increases in cAMP/cGMP brought about by following dopaminergic stimulation. activation of adenylyl and guanylyl cyclases are downre- [Key words: CAMP, cyclase, striatum, dopamine, basal gulated by multiple phosphodiesterase (PDE) enzymes. In ganglia, DARPP-321 brain, the calmodulin (CaM)-dependent isozymes are the major degradative activities and represent a unique point of Cyclic nucleotides, acting as “second messengers”or via direct intersection between the cyclic nucleotide- and calcium effects, regulate a diverse array of neuronal functions, from ion (Ca*+)-mediated second messenger systems. Here we de- channel conductance to gene expression. Hydrolysis of 3’,5’- scribe the distribution of the PDEl Bl (63 kDa) CaM-depen- cyclic nucleotidesto 5’-nucleosidemonophosphates is the major dent PDE in mouse brain. An anti-peptide antiserum to this mechanismfor decreasingintracellular cyclic nucleotide levels. isoform immunoprecipitated -3O-40% of cytosolic PDE ac- This reaction is catalyzed by cyclic nucleotide phosphodiester- tivity, whereas antiserum to PDElA2 (61 kDa isoform) re- ase (PDE) enzymes that constitute a large superfamily (Beavo moved 60-70%, demonstrating that these isoforms are the and Reifsynder, 1990).
    [Show full text]
  • Flow Reagents Single Color Antibodies CD Chart
    CD CHART CD N° Alternative Name CD N° Alternative Name CD N° Alternative Name Beckman Coulter Clone Beckman Coulter Clone Beckman Coulter Clone T Cells B Cells Granulocytes NK Cells Macrophages/Monocytes Platelets Erythrocytes Stem Cells Dendritic Cells Endothelial Cells Epithelial Cells T Cells B Cells Granulocytes NK Cells Macrophages/Monocytes Platelets Erythrocytes Stem Cells Dendritic Cells Endothelial Cells Epithelial Cells T Cells B Cells Granulocytes NK Cells Macrophages/Monocytes Platelets Erythrocytes Stem Cells Dendritic Cells Endothelial Cells Epithelial Cells CD1a T6, R4, HTA1 Act p n n p n n S l CD99 MIC2 gene product, E2 p p p CD223 LAG-3 (Lymphocyte activation gene 3) Act n Act p n CD1b R1 Act p n n p n n S CD99R restricted CD99 p p CD224 GGT (γ-glutamyl transferase) p p p p p p CD1c R7, M241 Act S n n p n n S l CD100 SEMA4D (semaphorin 4D) p Low p p p n n CD225 Leu13, interferon induced transmembrane protein 1 (IFITM1). p p p p p CD1d R3 Act S n n Low n n S Intest CD101 V7, P126 Act n p n p n n p CD226 DNAM-1, PTA-1 Act n Act Act Act n p n CD1e R2 n n n n S CD102 ICAM-2 (intercellular adhesion molecule-2) p p n p Folli p CD227 MUC1, mucin 1, episialin, PUM, PEM, EMA, DF3, H23 Act p CD2 T11; Tp50; sheep red blood cell (SRBC) receptor; LFA-2 p S n p n n l CD103 HML-1 (human mucosal lymphocytes antigen 1), integrin aE chain S n n n n n n n l CD228 Melanotransferrin (MT), p97 p p CD3 T3, CD3 complex p n n n n n n n n n l CD104 integrin b4 chain; TSP-1180 n n n n n n n p p CD229 Ly9, T-lymphocyte surface antigen p p n p n
    [Show full text]
  • Adenosine Receptors and Cancer
    Adenosine Receptors and Cancer P. Fishman, S. Bar-Yehuda, M. Synowitz, J.D. Powell, K.N. Klotz, S. Gessi, and P.A. Borea Contents 1 Introduction..................................................................................... 402 2A1 Adenosine Receptor........................................................................ 402 3A2A Adenosine Receptor...................................................................... 406 3.1 The A2AAR:ProtectorofHostTissue,ProtectorofTumors......................... 406 3.2 TumorsEvadetheImmuneSystembyInhibitingImmuneCellFunction........... 406 3.3 The A2AAR Negatively Regulates Immune Responses............................... 407 3.4 AdenosineProtectsTumorsfromImmuneDestruction............................... 408 3.5 A2AAR Antagonism as a Means of Enhancing Immunotherapy..................... 410 4A2B Adenosine Receptors..................................................................... 410 5A3 Adenosine Receptor........................................................................ 414 5.1 Overexpression of the A3AR in Tumor Versus Normal Adjacent Tissues........... 415 5.2 InVitroStudies......................................................................... 417 5.3 InVivoStudies.......................................................................... 419 5.4 Mechanisms of Action for the Anticancer Activity of the A3AR.................... 424 6 Anticancer Activity of A3AR Antagonists.................................................... 429 7 SummaryandConclusions...................................................................
    [Show full text]
  • A3 Adenosine Receptor As a Target for Cancer Therapy
    Anti-Cancer Drugs 2002, 13, pp. 437-443 Review paper A3 adenosine receptor as a target for cancer therapy Pnina Fishman,1,2 Sara Bar-Yehuda,1 Lea Madi2 and Ilan Cohn2 1Laboratory of Clinical and Tumor Immunology,The Felsenstein Medical Research Center,Tel-Aviv University, Rabin Medical Center, Petach Tikva 49100, Israel. 2Can-Fite BioPharma, Kiryat-Matalon, Petach Tikva 49160, Israel. Targeting the A3 adenosine receptor (A3AR) by adenosine or a tumor metastases are extremely rare in muscle tissue, synthetic agonist to this receptor (IB-MECA and Cl-IB-MECA) not withstanding the fact that it constitutes about results in a di¡erential e¡ect on tumor and on normal cells. Both the adenosine and the agonists inhibit the growth of various tumor 65–70% of lean body mass. This observation led to cell types such as melanoma, colon or prostate carcinoma and research that has its purpose to decipher the lymphoma. This e¡ect is speci¢c and is exerted on tumor cells physiological basis for this intruiging phenomenon. only. Moreover, exposure of peripheral blood mononuclear cells It was found that muscle cells secrete small mole- to adenosine or the agonists leads to the induction of granulocyte cules (MF) which inhibit growth of tumor cells.1,2 colony stimulating factor (G-CSF) production.When given orally to mice, the agonists suppress the growth of melanoma, colon and This growth inhibitory effect was observed on a prostate carcinoma in these animals, while inducing a myelopro- broad range of different tumor cell lines in vitro, tective e¡ect via the induction of G-CSF production.The de-regu- such as melanoma, carcinoma, leukomia and lym- lation of theWnt signaling pathway was found to be involved in the phoma.
    [Show full text]