Home LiteratureArticle Details
PMID: 21942629 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review

Molecular mechanism of β-arrestin-biased agonism at seven-transmembrane receptors.

Annual review of pharmacology and toxicology ·Vol. 52 ·2012-00-00 ·Pages 179-97

Reiter E, Ahn S, Shukla AK, Lefkowitz RJ

Abstract

The concept of biased agonism has recently come to the fore with the realization that seven-transmembrane receptors (7TMRs, also known as G protein-coupled receptors, or GPCRs) activate complex signaling networks and can adopt multiple active conformations upon agonist binding. As a consequence, the "efficacy" of receptors, which was classically considered linear, is now recognized as pluridimensional. Biased agonists selectively stabilize only a subset of receptor conformations induced by the natural "unbiased" ligand, thus preferentially activating certain signaling mechanisms. Such agonists thus reveal the intriguing possibility that one can direct cellular signaling with unprecedented precision and specificity and support the notion that biased agonists may identify new classes of therapeutic agents that have fewer side effects. This review focuses on one particular class of biased ligands that has the ability to alter the balance between G protein-dependent and β-arrestin-dependent signal transduction.

MeSH Terms
Animals Arrestins/metabolism Drug Discovery/methods Humans Ligands Models, Molecular Phosphorylation Protein Conformation Receptors, G-Protein-Coupled/agonists,metabolism Signal Transduction beta-Arrestins
Chemicals
Arrestins Ligands Receptors, G-Protein-Coupled beta-Arrestins seven-transmembrane G-protein-coupled receptor
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Reiter Eric
BIOS Group, INRA, UMR85, Unité Physiologie de la Reproduction et des Comportements, F-37380 Nouzilly, France.
Ahn Seungkirl
Shukla Arun K
Lefkowitz Robert J
References (89)
89 references, click to expand
  1. Structure and function of an irreversible agonist-β(2) adrenoceptor complex.
    Nature. 2011 Jan 13;469(7329):236-40 PMID: 21228876
  2. GPCR-GIP networks: a first step in the discovery of new therapeutic drugs?
    Curr Opin Drug Discov Devel. 2004 Sep;7(5):649-57 PMID: 15503867
  3. Different G protein-coupled receptor kinases govern G protein and beta-arrestin-mediated signaling of V2 vasopressin receptor.
    Proc Natl Acad Sci U S A. 2005 Feb 1;102(5):1448-53 PMID: 15671180
  4. Distinct phosphorylation sites on the β(2)-adrenergic receptor establish a barcode that encodes differential functions of β-arrestin.
    Sci Signal. 2011 Aug 9;4(185):ra51 PMID: 21868357
  5. Identification of two distinct inactive conformations of the beta2-adrenergic receptor reconciles structural and biochemical observations.
    Proc Natl Acad Sci U S A. 2009 Mar 24;106(12):4689-94 PMID: 19258456
  6. Molecular determinants underlying the formation of stable intracellular G protein-coupled receptor-beta-arrestin complexes after receptor endocytosis*.
    J Biol Chem. 2001 Jun 1;276(22):19452-60 PMID: 11279203
  7. beta-arrestin-dependent, G protein-independent ERK1/2 activation by the beta2 adrenergic receptor.
    J Biol Chem. 2006 Jan 13;281(2):1261-73 PMID: 16280323
  8. Transmembrane signaling by G protein-coupled receptors.
    Methods Mol Biol. 2006;332:3-49 PMID: 16878684
  9. Differential G-protein-coupled receptor phosphorylation provides evidence for a signaling bar code.
    J Biol Chem. 2011 Apr 1;286(13):11506-18 PMID: 21177246
  10. A beta-arrestin-biased agonist of the parathyroid hormone receptor (PTH1R) promotes bone formation independent of G protein activation.
    Sci Transl Med. 2009 Oct 7;1(1):1ra1 PMID: 20368153
  11. A phosphorylation cluster of five serine and threonine residues in the C-terminus of the follicle-stimulating hormone receptor is important for desensitization but not for beta-arrestin-mediated ERK activation.
    Mol Endocrinol. 2006 Nov;20(11):3014-26 PMID: 16887887
  12. New concepts in drug discovery: collateral efficacy and permissive antagonism.
    Nat Rev Drug Discov. 2005 Nov;4(11):919-27 PMID: 16264435
  13. GRKs and beta-arrestins: roles in receptor silencing, trafficking and signaling.
    Trends Endocrinol Metab. 2006 May-Jun;17(4):159-65 PMID: 16595179
  14. Multiple ligand-specific conformations of the β2-adrenergic receptor.
    Nat Chem Biol. 2011 Aug 21;7(10):692-700 PMID: 21857662
  15. A modification of receptor theory.
    Br J Pharmacol Chemother. 1956 Dec;11(4):379-93 PMID: 13383117
  16. Functional specialization of beta-arrestin interactions revealed by proteomic analysis.
    Proc Natl Acad Sci U S A. 2007 Jul 17;104(29):12011-6 PMID: 17620599
  17. Conformational changes in G-protein-coupled receptors-the quest for functionally selective conformations is open.
    Br J Pharmacol. 2008 Mar;153 Suppl 1:S358-66 PMID: 18059316
  18. Independent beta-arrestin 2 and G protein-mediated pathways for angiotensin II activation of extracellular signal-regulated kinases 1 and 2.
    Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):10782-7 PMID: 12949261
  19. Crystal structure of the human beta2 adrenergic G-protein-coupled receptor.
    Nature. 2007 Nov 15;450(7168):383-7 PMID: 17952055
  20. What is the role of beta-adrenergic signaling in heart failure?
    Circ Res. 2003 Nov 14;93(10):896-906 PMID: 14615493
  21. beta-Arrestin inhibits NF-kappaB activity by means of its interaction with the NF-kappaB inhibitor IkappaBalpha.
    Proc Natl Acad Sci U S A. 2004 Jun 8;101(23):8603-7 PMID: 15173580
  22. Dancing with different partners: protein kinase a phosphorylation of seven membrane-spanning receptors regulates their G protein-coupling specificity.
    Mol Pharmacol. 2002 Nov;62(5):971-4 PMID: 12391258
  23. beta-adrenergic receptor blockade in chronic heart failure.
    Circulation. 2000 Feb 8;101(5):558-69 PMID: 10662755
  24. beta-Arrestin1 mediates nicotinic acid-induced flushing, but not its antilipolytic effect, in mice.
    J Clin Invest. 2009 May;119(5):1312-21 PMID: 19349687
  25. Beta-arrestin-mediated activation of MAPK by inverse agonists reveals distinct active conformations for G protein-coupled receptors.
    Proc Natl Acad Sci U S A. 2003 Sep 30;100(20):11406-11 PMID: 13679574
  26. Teaching old receptors new tricks: biasing seven-transmembrane receptors.
    Nat Rev Drug Discov. 2010 May;9(5):373-86 PMID: 20431569
  27. FRET-based sensors for the human M1-, M3-, and M5-acetylcholine receptors.
    Bioorg Med Chem. 2011 Feb 1;19(3):1048-54 PMID: 20716489
  28. Transduction of receptor signals by beta-arrestins.
    Science. 2005 Apr 22;308(5721):512-7 PMID: 15845844
  29. Therapeutic potential of β-arrestin- and G protein-biased agonists.
    Trends Mol Med. 2011 Mar;17(3):126-39 PMID: 21183406
  30. Global phosphorylation analysis of beta-arrestin-mediated signaling downstream of a seven transmembrane receptor (7TMR).
    Proc Natl Acad Sci U S A. 2010 Aug 24;107(34):15299-304 PMID: 20686112
  31. The complex G protein-coupled receptor kinase 2 (GRK2) interactome unveils new physiopathological targets.
    Br J Pharmacol. 2010 Jun;160(4):821-32 PMID: 20590581
  32. Beta-arrestin-mediated localization of smoothened to the primary cilium.
    Science. 2008 Jun 27;320(5884):1777-81 PMID: 18497258
  33. The 2.6 angstrom crystal structure of a human A2A adenosine receptor bound to an antagonist.
    Science. 2008 Nov 21;322(5905):1211-7 PMID: 18832607
  34. Beta-arrestin-biased ligands at seven-transmembrane receptors.
    Trends Pharmacol Sci. 2007 Aug;28(8):416-22 PMID: 17644195
  35. Value of novelty?
    Nat Rev Drug Discov. 2002 Aug;1(8):571-2 PMID: 12402497
  36. Visual arrestin interaction with rhodopsin. Sequential multisite binding ensures strict selectivity toward light-activated phosphorylated rhodopsin.
    J Biol Chem. 1993 Jun 5;268(16):11628-38 PMID: 8505295
  37. Ligand-selective receptor conformations revisited: the promise and the problem.
    Trends Pharmacol Sci. 2003 Jul;24(7):346-54 PMID: 12871667
  38. Beta-arrestin-mediated beta1-adrenergic receptor transactivation of the EGFR confers cardioprotection.
    J Clin Invest. 2007 Sep;117(9):2445-58 PMID: 17786238
  39. Collateral efficacy in drug discovery: taking advantage of the good (allosteric) nature of 7TM receptors.
    Trends Pharmacol Sci. 2007 Aug;28(8):407-15 PMID: 17629960
  40. Beta-blockers alprenolol and carvedilol stimulate beta-arrestin-mediated EGFR transactivation.
    Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14555-60 PMID: 18787115
  41. Selective engagement of G protein coupled receptor kinases (GRKs) encodes distinct functions of biased ligands.
    Proc Natl Acad Sci U S A. 2009 Jun 16;106(24):9649-54 PMID: 19497875
  42. An Akt/beta-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior.
    Cell. 2005 Jul 29;122(2):261-73 PMID: 16051150
  43. Operational models of pharmacological agonism.
    Proc R Soc Lond B Biol Sci. 1983 Dec 22;220(1219):141-62 PMID: 6141562
  44. Distinct conformational changes in beta-arrestin report biased agonism at seven-transmembrane receptors.
    Proc Natl Acad Sci U S A. 2008 Jul 22;105(29):9988-93 PMID: 18621717
  45. High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor.
    Science. 2007 Nov 23;318(5854):1258-65 PMID: 17962520
  46. The structural basis for agonist and partial agonist action on a β(1)-adrenergic receptor.
    Nature. 2011 Jan 13;469(7329):241-4 PMID: 21228877
  47. Quantifying ligand bias at seven-transmembrane receptors.
    Mol Pharmacol. 2011 Sep;80(3):367-77 PMID: 21610196
  48. Probing the beta2 adrenoceptor binding site with catechol reveals differences in binding and activation by agonists and partial agonists.
    J Biol Chem. 2005 Jun 10;280(23):22165-71 PMID: 15817484
  49. G protein-coupled receptors. III. New roles for receptor kinases and beta-arrestins in receptor signaling and desensitization.
    J Biol Chem. 1998 Jul 24;273(30):18677-80 PMID: 9668034
  50. The minor binding pocket: a major player in 7TM receptor activation.
    Trends Pharmacol Sci. 2010 Dec;31(12):567-74 PMID: 20870300
  51. Structure of a nanobody-stabilized active state of the β(2) adrenoceptor.
    Nature. 2011 Jan 13;469(7329):175-80 PMID: 21228869
  52. GPCR engineering yields high-resolution structural insights into beta2-adrenergic receptor function.
    Science. 2007 Nov 23;318(5854):1266-73 PMID: 17962519
  53. Differential signaling of the endogenous agonists at the beta2-adrenergic receptor.
    J Biol Chem. 2010 Nov 12;285(46):36188-98 PMID: 20837485
  54. Allosteric modulation of G protein-coupled receptors.
    Annu Rev Pharmacol Toxicol. 2007;47:1-51 PMID: 17009927
  55. Novel receptor partners and function of receptor activity-modifying proteins.
    J Biol Chem. 2003 Jan 31;278(5):3293-7 PMID: 12446722
  56. A negative allosteric modulator demonstrates biased antagonism of the follicle stimulating hormone receptor.
    Mol Cell Endocrinol. 2011 Feb 20;333(2):143-50 PMID: 21184806
  57. Functional antagonism of different G protein-coupled receptor kinases for beta-arrestin-mediated angiotensin II receptor signaling.
    Proc Natl Acad Sci U S A. 2005 Feb 1;102(5):1442-7 PMID: 15671181
  58. Molecular mechanism of 7TM receptor activation--a global toggle switch model.
    Annu Rev Pharmacol Toxicol. 2006;46:481-519 PMID: 16402913
  59. Physical interaction of calmodulin with the 5-hydroxytryptamine2C receptor C-terminus is essential for G protein-independent, arrestin-dependent receptor signaling.
    Mol Biol Cell. 2008 Nov;19(11):4640-50 PMID: 18768750
  60. Regulation of GPCR signal networks via membrane trafficking.
    Mol Cell Endocrinol. 2011 Jan 15;331(2):205-14 PMID: 20654691
  61. Fluorescence resonance energy transfer analysis of alpha 2a-adrenergic receptor activation reveals distinct agonist-specific conformational changes.
    Mol Pharmacol. 2009 Mar;75(3):534-41 PMID: 19106230
  62. beta-Arrestin 1 and Galphaq/11 coordinately activate RhoA and stress fiber formation following receptor stimulation.
    J Biol Chem. 2005 Mar 4;280(9):8041-50 PMID: 15611106
  63. Nicotinic acid: an old drug with a promising future.
    Br J Pharmacol. 2008 Mar;153 Suppl 1:S68-75 PMID: 18037924
  64. Functional selectivity and classical concepts of quantitative pharmacology.
    J Pharmacol Exp Ther. 2007 Jan;320(1):1-13 PMID: 16803859
  65. Unique agonist-bound cannabinoid CB1 receptor conformations indicate agonist specificity in signaling.
    Eur J Pharmacol. 2008 Feb 26;581(1-2):19-29 PMID: 18162180
  66. Distinct beta-arrestin- and G protein-dependent pathways for parathyroid hormone receptor-stimulated ERK1/2 activation.
    J Biol Chem. 2006 Apr 21;281(16):10856-64 PMID: 16492667
  67. 3-(1H-tetrazol-5-yl)-1,4,5,6-tetrahydro-cyclopentapyrazole (MK-0354): a partial agonist of the nicotinic acid receptor, G-protein coupled receptor 109a, with antilipolytic but no vasodilatory activity in mice.
    J Med Chem. 2008 Aug 28;51(16):5101-8 PMID: 18665582
  68. The active conformation of beta-arrestin1: direct evidence for the phosphate sensor in the N-domain and conformational differences in the active states of beta-arrestins1 and -2.
    J Biol Chem. 2007 Jul 20;282(29):21370-81 PMID: 17513300
  69. A mutation-induced activated state of the beta 2-adrenergic receptor. Extending the ternary complex model.
    J Biol Chem. 1993 Mar 5;268(7):4625-36 PMID: 8095262
  70. Structure and conformational changes in the C-terminal domain of the beta2-adrenoceptor: insights from fluorescence resonance energy transfer studies.
    J Biol Chem. 2007 May 4;282(18):13895-905 PMID: 17347144
  71. Activation-dependent conformational changes in {beta}-arrestin 2.
    J Biol Chem. 2004 Dec 31;279(53):55744-53 PMID: 15501822
  72. Ligand-specific regulation of the extracellular surface of a G-protein-coupled receptor.
    Nature. 2010 Jan 7;463(7277):108-12 PMID: 20054398
  73. Monitoring agonist-promoted conformational changes of beta-arrestin in living cells by intramolecular BRET.
    EMBO Rep. 2005 Apr;6(4):334-40 PMID: 15776020
  74. Biochemical and pharmacological control of the multiplicity of coupling at G-protein-coupled receptors.
    Pharmacol Ther. 2003 Jul;99(1):25-44 PMID: 12804697
  75. Structure of a beta1-adrenergic G-protein-coupled receptor.
    Nature. 2008 Jul 24;454(7203):486-91 PMID: 18594507
  76. Efficacy at G-protein-coupled receptors.
    Nat Rev Drug Discov. 2002 Feb;1(2):103-10 PMID: 12120091
  77. Bimodal regulation of the human H1 histamine receptor by G protein-coupled receptor kinase 2.
    J Biol Chem. 2005 Jan 21;280(3):2197-204 PMID: 15542600
  78. Differential affinities of visual arrestin, beta arrestin1, and beta arrestin2 for G protein-coupled receptors delineate two major classes of receptors.
    J Biol Chem. 2000 Jun 2;275(22):17201-10 PMID: 10748214
  79. The evasive nature of drug efficacy: implications for drug discovery.
    Trends Pharmacol Sci. 2007 Aug;28(8):423-30 PMID: 17659355
  80. Conformational complexity of G-protein-coupled receptors.
    Trends Pharmacol Sci. 2007 Aug;28(8):397-406 PMID: 17629961
  81. Identification of beta-arrestin2 as a G protein-coupled receptor-stimulated regulator of NF-kappaB pathways.
    Mol Cell. 2004 May 7;14(3):303-17 PMID: 15125834
  82. {beta}-Arrestin-2 Mediates Anti-apoptotic Signaling through Regulation of BAD Phosphorylation.
    J Biol Chem. 2009 Mar 27;284(13):8855-65 PMID: 19171933
  83. Beta-arrestin-mediated signaling regulates protein synthesis.
    J Biol Chem. 2008 Apr 18;283(16):10611-20 PMID: 18276584
  84. Structural diversity of G protein-coupled receptors and significance for drug discovery.
    Nat Rev Drug Discov. 2008 Apr;7(4):339-57 PMID: 18382464
  85. Selectively engaging β-arrestins at the angiotensin II type 1 receptor reduces blood pressure and increases cardiac performance.
    J Pharmacol Exp Ther. 2010 Dec;335(3):572-9 PMID: 20801892
  86. A unique mechanism of beta-blocker action: carvedilol stimulates beta-arrestin signaling.
    Proc Natl Acad Sci U S A. 2007 Oct 16;104(42):16657-62 PMID: 17925438
  87. Dynamics and flexibility of G-protein-coupled receptor conformations and their relevance to drug design.
    Drug Discov Today. 2010 Nov;15(21-22):951-7 PMID: 20831898
  88. Site-specific phosphorylation of CXCR4 is dynamically regulated by multiple kinases and results in differential modulation of CXCR4 signaling.
    J Biol Chem. 2010 Mar 5;285(10):7805-17 PMID: 20048153
  89. Coupling ligand structure to specific conformational switches in the beta2-adrenoceptor.
    Nat Chem Biol. 2006 Aug;2(8):417-22 PMID: 16799554
Article Info
Journal
Annual review of pharmacology and toxicology
Abbr.
Annu Rev Pharmacol Toxicol
ISSN
1545-4304
DOI
10.1146/annurev.pharmtox.010909.105800
Published
2012-00-00
Epub
2011-00-19
Pages
179-97
Language
English
Region
United States
NLM ID
7607088
PMCID
PMC3628752
Subset
IM
Grants
NHLBI NIH HHS · HL 70631 · United States
NHLBI NIH HHS · R01 HL016037 · United States
Howard Hughes Medical Institute · United States
NHLBI NIH HHS · R01 HL070631 · United States
NHLBI NIH HHS · R01 HL16037 · United States
External Links
PubMed source DOI: 10.1146/annurev.pharmtox.010909.105800 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2