Allosteric and biased G protein-coupled receptor signaling regulation: Potentials for new therapeutics

Frontiers in Endocrinology

Volumn 5, Issue MAY, 2014, Pages

  Khoury, Etienne ^a   Clément, Stéphanie ^a   Laporte, Stéphane A ^a  

^a RESEARCH INSTITUTE OF THE MCGILL UNIVERSITY HEALTH CENTRE   (Canada)

Author keywords

Allosterism; Biased signaling; Functional selectivity; G protein coupled receptors; Receptor domains

Indexed keywords

ADENOSINE A2B RECEPTOR; ADX10059; ADX48621; ADX71149; AGENTS INTERACTING WITH TRANSMITTER, HORMONE OR DRUG RECEPTORS; AZD8529; BETA ARRESTIN; CHEMOKINE RECEPTOR CCR5; CHEMOKINE RECEPTOR CXCR4; CINACALCET; DIPRAGLURANT; FENOBAM; G PROTEIN COUPLED RECEPTOR; G PROTEIN COUPLED RECEPTOR CLASS A; G PROTEIN COUPLED RECEPTOR CLASS C; LUTEINIZING HORMONE RECEPTOR; MARAVIROC; MAVOGLURANT; MORPHINE; MUSCARINIC M3 RECEPTOR; PARATHYROID HORMONE RECEPTOR 1; PDC31; PROSTAGLANDIN F2 ALPHA RECEPTOR; REPARIXIN; RHODOPSIN RECEPTOR; RO4917523; SOMATOSTATIN RECEPTOR; STX107; TRV120027; TRV130; UNCLASSIFIED DRUG; UNINDEXED DRUG; VASOPRESSIN V1A RECEPTOR; VASOPRESSIN V2 RECEPTOR;

ALLOSTERISM; BINDING SITE; HUMAN; NONHUMAN; REGULATORY MECHANISM; REVIEW; SIGNAL TRANSDUCTION;

EID: 84905443315     PISSN: None     EISSN: 16642392     Source Type: Journal    
DOI: 10.3389/fendo.2014.00068     Document Type: Review

References (69)

1. Lagerstrom MC, Schioth HB. Structural diversity of G protein-coupled receptors and significance for drug discovery. Nat Rev Drug Discov (2008) 7(4):339-57. doi: 10.1038/nrd2518
2. Violin JD, Lefkowitz RJ. Beta-arrestin-biased ligands at seven-transmembrane receptors. Trends Pharmacol Sci (2007) 28(8):416-22. doi:10.1016/j.tips.2007.06.006
3. Rajagopal S, Rajagopal K, Lefkowitz RJ. Teaching old receptors new tricks: biasing seven-transmembrane receptors. Nat Rev Drug Discov (2010) 9(5):373-86. doi:10.1038/nrd3024
4. Luttrell LM. Arrestin pathways as drug targets. Prog Mol Biol Transl Sci (2013) 118:469-97. doi:10.1016/B978-0-12-394440-5.00018-8
5. Monod J, Wyman J, Changeux JP. On the nature of allosteric transitions: a plausible model. J Mol Biol (1965) 12:88-118. doi:10.1016/S0022-2836(65)80285-6
6. May LT, Leach K, Sexton PM, Christopoulos A. Allosteric modulation of G protein-coupled receptors. Annu Rev Pharmacol Toxicol (2007) 47:1-51. doi:10.1146/annurev.pharmtox.47.120505.105159
7. Mishra RK, Makman MH, Costain WJ, Nair VD, Johnson RL. Modulation of agonist stimulated adenylyl cyclase and GTPase activity by l-pro-l-leu-glycinamide and its peptidomimetic analogue in rat striatal membranes. Neurosci Lett (1999) 269(1):21-4. doi:10.1016/S0304-3940(99)00413-9
8. Goupil E, Laporte SA, Hébert TE. Functional selectivity in GPCR signaling: understanding the full spectrum of receptor conformations. Mini Rev Med Chem (2012) 12(9):817-30. doi:10.2174/138955712800959143
9. Wootten D, Christopoulos A, Sexton PM. Emerging paradigms in GPCR allostery: implications for drug discovery. Nat Rev Drug Discov (2013) 12(8):630-44. doi:10.1038/nrd4052
10. Hemstapat K, Da Costa H, Nong Y, Brady AE, Luo Q, Niswender CM, et al. A novel family of potent negative allosteric modulators of group II metabotropic glutamate receptors. J Pharmacol Exp Ther (2007) 322(1):254-64. doi:10.1124/jpet.106.117093
11. Lee T, Schwandner R, Swaminath G, Weiszmann J, Cardozo M, Greenberg J, et al. Identification and functional characterization of allosteric agonists for the G protein-coupled receptor FFA2. Mol Pharmacol (2008) 74(6):1599-609. doi:10.1124/mol.108.049536
12. Goupil E, Tassy D, Bourguet C, Quiniou C, Wisehart V, Pétrin D, et al. A novel biased allosteric compound inhibitor of parturition selectively impedes the prostaglandin F2alpha-mediated Rho/ROCK signaling pathway. J Biol Chem (2010) 285(33):25624-36. doi:10.1074/jbc. M110.115196
13. Makita N, Sato J, Manaka K, Shoji Y, Oishi A, Hashimoto M, et al. An acquired hypocalciuric hypercalcemia autoantibody induces allosteric transition among active human Ca-sensing receptor conformations. Proc Natl Acad Sci U S A (2007) 104(13):5443-8. doi:10.1073/pnas.0701290104
14. Tateyama M, Kubo Y. Dual signaling is differentially activated by different active states of the metabotropic glutamate receptor 1alpha. Proc Natl Acad Sci U S A (2006) 103(4):1124-8. doi:10.1073/pnas.0505925103
15. Quoyer J, Janz JM, Luo J, Ren Y, Armando S, Lukashova V, et al. Pepducin targeting the C-X-C chemokine receptor type 4 acts as a biased agonist favoring activation of the inhibitory G protein. Proc Natl Acad Sci U S A (2013) 110(52):E5088-97. doi:10.1073/pnas.1312515110
16. Ahn KH, Mahmoud MM, Kendall DA. Allosteric modulator ORG27569 induces CB1 cannabinoid receptor high affinity agonist binding state, receptor internalization, and Gi protein-independent ERK1/2 kinase activation. J Biol Chem (2012) 287(15):12070-82. doi:10.1074/jbc. M111.316463
17. Ahn KH, Mahmoud MM, Shim JY, Kendall DA. Distinct roles of beta-arrestin 1 and beta-arrestin 2 in ORG27569-induced biased signaling and internalization of the cannabinoid receptor 1 (CB1). J Biol Chem (2013) 288(14):9790-800. doi:10.1074/jbc. M112.438804
18. Percherancier Y, Berchiche YA, Slight I, Volkmer-Engert R, Tamamura H, Fujii N, et al. Bioluminescence resonance energy transfer reveals ligand-induced conformational changes in CXCR4 homo- and heterodimers. J Biol Chem (2005) 280(11):9895-903. doi:10.1074/jbc. M411151200
19. Décaillot FM, Kazmi MA, Lin Y, Ray-Saha S, Sakmar TP, Sachdev P. CXCR7/CXCR4 heterodimer constitutively recruits beta-arrestin to enhance cell migration. J Biol Chem (2011) 286(37):32188-97. doi:10.1074/jbc. M111.277038
20. Smith NJ, Milligan G. Allostery at G protein-coupled receptor homo- and heteromers: uncharted pharmacological landscapes. Pharmacol Rev (2010) 62(4):701-25. doi:10.1124/pr.110.002667
21. Goupil E, Laporte SA, Hébert TE. GPCR heterodimers: asymmetries in ligand binding and signalling output offer new targets for drug discovery. Br J Pharmacol (2013) 168(5):1101-3. doi:10.1111/bph.12040
22. Satake H, Matsubara S, Aoyama M, Kawada T, Sakai T. GPCR Heterodimerization in the Reproductive System: functional Regulation and Implication for Biodiversity. Front Endocrinol (Lausanne) (2013) 4:100. doi:10.3389/fendo.2013.00100
23. Hebert TE, Moffett S, Morello JP, Loisel TP, Bichet DG, Barret C, et al. A peptide derived from a beta2-adrenergic receptor transmembrane domain inhibits both receptor dimerization and activation. J Biol Chem (1996) 271(27):16384-92. doi:10.1074/jbc.271.27.16384
24. Tarasova NI, Rice WG, Michejda CJ. Inhibition of G-protein-coupled receptor function by disruption of transmembrane domain interactions. J Biol Chem (1999) 274(49):34911-5. doi:10.1074/jbc.274.49.34911
25. Hawes BE, Luttrell LM, Exum ST, Lefkowitz RJ. Inhibition of G protein-coupled receptor signaling by expression of cytoplasmic domains of the receptor. J Biol Chem (1994) 269(22):15776-85.
26. Hayashida W, Horiuchi M, Dzau VJ. Intracellular third loop domain of angiotensin II type-2 receptor. Role in mediating signal transduction and cellular function. J Biol Chem (1996) 271(36):21985-92. doi:10.1074/jbc.271.36.21985
27. Krupnick JG, Gurevich VV, Schepers T, Hamm HE, Benovic JL. Arrestin-rhodopsin interaction. Multi-site binding delineated by peptide inhibition. J Biol Chem (1994) 269(5):3226-32.
28. Mukherjee S, Palczewski K, Gurevich VV, Hunzicker-Dunn M. Beta-arrestin-dependent desensitization of luteinizing hormone/choriogonadotropin receptor is prevented by a synthetic peptide corresponding to the third intracellular loop of the receptor. J Biol Chem (1999) 274(19):12984-9. doi:10.1074/jbc.274.19.12984
29. Staus DP, Wingler LM, Strachan RT, Rasmussen SG, Pardon E, Ahn S, et al. Regulation of beta2-adrenergic receptor function by conformationally selective single-domain intrabodies. Mol Pharmacol (2014) 85(3):472-81. doi:10.1124/mol.113.089516
30. Auger GA, Pease JE, Shen X, Xanthou G, Barker MD. Alanine scanning mutagenesis of CCR3 reveals that the three intracellular loops are essential for functional receptor expression. Eur J Immunol (2002) 32(4):1052-8. doi:10.1002/1521-4141(200204)32:4<1052::AID-IMMU1052>3.3.CO;2-C
31. Lan H, Teeter MM, Gurevich VV, Neve KA. An intracellular loop 2 amino acid residue determines differential binding of arrestin to the dopamine D2 and D3 receptors. Mol Pharmacol (2009) 75(1):19-26. doi:10.1124/mol.108.050542
32. Small KM, Forbes SL, Rahman FF, Bridges KM, Liggett SB. A four amino acid deletion polymorphism in the third intracellular loop of the human alpha 2C-adrenergic receptor confers impaired coupling to multiple effectors. J Biol Chem (2000) 275(30):23059-64. doi:10.1074/jbc. M000796200
33. Conner M, Hawtin SR, Simms J, Wootten D, Lawson Z, Conner AC, et al. Systematic analysis of the entire second extracellular loop of the V(1a) vasopressin receptor: key residues, conserved throughout a G-protein-coupled receptor family, identified. J Biol Chem (2007) 282(24):17405-12. doi:10.1074/jbc. M702151200
34. Rihakova L, Quiniou C, Hamdan FF, Kaul R, Brault S, Hou X, et al. VRQ397 (CRAVKY): a novel noncompetitive V2 receptor antagonist. Am J Physiol Regul Integr Comp Physiol (2009) 297(4):R1009-18. doi:10.1152/ajpregu.90766.2008
35. Scarselli M, Li B, Kim SK, Wess J. Multiple residues in the second extracellular loop are critical for M3 muscarinic acetylcholine receptor activation. J Biol Chem (2007) 282(10):7385-96. doi:10.1074/jbc. M610394200
36. Leu FP, Nandi M. GPCR somatostatin receptor extracellular loop 2 is a key ectodomain for making subtype-selective antibodies with agonist-like activities in the pancreatic neuroendocrine tumor BON cell line. Pancreas (2010) 39(8):1155-66. doi:10.1097/MPA.0b013e3181de8c05
37. Peri KG, Quiniou C, Hou X, Abran D, Varma DR, Lubell WD, et al. THG113: a novel selective FP antagonist that delays preterm labor. Semin Perinatol (2002) 26(6):389-97. doi:10.1053/sper.2002.37307
38. Blanpain C, Vanderwinden JM, Cihak J, Wittamer V, Le Poul E, Issafras H, et al. Multiple active states and oligomerization of CCR5 revealed by functional properties of monoclonal antibodies. Mol Biol Cell (2002) 13(2):723-37. doi:10.1091/mbc.01-03-0129
39. Dogo-Isonagie C, Lam S, Gustchina E, Acharya P, Yang Y, Shahzad-ul-Hussan S, et al. Peptides from second extracellular loop of C-C chemokine receptor type 5 (CCR5) inhibit diverse strains of HIV-1. J Biol Chem (2012) 287(18):15076-86. doi:10.1074/jbc. M111.332361
40. Thathiah A, Horré K, Snellinx A, Vandewyer E, Huang Y, Ciesielska M, et al. Beta-arrestin 2 regulates Abeta generation and gamma-secretase activity in Alzheimer's disease. Nat Med (2013) 19(1):43-9. doi:10.1038/nm.3023
41. Lee C, Luck MD, Jüppner H, Potts JT Jr, Kronenberg HM, Gardella TJ. Homolog-scanning mutagenesis of the parathyroid hormone (PTH) receptor reveals PTH-(1-34) binding determinants in the third extracellular loop. Mol Endocrinol (1995) 9(10):1269-78. doi:10.1210/me.9.10.1269
42. Peeters MC, van Westen GJ, Guo D, Wisse LE, Müller CE, Beukers MW, et al. GPCR structure and activation: an essential role for the first extracellular loop in activating the adenosine A2B receptor. FASEB J (2011) 25(2):632-43. doi:10.1096/fj.10-164319
43. Samson M, LaRosa G, Libert F, Paindavoine P, Detheux M, Vassart G, et al. The second extracellular loop of CCR5 is the major determinant of ligand specificity. J Biol Chem (1997) 272(40):24934-41. doi:10.1074/jbc.272.40.24934
44. Shi L, Javitch JA. The second extracellular loop of the dopamine D2 receptor lines the binding-site crevice. Proc Natl Acad Sci U S A (2004) 101(2):440-5. doi:10.1073/pnas.2237265100
45. Klco JM, Wiegand CB, Narzinski K, Baranski TJ. Essential role for the second extracellular loop in C5a receptor activation. Nat Struct Mol Biol (2005) 12(4):320-6. doi:10.1038/nsmb913
46. Ahuja S, Hornak V, Yan EC, Syrett N, Goncalves JA, Hirshfeld A, et al. Helix movement is coupled to displacement of the second extracellular loop in rhodopsin activation. Nat Struct Mol Biol (2009) 16(2):168-75. doi:10.1038/nsmb.1549
47. Xiao J, Huang Z, Chen CZ, Agoulnik IU, Southall N, Hu X, et al. Identification and optimization of small-molecule agonists of the human relaxin hormone receptor RXFP1. Nat Commun (2013) 4:1953. doi:10.1038/ncomms2953
48. Smith NJ, Ward RJ, Stoddart LA, Hudson BD, Kostenis E, Ulven T, et al. Extracellular loop 2 of the free fatty acid receptor 2 mediates allosterism of a phenylacetamide ago-allosteric modulator. Mol Pharmacol (2011) 80(1):163-73. doi:10.1124/mol.110.070789
49. Wang C, Wu H, Katritch V, Han GW, Huang XP, Liu W, et al. Structure of the human smoothened receptor bound to an antitumour agent. Nature (2013) 497(7449):338-43. doi:10.1038/nature12167
50. Valant C, Felder CC, Sexton PM, Christopoulos A. Probe dependence in the allosteric modulation of a G protein-coupled receptor: implications for detection and validation of allosteric ligand effects. Mol Pharmacol (2012) 81(1):41-52. doi:10.1124/mol.111.074872
51. Kruse AC, Ring AM, Manglik A, Hu J, Hu K, Eitel K, et al. Activation and allosteric modulation of a muscarinic acetylcholine receptor. Nature (2013) 504(7478):101-6. doi:10.1038/nature12735
52. Fisher A, Heldman E, Gurwitz D, Haring R, Barak D, Meshulam H, et al. Selective signaling via unique M1 muscarinic agonists. Ann N Y Acad Sci (1993) 695:300-3. doi:10.1111/j.1749-6632.1993.tb23070.x
53. Gurwitz D, Haring R, Heldman E, Fraser CM, Manor D, Fisher A. Discrete activation of transduction pathways associated with acetylcholine m1 receptor by several muscarinic ligands. Eur J Pharmacol (1994) 267(1):21-31. doi:10.1016/0922-4106(94)90220-8
54. Violin JD, DeWire SM, Yamashita D, Rominger DH, Nguyen L, Schiller K, et al. Selectively engaging beta-arrestins at the angiotensin II type 1 receptor reduces blood pressure and increases cardiac performance. J Pharmacol Exp Ther (2010) 335(3):572-9. doi:10.1124/jpet.110.173005
55. Boerrigter G, Soergel DG, Violin JD, Lark MW, Burnett JC Jr. TRV120027, a novel beta-arrestin biased ligand at the angiotensin II type I receptor, unloads the heart and maintains renal function when added to furosemide in experimental heart failure. Circ Heart Fail (2012) 5(5):627-34. doi:10.1161/CIRCHEARTFAILURE.112.969220
56. DeWire SM, Yamashita DS, Rominger DH, Liu G, Cowan CL, Graczyk TM, et al. A G protein-biased ligand at the mu-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine. J Pharmacol Exp Ther (2013) 344(3):708-17. doi:10.1124/jpet.112.201616
57. Zerbib F, Keywood C, Strabach G. Efficacy, tolerability and pharmacokinetics of a modified release formulation of ADX10059, a negative allosteric modulator of metabotropic glutamate receptor 5: an esophageal pH-impedance study in healthy subjects. Neurogastroenterol Motil (2010) 22(8):859-65. doi:10.1111/j.1365-2982.2010.01484.x
58. Zerbib F, Bruley des Varannes S, Roman S, Tutuian R, Galmiche JP, Mion F, et al. Randomised clinical trial: effects of monotherapy with ADX10059, a mGluR5 inhibitor, on symptoms and reflux events in patients with gastro-oesophageal reflux disease. Aliment Pharmacol Ther (2011) 33(8):911-21. doi:10.1111/j.1365-2036.2011.04596.x
59. Bertini R, Allegretti M, Bizzarri C, Moriconi A, Locati M, Zampella G, et al. Noncompetitive allosteric inhibitors of the inflammatory chemokine receptors CXCR1 and CXCR2: prevention of reperfusion injury. Proc Natl Acad Sci U S A (2004) 101(32):11791-6. doi:10.1073/pnas.0402090101
60. Ginestier C, Liu S, Diebel ME, Korkaya H, Luo M, Brown M, et al. CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts. J Clin Invest (2010) 120(2):485-97. doi:10.1172/JCI39397
61. Fätkenheuer G, Pozniak AL, Johnson MA, Plettenberg A, Staszewski S, Hoepelman AI, et al. Efficacy of short-term monotherapy with maraviroc, a new CCR5 antagonist, in patients infected with HIV-1. Nat Med (2005) 11(11):1170-2. doi:10.1038/nm1319
62. Olson DM, Ammann C. Role of the prostaglandins in labour and prostaglandin receptor inhibitors in the prevention of preterm labour. Front Biosci (2007) 12:1329-43. doi:10.2741/2151
63. Goodman WG, Frazao JM, Goodkin DA, Turner SA, Liu W, Coburn JW. A calcimimetic agent lowers plasma parathyroid hormone levels in patients with secondary hyperparathyroidism. Kidney Int (2000) 58:436-45. doi:10.1046/j.1523-1755.2000.00183.x
64. Zarbock A, Allegretti M, Ley K. Therapeutic inhibition of CXCR2 by Reparixin attenuates acute lung injury in mice. Br J Pharmacol (2008) 155(3):357-64. doi:10.1038/bjp.2008.270
65. Hashimoto K, Malchow B, Falkai P, Schmitt A. Glutamate modulators as potential therapeutic drugs in schizophrenia and affective disorders. Eur Arch Psychiatry Clin Neurosci (2013) 263(5):367-77. doi:10.1007/s00406-013-0399-y
66. Berg D, Godau J, Trenkwalder C, Eggert K, Csoti I, Storch A, et al. AFQ056 treatment of levodopa-induced dyskinesias: results of 2 randomized controlled trials. Mov Disord (2011) 26(7):1243-50. doi:10.1002/mds.23616
67. Jacquemont S, Curie A, des Portes V, Torrioli MG, Berry-Kravis E, Hagerman RJ, et al. Epigenetic modification of the FMR1 gene in fragile X syndrome is associated with differential response to the mGluR5 antagonist AFQ056. Sci Transl Med (2011) 3(64):64ra1. doi:10.1126/scitranslmed.3001708
68. Stocchi F, Rascol O, Destee A, Hattori N, Hauser RA, Lang AE, et al. 15th International Congress of Parkinson's Disease and Movement Disorders. Toronto (2011).
69. Berry-Kravis E, Hessl D, Coffey S, Hervey C, Schneider A, Yuhas J, et al. A pilot open label, single dose trial of fenobam in adults with fragile X syndrome. J Med Genet (2009) 46(4):266-71. doi:10.1136/jmg.2008.063701