Probing heterotrimeric G protein activation: Applications to biased ligands

Current Pharmaceutical Design

Volumn 18, Issue 2, 2012, Pages 128-144

  Denis, Colette ^a   Saulière, Aude ^a   Galandrin, Ségolène ^b   Sénard, Jean Michel ^a   Galés, Céline ^a  

^a University Hospital of Toulouse   (France)

^b INSTITUT DE PHARMACOLOGIE ET DE BIOLOGIE STRUCTURALE   (France)

Author keywords

Biased agonist; G protein; G protein sensors; GPCRs; Ligand efficacy; Ligand directed trafficking; Signaling pathways

Indexed keywords

BACTERIAL TOXIN; CYCLIC AMP; G PROTEIN COUPLED RECEPTOR; GUANINE NUCLEOTIDE BINDING PROTEIN; PASTEURELLA MULTOCIDA TOXIN; PERTUSSIS TOXIN; PROTEIN C; PROTEIN INHIBITOR; PROTEIN KINASE C; QS 3666; UNCLASSIFIED DRUG; YM 254890;

BIOLUMINESCENCE RESONANCE ENERGY TRANSFER; CALCIUM CELL LEVEL; CALCIUM MOBILIZATION; CELL MEMBRANE; CELL MIGRATION; CELL SURFACE; CROSS LINKING; CYTOLOGY; DRUG DEVELOPMENT; ENZYME ACTIVATION; ENZYME ACTIVITY; FLUORESCENCE RESONANCE ENERGY TRANSFER; GENETIC TRANSFECTION; HIGH THROUGHPUT SCREENING; HUMAN; LIGAND BINDING; MOLECULAR PROBE; NONHUMAN; PLASMON WAVEGUIDE RESONANCE; PLEIOTROPY; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN DETERMINATION; PROTEIN FAMILY; PROTEIN HYDROLYSIS; PROTEIN INTERACTION; PROTEIN STRUCTURE; RECEPTOR OCCUPANCY; REVIEW; SENSOR; SEQUENCE HOMOLOGY; SIGNAL TRANSDUCTION; SURFACE PLASMON RESONANCE;

ANIMALS; DRUG DISCOVERY; HETEROTRIMERIC GTP-BINDING PROTEINS; HUMANS; LIGANDS; RECEPTOR CROSS-TALK; RECEPTORS, G-PROTEIN-COUPLED; SIGNAL TRANSDUCTION;

EID: 84856414025     PISSN: 13816128     EISSN: 18734286     Source Type: Journal    
DOI: 10.2174/138161212799040466     Document Type: Review

References (160)

1. Hopkins AL, Groom CR. The druggable genome. Nat Rev Drug Discov 2002; 1: 727-30.
2. Vassilatis DK, Hohmann JG, Zeng H, et al. The G protein-coupled receptor repertoires of human and mouse. Proc Natl Acad Sci USA 2003; 100: 4903-8.
3. Jacoby E, Bouhelal R, Gerspacher M, Seuwen K. The 7 TM Gprotein-coupled receptor target family. ChemMedChem 2006; 1: 761-82.
4. Ritter SL, Hall RA. Fine-tuning of GPCR activity by receptorinteracting proteins. Nat Rev Mol Cell Biol 2009; 10: 819-30.
5. Kenakin T. Agonist-receptor efficacy. II. Agonist trafficking of receptor signals. Trends Pharmacol Sci 1995; 16: 232-8.
6. Kenakin T. Functional selectivity through protean and biased agonism: who steers the ship? Mol Pharmacol 2007; 72: 1393-401.
7. Galandrin S, Oligny-Longpre G, Bouvier M. The evasive nature of drug efficacy: implications for drug discovery. Trends Pharmacol Sci 2007; 28: 423-30.
8. Gilman AG. G proteins: transducers of receptor-generated signals. Annu Rev Biochem 1987; 56: 615-49.
9. Rodbell M. The role of hormone receptors and GTP-regulatory proteins in membrane transduction. Nature 1980; 284: 17-22.
10. McIntire WE. Structural determinants involved in the formation and activation of G protein betagamma dimers. Neurosignals 2009; 17: 82-99.
11. Hynes TR, Mervine SM, Yost EA, Sabo JL, Berlot CH. Live cell imaging of Gs and the beta2-adrenergic receptor demonstrates that both alphas and beta1gamma7 internalize upon stimulation and exhibit similar trafficking patterns that differ from that of the beta2-adrenergic receptor. J Biol Chem 2004; 279: 44101-12.
12. Oldham WM, Hamm HE. Heterotrimeric G protein activation by G-protein-coupled receptors. Nat Rev Mol Cell Biol 2008; 9: 60-71.
13. Iiri T, Farfel Z, Bourne HR. G-protein diseases furnish a model for the turn-on switch. Nature 1998; 394: 35-8.
14. Hamm HE. The many faces of G protein signaling. J Biol Chem 1998; 273: 669-72.
15. Wall MA, Coleman DE, Lee E, et al. The structure of the G protein heterotrimer Gi alpha 1 beta 1 gamma 2. Cell 1995; 83: 1047-58.
16. Lambright DG, Sondek J, Bohm A, Skiba NP, Hamm HE, Sigler PB. The 2.0 A crystal structure of a heterotrimeric G protein. Nature 1996; 379: 311-9.
17. Michaelson D, Ahearn I, Bergo M, Young S, Philips M. Membrane trafficking of heterotrimeric G proteins via the endoplasmic reticulum and Golgi. Mol Biol Cell 2002; 13: 3294-302.
18. Bourne HR. How receptors talk to trimeric G proteins. Curr Opin Cell Biol 1997; 9: 134-42.
19. Bourne HR, Sanders DA, McCormick F. The GTPase superfamily: conserved structure and molecular mechanism. Nature 1991; 349: 117-27.
20. Gales C, Van Durm JJ, Schaak S, et al. Probing the activationpromoted structural rearrangements in preassembled receptor-G protein complexes. Nat Struct Mol Biol 2006; 13: 778-86.
21. Bunemann M, Frank M, Lohse MJ. Gi protein activation in intact cells involves subunit rearrangement rather than dissociation. Proc Natl Acad Sci USA 2003; 100: 16077-82.
22. Sato M, Blumer JB, Simon V, Lanier SM. Accessory proteins for G proteins: partners in signaling. Annu Rev Pharmacol Toxicol 2006; 46: 151-87.
23. Siderovski DP, Willard FS. The GAPs, GEFs, and GDIs of heterotrimeric G-protein alpha subunits. Int J Biol Sci 2005; 1: 51-66.
24. Ross EM, Wilkie TM. GTPase-activating proteins for heterotrimeric G proteins: regulators of G protein signaling (RGS) and RGS-like proteins. Annu Rev Biochem 2000; 69: 795-827.
25. Cabrera-Vera TM, Vanhauwe J, Thomas TO, et al. Insights into G protein structure, function, and regulation. Endocr Rev 2003; 24: 765-81.
26. Milligan G, Kostenis E. Heterotrimeric G-proteins: a short history. Br J Pharmacol 2006; 147 Suppl 1: S46-55.
27. Dupre DJ, Robitaille M, Rebois RV, Hebert TE. The role of Gbetagamma subunits in the organization, assembly, and function of GPCR signaling complexes. Annu Rev Pharmacol Toxicol 2009; 49: 31-56.
28. Navarro-Olmos R, Kawasaki L, Dominguez-Ramirez L, Ongay-Larios L, Perez-Molina R, Coria R. The beta subunit of the heterotrimeric G protein triggers the Kluyveromyces lactis pheromone response pathway in the absence of the gamma subunit. Mol Biol Cell 2010; 21: 489-98.
29. Nakai C, Brooker G. Assay for adenylate cyclase and cyclic nucleotide phosphodiesterases and the preparation of high specific activity 32-P-labeled substrates. Biochim Biophys Acta 1975; 391: 222-39.
30. Steiner AL, Kipnis DM, Utiger R, Parker C. Radioimmunoassay for the measurement of adenosine 3',5'-cyclic phosphate. Proc Natl Acad Sci USA 1969; 64: 367-73.
31. Nikolaev VO, Hoffmann C, Bunemann M, Lohse MJ, Vilardaga JP. Molecular basis of partial agonism at the neurotransmitter alpha2A-adrenergic receptor and Gi-protein heterotrimer. J Biol Chem 2006; 281: 24506-11.
32. Willoughby D, Cooper DM. Live-cell imaging of cAMP dynamics. Nat Methods 2008; 5: 29-36.
33. DiPilato LM, Cheng X, Zhang J. Fluorescent indicators of cAMP and Epac activation reveal differential dynamics of cAMP signaling within discrete subcellular compartments. Proc Natl Acad Sci USA 2004; 101: 16513-8.
34. Zhang J, Ma Y, Taylor SS, Tsien RY. Genetically encoded reporters of protein kinase A activity reveal impact of substrate tethering. Proc Natl Acad Sci USA 2001; 98: 14997-5002.
35. Prinz A, Diskar M, Erlbruch A, Herberg FW. Novel, isotypespecific sensors for protein kinase A subunit interaction based on bioluminescence resonance energy transfer (BRET). Cell Signal 2006; 18: 1616-25.
36. Pantel J, Williams SY, Mi D, et al. Development of a high throughput screen for allosteric modulators of melanocortin-4 receptor signaling using a real time cAMP assay. Eur J Pharmacol 2011.
37. Tesmer JJ, Sunahara RK, Gilman AG, Sprang SR. Crystal structure of the catalytic domains of adenylyl cyclase in a complex with Gsalpha. GTPgammaS. Science 1997; 278: 1907-16.
38. Ghahremani MH, Cheng P, Lembo PM, Albert PR. Distinct roles for Galphai2, Galphai3, and Gbeta gamma in modulation offorskolin-or Gs-mediated cAMP accumulation and calcium mobilization by dopamine D2S receptors. J Biol Chem 1999; 274: 9238-45.
39. Sutkowski EM, Tang WJ, Broome CW, Robbins JD, Seamon KB. Regulation of forskolin interactions with type I, II, V, and VI adenylyl cyclases by Gs alpha. Biochemistry 1994; 33: 12852-9.
40. Conklin BR, Farfel Z, Lustig KD, Julius D, Bourne HR. Substitution of three amino acids switches receptor specificity of Gq alpha to that of Gi alpha. Nature 1993; 363: 274-6.
41. Offermanns S, Simon MI. G alpha 15 and G alpha 16 couple a wide variety of receptors to phospholipase C. J Biol Chem 1995; 270: 15175-80.
42. Mody SM, Ho MK, Joshi SA, Wong YH. Incorporation of Galpha(z)-specific sequence at the carboxyl terminus increases the promiscuity of galpha(16) toward G(i)-coupled receptors. Mol Pharmacol 2000; 57: 13-23.
43. Hazari A, Lowes V, Chan JH, Wong CS, Ho MK, Wong YH. Replacement of the alpha5 helix of Galpha16 with Galphas-specific sequences enhances promiscuity of Galpha16 toward Gs-coupled receptors. Cell Signal 2004; 16: 51-62.
44. Liu AM, Ho MK, Wong CS, Chan JH, Pau AH, Wong YH. Galpha(16/z) chimeras efficiently link a wide range of G proteincoupled receptors to calcium mobilization. J Biomol Screen 2003; 8: 39-49.
45. Heydorn A, Ward RJ, Jorgensen R, et al. Identification of a novel site within G protein alpha subunits important for specificity of receptor-G protein interaction. Mol Pharmacol 2004; 66: 250-9.
46. Kostenis E, Martini L, Ellis J, et al. A highly conserved glycine within linker I and the extreme C terminus of G protein alpha subunits interact cooperatively in switching G protein-coupled receptor-to-effector specificity. J Pharmacol Exp Ther 2005; 313: 78-87.
47. Selvam C, Oueslati N, Lemasson IA, et al. A virtual screening hit reveals new possibilities for developing group III metabotropic glutamate receptor agonists. J Med Chem 2010; 53: 2797-813.
48. Kostenis E, Waelbroeck M, Milligan G. Techniques: promiscuous Galpha proteins in basic research and drug discovery. Trends Pharmacol Sci 2005; 26: 595-602.
49. De Vivo M. Assays for G-protein regulation of phospholipase C activity. Methods Enzymol 1994; 238: 131-40.
50. Mullinax TR, Henrich G, Kasila P, et al. Monitoring Inositol-Specific Phospholipase C Activity Using a Phospholipid Flash-Plate(R). J Biomol Screen 1999; 4: 151-5.
51. Dangelmaier CA, Daniel JL, Smith JB. Determination of basal and stimulated levels of inositol triphosphate in [32P]orthophosphatelabeled platelets. Anal Biochem 1986; 154: 414-9.
52. Barker CJ, Berggren PO. The role of inositol and the principles of labelling, extraction, and analysis of inositides in mammalian cells. Methods Mol Biol 2010; 645: 1-19.
53. Sauer K, Huang YH, Lin H, Sandberg M, Mayr GW. Phosphoinositide and inositol phosphate analysis in lymphocyte activation. Curr Protoc Immunol 2009; Chapter 11: Unit11 1.
54. Eglen RM. Functional G protein-coupled receptor assays for primary and secondary screening. Comb Chem High Throughput Screen 2005; 8: 311-8.
55. Trinquet E, Fink M, Bazin H, et al. D-myo-inositol 1-phosphate as a surrogate of D-myo-inositol 1,4,5-tris phosphate to monitor G protein-coupled receptor activation. Anal Biochem 2006; 358: 126-35.
56. Paredes RM, Etzler JC, Watts LT, Zheng W, Lechleiter JD. Chemical calcium indicators. Methods 2008; 46: 143-51.
57. Shimomura O, Johnson FH, Saiga Y. Extraction, purification and properties of aequorin, a bioluminescent protein from the luminous hydromedusan, Aequorea. J Cell Comp Physiol 1962; 59: 223-39.
58. Pinton P, Rimessi A, Romagnoli A, Prandini A, Rizzuto R. Biosensors for the detection of calcium and pH. Methods Cell Biol 2007; 80: 297-325.
59. Miyawaki A, Llopis J, Heim R, et al. Fluorescent indicators for Ca2+ based on green fluorescent proteins and calmodulin. Nature 1997; 388: 882-7.
60. Demaurex N. Calcium measurements in organelles with Ca2+-sensitive fluorescent proteins. Cell Calcium 2005; 38: 213-22.
61. Palmer AE, Tsien RY. Measuring calcium signaling using genetically targetable fluorescent indicators. Nat Protoc 2006; 1: 1057-65.
62. Riobo NA, Manning DR. Receptors coupled to heterotrimeric G proteins of the G12 family. Trends Pharmacol Sci 2005; 26: 146-54.
63. Worzfeld T, Wettschureck N, Offermanns S. G(12)/G(13)-mediated signalling in mammalian physiology and disease. Trends Pharmacol Sci 2008; 29: 582-9.
64. Regard JB, Kataoka H, Cano DA, et al. Probing cell type-specific functions of Gi in vivo identifies GPCR regulators of insulin secretion. J Clin Invest 2007; 117: 4034-43.
65. Higashijima T, Uzu S, Nakajima T, Ross EM. Mastoparan, a peptide toxin from wasp venom, mimics receptors by activating GTP-binding regulatory proteins (G proteins). J Biol Chem 1988; 263: 6491-4.
66. Sukumar M, Ross EM, Higashijima T. A Gs-selective analog of the receptor-mimetic peptide mastoparan binds to Gs alpha in a kinked helical conformation. Biochemistry 1997; 36: 3632-9.
67. Van Dop C, Tsubokawa M, Bourne HR, Ramachandran J. Amino acid sequence of retinal transducin at the site ADP-ribosylated by cholera toxin. J Biol Chem 1984; 259: 696-8.
68. Northup JK, Sternweis PC, Smigel MD, Schleifer LS, Ross EM, Gilman AG. Purification of the regulatory component of adenylate cyclase. Proc Natl Acad Sci USA 1980; 77: 6516-20.
69. Freissmuth M, Boehm S, Beindl W, et al. Suramin analogues as subtype-selective G protein inhibitors. Mol Pharmacol 1996; 49: 602-11.
70. Hohenegger M, Waldhoer M, Beindl W, et al. Gsalpha-selective G protein antagonists. Proc Natl Acad Sci USA 1998; 95: 346-51.
71. Wilson BA, Zhu X, Ho M, Lu L. Pasteurella multocida toxin activates the inositol triphosphate signaling pathway in Xenopus oocytes via G(q)alpha-coupled phospholipase C-beta1. J Biol Chem 1997; 272: 1268-75.
72. Zywietz A, Gohla A, Schmelz M, Schultz G, Offermanns S. Pleiotropic effects of Pasteurella multocida toxin are mediated by Gqdependent and-independent mechanisms. involvement of Gq but not G11. J Biol Chem 2001; 276: 3840-5.
73. Wilson BA, Ho M. Pasteurella multocida toxin as a tool for studying Gq signal transduction. Rev Physiol Biochem Pharmacol 2004; 152: 93-109.
74. Kawasaki T, Taniguchi M, Moritani Y, et al. Antithrombotic and thrombolytic efficacy of YM-254890, a G q/11 inhibitor, in a rat model of arterial thrombosis. Thromb Haemost 2003; 90: 406-13.
75. Nishimura A, Kitano K, Takasaki J, et al. Structural basis for the specific inhibition of heterotrimeric Gq protein by a small molecule. Proc Natl Acad Sci USA 2010; 107: 13666-71.
76. Ayoub MA, Damian M, Gespach C, et al. Inhibition of heterotrimeric G protein signaling by a small molecule acting on Galpha subunit. J Biol Chem 2009; 284: 29136-45.
77. Rasenick MM, Watanabe M, Lazarevic MB, Hatta S, Hamm HE. Synthetic peptides as probes for G protein function. Carboxylterminal G alpha s peptides mimic Gs and evoke high affinity agonist binding to beta-adrenergic receptors. J Biol Chem 1994; 269: 21519-25.
78. Gilchrist A, Vanhauwe JF, Li A, Thomas TO, Voyno-Yasenetskaya T, Hamm HE. G alpha minigenes expressing C-terminal peptides serve as specific inhibitors of thrombin-mediated endothelial activation. J Biol Chem 2001; 276: 25672-9.
79. Gilchrist A, Li A, Hamm HE. G alpha COOH-terminal minigene vectors dissect heterotrimeric G protein signaling. Sci STKE 2002; 2002: pl1.
80. Atwood BK, Lopez J, Wager-Miller J, Mackie K, Straiker A. Expression of G protein-coupled receptors and related proteins in HEK293, AtT20, BV2, and N18 cell lines as revealed by microarray analysis. BMC Genomics 2011; 12: 14.
81. Wettschureck N, Moers A, Offermanns S. Mouse models to study G-protein-mediated signaling. Pharmacol Ther 2004; 101: 75-89.
82. Krumins AM, Gilman AG. Targeted knockdown of G protein subunits selectively prevents receptor-mediated modulation of effectors and reveals complex changes in non-targeted signaling proteins. J Biol Chem 2006; 281: 10250-62.
83. Hilf G, Gierschik P, Jakobs KH. Muscarinic acetylcholine receptorstimulated binding of guanosine 5'-O-(3-thiotriphosphate) to guanine-nucleotide-binding proteins in cardiac membranes. Eur J Biochem 1989; 186: 725-31.
84. Wieland T, Liedel K, Kaldenberg-Stasch S, Meyer zu Heringdorf D, Schmidt M, Jakobs KH. Analysis of receptor-G protein interactions in permeabilized cells. Naunyn Schmiedebergs Arch Pharmacol 1995; 351: 329-36.
85. Sim LJ, Selley DE, Childers SR. In vitro autoradiography of receptor-activated G proteins in rat brain by agonist-stimulated guanylyl 5'-[gamma-[35S]thio]-triphosphate binding. Proc Natl Acad Sci USA 1995; 92: 7242-6.
86. Harrison C, Traynor JR. The [35S]GTPgammaS binding assay: approaches and applications in pharmacology. Life Sci 2003; 74: 489-508.
87. Newman-Tancredi A, Conte C, Chaput C, Verriele L, Millan MJ. Agonist and inverse agonist efficacy at human recombinant serotonin 5-HT1A receptors as a function of receptor:G-protein stoichiometry. Neuropharmacology 1997; 36: 451-9.
88. Barr AJ, Brass LF, Manning DR. Reconstitution of receptors and GTP-binding regulatory proteins (G proteins) in Sf9 cells. A direct evaluation of selectivity in receptor. G protein coupling. J Biol Chem 1997; 272: 2223-9.
89. Seifert R, Lee TW, Lam VT, Kobilka BK. Reconstitution of beta2-adrenoceptor-GTP-binding-protein interaction in Sf9 cells--high coupling efficiency in a beta2-adrenoceptor-G(s alpha) fusion protein. Eur J Biochem 1998; 255: 369-82.
90. Kenakin T. Ligand-selective receptor conformations revisited: the promise and the problem. Trends Pharmacol Sci 2003; 24: 346-54.
91. Pauwels PJ, Rauly I, Wurch T, Colpaert FC. Evidence for protean agonism of RX 831003 at alpha 2A-adrenoceptors by coexpression with different G alpha protein subunits. Neuropharmacology 2002; 42: 855-63.
92. Windh RT, Lee MJ, Hla T, An S, Barr AJ, Manning DR. Differential coupling of the sphingosine 1-phosphate receptors Edg-1, Edg-3, and H218/Edg-5 to the G(i), G(q), and G(12) families of heterotrimeric G proteins. J Biol Chem 1999; 274: 27351-8.
93. McLean AJ, Zeng FY, Behan D, Chalmers D, Milligan G. Generation and analysis of constitutively active and physically destabilized mutants of the human beta(1)-adrenoceptor. Mol Pharmacol 2002; 62: 747-55.
94. DeLapp NW. The antibody-capture [(35)S]GTPgammaS scintillation proximity assay: a powerful emerging technique for analysis of GPCR pharmacology. Trends Pharmacol Sci 2004; 25: 400-1.
95. Johnson EN, Shi X, Cassaday J, Ferrer M, Strulovici B, Kunapuli P. A 1,536-well [(35)S]GTPgammaS scintillation proximity binding assay for ultra-high-throughput screening of an orphan galphaicoupled GPCR. Assay Drug Dev Technol 2008; 6: 327-37.
96. Frang H, Mukkala VM, Syysto R, et al. Nonradioactive GTP binding assay to monitor activation of g protein-coupled receptors. Assay Drug Dev Technol 2003; 1: 275-80.
97. Koval A, Kopein D, Purvanov V, Katanaev VL. Europium-labeled GTP as a general nonradioactive substitute for [(35)S]GTPgammaS in high-throughput G protein studies. Anal Biochem 2010; 397: 202-7.
98. McEwen DP, Gee KR, Kang HC, Neubig RR. Fluorescent BODIPY-GTP analogs: real-time measurement of nucleotide binding to G proteins. Anal Biochem 2001; 291: 109-17.
99. Jameson EE, Roof RA, Whorton MR, et al. Real-time detection of basal and stimulated G protein GTPase activity using fluorescent GTP analogues. J Biol Chem 2005; 280: 7712-9.
100. Bertin B, Freissmuth M, Jockers R, Strosberg AD, Marullo S. Cellular signaling by an agonist-activated receptor/Gs alpha fusion protein. Proc Natl Acad Sci USA 1994; 91: 8827-31.
101. Wise A, Carr IC, Milligan G. Measurement of agonist-induced guanine nucleotide turnover by the G-protein Gi1alpha when constrained within an alpha2A-adrenoceptor-Gi1alpha fusion protein. Biochem J 1997; 325 (Pt 1): 17-21.
102. Massotte D, Brillet K, Kieffer B, Milligan G. Agonists activate Gi1 alpha or Gi2 alpha fused to the human mu opioid receptor differently. J Neurochem 2002; 81: 1372-82.
103. Lane JR, Powney B, Wise A, Rees S, Milligan G. Protean agonism at the dopamine D2 receptor: (S)-3-(3-hydroxyphenyl)-Npropylpiperidine is an agonist for activation of Go1 but an antagonist/ inverse agonist for Gi1, Gi2, and Gi3. Mol Pharmacol 2007; 71: 1349-59.
104. Wenzel-Seifert K, Seifert R. Molecular analysis of beta(2)-adrenoceptor coupling to G(s)-, G(i)-, and G(q)-proteins. Mol Pharmacol 2000; 58: 954-66.
105. Milligan G, Parenty G, Stoddart LA, Lane JR. Novel pharmacological applications of G-protein-coupled receptor-G protein fusions. Curr Opin Pharmacol 2007; 7: 521-6.
106. Pascal G, Milligan G. Functional complementation and the analysis of opioid receptor homodimerization. Mol Pharmacol 2005; 68: 905-15.
107. Han Y, Moreira IS, Urizar E, Weinstein H, Javitch JA. Allosteric communication between protomers of dopamine class A GPCR dimers modulates activation. Nat Chem Biol 2009; 5: 688-95.
108. Salamon Z, Macleod HA, Tollin G. Coupled plasmon-waveguide resonators: a new spectroscopic tool for probing proteolipid film structure and properties. Biophys J 1997; 73: 2791-7.
109. Tollin G, Salamon Z, Hruby VJ. Techniques: plasmon-waveguide resonance (PWR) spectroscopy as a tool to study ligand-GPCR interactions. Trends Pharmacol Sci 2003; 24: 655-9.
110. Alves ID, Salamon Z, Varga E, Yamamura HI, Tollin G, Hruby VJ. Direct observation of G-protein binding to the human delta-opioid receptor using plasmon-waveguide resonance spectroscopy. J Biol Chem 2003; 278: 48890-7.
111. Salamon Z, Tollin G, Alves I, Hruby V. Chapter 6. Plasmon resonance methods in membrane protein biology applications to GPCR signaling. Methods Enzymol 2009; 461: 123-46.
112. Devanathan S, Yao Z, Salamon Z, Kobilka B, Tollin G. Plasmonwaveguide resonance studies of ligand binding to the human beta 2-adrenergic receptor. Biochemistry 2004; 43: 3280-8.
113. Alves ID, Delaroche D, Mouillac B, et al. The two NK-1 binding sites correspond to distinct, independent, and non-interconvertible receptor conformational states as confirmed by plasmon-waveguide resonance spectroscopy. Biochemistry 2006; 45: 5309-18.
114. Georgieva T, Devanathan S, Stropova D, et al. Unique agonistbound cannabinoid CB1 receptor conformations indicate agonist specificity in signaling. Eur J Pharmacol 2008; 581: 19-29.
115. Förster T. Naturwissenschaften 1946; 6: 166-75.
116. Boute N, Jockers R, Issad T. The use of resonance energy transfer in high-throughput screening: BRET versus FRET. Trends Pharmacol Sci 2002; 23: 351-4.
117. Pfleger KD, Eidne KA. Monitoring the formation of dynamic Gprotein-coupled receptor-protein complexes in living cells. Biochem J 2005; 385: 625-37.
118. Dacres H, Dumancic MM, Horne I, Trowell SC. Direct comparison of bioluminescence-based resonance energy transfer methods for monitoring of proteolytic cleavage. Anal Biochem 2009; 385: 194-202.
119. Loening AM, Wu AM, Gambhir SS. Red-shifted Renilla reniformis luciferase variants for imaging in living subjects. Nat Methods 2007; 4: 641-3.
120. De A, Loening AM, Gambhir SS. An improved bioluminescence resonance energy transfer strategy for imaging intracellular events in single cells and living subjects. Cancer Res 2007; 67: 7175-83.
121. Gales C, Rebois RV, Hogue M, et al. Real-time monitoring of receptor and G-protein interactions in living cells. Nat Methods 2005; 2: 177-84.
122. Hein P, Frank M, Hoffmann C, Lohse MJ, Bunemann M. Dynamics of receptor/G protein coupling in living cells. Embo J 2005; 24: 4106-14.
123. Audet N, Gales C, Archer-Lahlou E, et al. Bioluminescence resonance energy transfer assays reveal ligand-specific conformational changes within preformed signaling complexes containing deltaopioid receptors and heterotrimeric G proteins. J Biol Chem 2008; 283: 15078-88.
124. Galandrin S, Oligny-Longpre G, Bonin H, Ogawa K, Gales C, Bouvier M. Conformational rearrangements and signaling cascades involved in ligand-biased mitogen-activated protein kinase signaling through the beta1-adrenergic receptor. Mol Pharmacol 2008; 74: 162-72.
125. Ayoub MA, Maurel D, Binet V, et al. Real-time analysis of agonist-induced activation of protease-activated receptor 1/Galphai1 protein complex measured by bioluminescence resonance energy transfer in living cells. Mol Pharmacol 2007; 71: 1329-40.
126. Ayoub MA, Trinquet E, Pfleger KD, Pin JP. Differential association modes of the thrombin receptor PAR1 with Galphai1, Galpha12, and beta-arrestin 1. Faseb J 2010; 24: 3522-35.
127. Janetopoulos C, Jin T, Devreotes P. Receptor-mediated activation of heterotrimeric G-proteins in living cells. Science 2001; 291: 2408-11.
128. Azpiazu I, Gautam N. A fluorescence resonance energy transferbased sensor indicates that receptor access to a G protein is unrestricted in a living mammalian cell. J Biol Chem 2004; 279: 27709-18.
129. Frank M, Thumer L, Lohse MJ, Bunemann M. G Protein activation without subunit dissociation depends on a G{alpha}(i)-specific region. J Biol Chem 2005; 280: 24584-90.
130. Gibson SK, Gilman AG. Gialpha and Gbeta subunits both define selectivity of G protein activation by alpha2-adrenergic receptors. Proc Natl Acad Sci USA 2006; 103: 212-7.
131. Nobles M, Benians A, Tinker A. Heterotrimeric G proteins precouple with G protein-coupled receptors in living cells. Proc Natl Acad Sci USA 2005; 102: 18706-11.
132. Chisari M, Saini DK, Cho JH, Kalyanaraman V, Gautam N. G protein subunit dissociation and translocation regulate cellular response to receptor stimulation. PLoS One 2009; 4: e7797.
133. Lohse MJ, Vilardaga JP, Bunemann M. Direct optical recording of intrinsic efficacy at a G protein-coupled receptor. Life Sci 2003; 74: 397-404.
134. Gao ZG, Jacobson KA. Translocation of arrestin induced by human A(3) adenosine receptor ligands in an engineered cell line: comparison with G protein-dependent pathways. Pharmacol Res 2008; 57: 303-11.
135. Whalen EJ, Rajagopal S, Lefkowitz RJ. Therapeutic potential of beta-arrestin-and G protein-biased agonists. Trends Mol Med 2011; 17: 126-39.
136. Bisello A, Chorev M, Rosenblatt M, Monticelli L, Mierke DF, Ferrari SL. Selective ligand-induced stabilization of active and desensitized parathyroid hormone type 1 receptor conformations. J Biol Chem 2002; 277: 38524-30.
137. Wehbi V, Decourtye J, Piketty V, Durand G, Reiter E, Maurel MC. Selective modulation of follicle-stimulating hormone signaling pathways with enhancing equine chorionic gonadotropin/antibody immune complexes. Endocrinology 2010; 151: 2788-99.
138. Rafei M, Berchiche YA, Birman E, et al. An engineered GM-CSFCCL2 fusokine is a potent inhibitor of CCR2-driven inflammation as demonstrated in a murine model of inflammatory arthritis. J Immunol 2009; 183: 1759-66.
139. Jorgensen R, Kubale V, Vrecl M, Schwartz TW, Elling CE. Oxyntomodulin differentially affects glucagon-like peptide-1 receptor beta-arrestin recruitment and signaling through Galpha(s). J Pharmacol Exp Ther 2007; 322: 148-54.
140. Reversi A, Rimoldi V, Marrocco T, et al. The oxytocin receptor antagonist atosiban inhibits cell growth via a "biased agonist" mechanism. J Biol Chem 2005; 280: 16311-8.
141. Sensken SC, Staubert C, Keul P, Levkau B, Schoneberg T, Graler MH. Selective activation of G alpha i mediated signalling of S1P3 by FTY720-phosphate. Cell Signal 2008; 20: 1125-33.
142. Rajagopal S, Rajagopal K, Lefkowitz RJ. Teaching old receptors new tricks: biasing seven-transmembrane receptors. Nat Rev Drug Discov 2010; 9: 373-86.
143. Wei H, Ahn S, Shenoy SK, et al. 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 USA 2003; 100: 10782-7.
144. Kim IM, Tilley DG, Chen J, et al. Beta-blockers alprenolol and carvedilol stimulate beta-arrestin-mediated EGFR transactivation. Proc Natl Acad Sci USA 2008; 105: 14555-60.
145. Wisler JW, DeWire SM, Whalen EJ, et al. A unique mechanism of beta-blocker action: carvedilol stimulates beta-arrestin signaling. Proc Natl Acad Sci USA 2007; 104: 16657-62.
146. Rajagopal S, Kim J, Ahn S, et al. Beta-arrestin-but not G proteinmediated signaling by the "decoy" receptor CXCR7. Proc Natl Acad Sci USA 2010; 107: 628-32.
147. Verkaar F, van Rosmalen JW, Blomenrohr M, et al. G proteinindependent cell-based assays for drug discovery on seventransmembrane receptors. Biotechnol Annu Rev 2008; 14: 253-74.
148. Drake MT, Violin JD, Whalen EJ, Wisler JW, Shenoy SK, Lefkowitz RJ. beta-arrestin-biased agonism at the beta2-adrenergic receptor. J Biol Chem 2008; 283: 5669-76.
149. Hansen JL, Aplin M, Hansen JT, et al. The human angiotensin AT(1) receptor supports G protein-independent extracellular signalregulated kinase 1/2 activation and cellular proliferation. Eur J Pharmacol 2008; 590: 255-63.
150. Luker KE, Gupta M, Luker GD. Imaging CXCR4 signaling with firefly luciferase complementation. Anal Chem 2008; 80: 5565-73.
151. van Der Lee MM, Bras M, van Koppen CJ, Zaman GJ. beta-Arrestin recruitment assay for the identification of agonists of the sphingosine 1-phosphate receptor EDG1. J Biomol Screen 2008; 13: 986-98.
152. Charest PG, Terrillon S, Bouvier M. Monitoring agonist-promoted conformational changes of beta-arrestin in living cells by intramolecular BRET. EMBO Rep 2005; 6: 334-40.
153. Shukla AK, Violin JD, Whalen EJ, Gesty-Palmer D, Shenoy SK, Lefkowitz RJ. Distinct conformational changes in beta-arrestin report biased agonism at seven-transmembrane receptors. Proc Natl Acad Sci USA 2008; 105: 9988-93.
154. Luttrell LM, Ferguson SS, Daaka Y, et al. Beta-arrestin-dependent formation of beta2 adrenergic receptor-Src protein kinase complexes. Science 1999; 283: 655-61.
155. Ahn S, Shenoy SK, Wei H, Lefkowitz RJ. Differential kinetic and spatial patterns of beta-arrestin and G protein-mediated ERK activation by the angiotensin II receptor. J Biol Chem 2004; 279: 35518-25.
156. Callander GE, Thomas WG, Bathgate RA. Prolonged RXFP1 and RXFP2 signaling can be explained by poor internalization and a lack of beta-arrestin recruitment. Am J Physiol Cell Physiol 2009; 296: C1058-66.
157. Milligan G. Principles: extending the utility of [35S]GTP gamma S binding assays. Trends Pharmacol Sci 2003; 24: 87-90.
158. Leduc M, Breton B, Gales C, et al. Functional selectivity of natural and synthetic prostaglandin EP4 receptor ligands. J Pharmacol Exp Ther 2009; 331: 297-307.
159. Galandrin S, Bouvier M. Distinct signaling profiles of beta1 and beta2 adrenergic receptor ligands toward adenylyl cyclase and mitogen-activated protein kinase reveals the pluridimensionality of efficacy. Mol Pharmacol 2006; 70: 1575-84.
160. Luttrell LM, Lefkowitz RJ. The role of beta-arrestins in the termination and transduction of G-protein-coupled receptor signals. J Cell Sci 2002; 115: 455-65.