Biophysical detection of diversity and bias in GPCR function

Frontiers in Endocrinology

Volumn 5, Issue MAR, 2014, Pages

  Jaeger, Werner C ^a   Armstrong, Stephen P ^a   Hill, Stephen J ^b   Pfleger, Kevin D G ^a,c  

^a UNIVERSITY OF WESTERN AUSTRALIA   (Australia)

^b UNIVERSITY OF NOTTINGHAM   (United Kingdom)

^c Dimerix Bioscience Pty Ltd   (Australia)

Author keywords

Bioluminescence resonance energy transfer; BRET; Fluorescence resonance energy transfer; FRET; GPCR; GPCR HIT; Heteromer; Receptor HIT

Indexed keywords

BETA ARRESTIN 2; CHEMOKINE RECEPTOR CCR2; CHEMOKINE RECEPTOR CCR5; CHEMOKINE RECEPTOR CXCR4; EPIDERMAL GROWTH FACTOR RECEPTOR; G PROTEIN COUPLED RECEPTOR; GREEN FLUORESCENT PROTEIN; GUANOSINE TRIPHOSPHATASE; LIGAND; NANODISC; PROTEIN TYROSINE KINASE; RENILLA LUCIFERIN 2 MONOOXYGENASE; RETINA S ANTIGEN; UBIQUITIN; YELLOW FLUORESCENT PROTEIN;

BIOLUMINESCENCE RESONANCE ENERGY TRANSFER; BIOPHYSICS; BIOSENSOR; CELL MEMBRANE; FLUORESCENCE CORRELATION SPECTROSCOPY; FLUORESCENCE RESONANCE ENERGY TRANSFER; GENETIC COMPLEMENTATION; GENETIC VARIABILITY; HUMAN; LIGAND BINDING; LIGATION; MOLECULAR INTERACTION; NONHUMAN; PROTEIN ANALYSIS; PROTEIN BINDING; PROTEIN DEPHOSPHORYLATION; PROTEIN DETERMINATION; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; REVIEW;

EID: 84901050967     PISSN: None     EISSN: 16642392     Source Type: Journal    
DOI: 10.3389/fendo.2014.00026     Document Type: Review

References (149)

1. Bockaert J, Philippe Pin J. Molecular tinkering of G protein-coupled receptors: an evolutionary success. EMBO J (1999) 18(7):1723-9. doi: 10.1093/emboj/18.7.1723.
2. Wise A, Gearing K, Rees S. Target validation of G-protein coupled receptors. Drug Discov Today (2002) 7(4):235-46. doi:10.1016/s1359-6446(01)02131-6.
3. Dorsam RT, Gutkind JS. G-protein-coupled receptors and cancer. Nat Rev Cancer (2007) 7(2):79-94. doi:10.1038/nrc2069.
4. Wilson S, Bergsma D. Orphan G-protein coupled receptors: novel drug targets for the pharmaceutical industry. Drug Des Discov (2000) 17(2):105-14.
5. Garland SL. Are GPCRs still a source of new targets? J Biomol Screen (2013) 18(9):947-66. doi:10.1177/1087057113498418.
6. Agnati LF, Ferré S, Lluis C, Franco R, Fuxe K. Molecular mechanisms and therapeutical implications of intramembrane receptor/receptor interactions among heptahelical receptors with examples from the striatopallidal GABA neurons. Pharmacol Rev (2003) 55(3):509-50. doi:10.1124/pr.55.3.2.
7. Angers S, Salahpour A, Bouvier M. Dimerization: an emerging concept for G protein-coupled receptor ontogeny and function. Annu Rev Pharmacol Toxicol (2002) 42:409-35. doi:10.1146/annurev.pharmtox.42.091701.082314.
8. Gonzalez-Maeso J. GPCR oligomers in pharmacology and signaling. Mol Brain (2011) 4(1):20. doi:10.1186/1756-6606-4-20.
9. Jones KA, Borowsky B, Tamm JA, Craig DA, Durkin MM, Dai M, et al. GABAB receptors function as a heteromeric assembly of the subunits GABABR1 and GABABR2. Nature (1998) 396(6712):674-9. doi:10.1038/25460.
10. Kaupmann K, Malitschek B, Schuler V, Heid J, Froestl W, Beck P, et al. GABAB-receptor subtypes assemble into functional heteromeric complexes. Nature (1998) 396(6712):683-7. doi:10.1038/25360.
11. White JH, Wise A, Main MJ, Green A, Fraser NJ, Disney GH, et al. Heterodimerization is required for the formation of a functional GABA(B) receptor. Nature (1998) 396(6712):679-82. doi:10.1038/25354.
12. Li X, Staszewski L, Xu H, Durick K, Zoller M, Adler E. Human receptors for sweet and umami taste. Proc Natl Acad Sci U S A (2002) 99(7):4692-6. doi:10.1073/pnas.072090199.
13. Nelson G, Chandrashekar J, Hoon MA, Feng L, Zhao G, Ryba NJ, et al. An amino-acid taste receptor. Nature (2002) 416(6877):199-202. doi:10.1038/nature726.
14. Nelson G, Hoon MA, Chandrashekar J, Zhang Y, Ryba NJ, Zuker CS. Mammalian sweet taste receptors. Cell (2001) 106(3):381-90. doi:10.1016/S0092-8674(01)00451-2.
15. González S, Moreno-Delgado D, Moreno E, Pérez-Capote K, Franco R, Mallol J, et al. Circadian-related heteromerization of adrenergic and dopamine D4 receptors modulates melatonin synthesis and release in the pineal gland. PLoS Biol (2012) 10(6):e1001347. doi:10.1371/journal.pbio.1001347.
16. Kern A, Albarran-Zeckler R, Walsh Heidi E, Smith Roy G. Apo-Ghrelin receptor forms heteromers with DRD2 in hypothalamic neurons and is essential for anorexigenic effects of DRD2 agonism. Neuron (2012) 73(2):317-32. doi:10.1016/j.neuron.2011.10.038.
17. Liu X-Y, Liu Z-C, Sun Y-G, Ross M, Kim S, Tsai F-F, et al. Unidirectional cross-activation of GRPR by MOR1D uncouples itch and analgesia induced by opioids. Cell (2011) 147(2):447-58. doi:10.1016/j.cell.2011.08.043.
18. Rivero-Müller A, Chou Y-Y, Ji I, Lajic S, Hanyaloglu AC, Jonas K, et al. Rescue of defective G protein-coupled receptor function in vivo by intermolecular cooperation. Proc Natl Acad Sci U S A (2010) 107(5):2319-24. doi:10.1073/pnas.0906695106.
19. Fribourg M, Moreno José L, Holloway T, Provasi D, Baki L, Mahajan R, et al. Decoding the signaling of a GPCR heteromeric complex reveals a unifying mechanism of action of antipsychotic drugs. Cell (2011) 147(5):1011-23. doi:10.1016/j.cell.2011.09.055.
20. Costantino CM, Gomes I, Stockton SD, Lim MP, Devi LA. Opioid receptor heteromers in analgesia. Expert Rev Mol Med (2012) 14:e9. doi:10.1017/erm.2012.5.
21. Kroeger KM, Pfleger KDG, Eidne KA. Biophysical and biochemical methods to study GPCR oligomerization. In: Devi LA editor. The G Protein-Coupled Receptors Handbook. Contemporary Clinical Neuroscience. Totowa, NJ: Humana Press (2005). p. 217-41.
22. Dalrymple MB, Pfleger KDG, Eidne KA. G protein-coupled receptor dimers: functional consequences, disease states and drug targets. Pharmacol Ther (2008) 118(3):359-71. doi:10.1016/j.pharmthera.2008.03.004.
23. Rozenfeld R, Devi LA. Exploring a role for heteromerization in GPCR signalling specificity. Biochem J (2010) 433(1):11-8. doi:10.1042/bj20100458.
24. Kamal M, Jockers R. Biological significance of GPCR heteromerization in the neuro-endocrine system. Front Endocrinol (Lausanne) (2011) 2:2. doi:10.3389/fendo.2011.00002.
25. Vischer HF, Watts AO, Nijmeijer S, Leurs R. G protein-coupled receptors: walking hand-in-hand, talking hand-in-hand? Br J Pharmacol (2011) 163(2):246-60. doi:10.1111/j.1476-5381.2011.01229.x.
26. Loening AM, Wu AM, Gambhir SS. Red-shifted Renilla reniformis luciferase variants for imaging in living subjects. Nat Methods (2007) 4(8):641-3. doi:10.1038/nmeth1070.
27. Loening AM, Fenn TD, Wu AM, Gambhir SS. Consensus guided mutagenesis of Renilla luciferase yields enhanced stability and light output. Protein Eng Des Sel (2006) 19(9):391-400. doi:10.1093/protein/gzl023.
28. Hall MP, Unch J, Binkowski BF, Valley MP, Butler BL, Wood MG, et al. Engineered luciferase reporter from a deep sea shrimp utilizing a novel imidazopyrazinone substrate. ACS Chem Biol (2012) 7(11):1848-57. doi:10.1021/cb3002478.
29. Pfleger KDG, Eidne KA. Illuminating insights into protein-protein interactions using bioluminescence resonance energy transfer (BRET). Nat Methods (2006) 3(3):165-74. doi:10.1038/nmeth841.
30. Ayoub MA, Pfleger KDG. Recent advances in bioluminescence resonance energy transfer technologies to study GPCR heteromerization. Curr Opin Pharmacol (2010) 10(1):44-52. doi:10.1016/j.coph.2009.09.012.
31. Jaeger WC, Pfleger KDG, Eidne KA. Monitoring GPCR-protein complexes using bioluminescence resonance energy transfer. In: Poyner DR, Wheatley M, editors. G Protein-Coupled Receptors: Essential Methods. Oxford, UK: Wiley-Blackwell (2010). p. 111-32. doi:10.1002/9780470749210.ch6.
32. Miyawaki A. Development of probes for cellular functions using fluorescent proteins and fluorescence resonance energy transfer. Annu Rev Biochem (2011) 80(1):357-73. doi:10.1146/annurev-biochem-072909-094736.
33. Pfleger KD, Eidne KA. Monitoring the formation of dynamic G-protein-coupled receptor-protein complexes in living cells. Biochem J (2005) 385(Pt 3):625-37. doi:10.1042/BJ20041361.
34. Mustafa S, Hannagan J, Rigby P, Pfleger K, Corry B. Quantitative Förster resonance energy transfer efficiency measurements using simultaneous spectral unmixing of excitation and emission spectra. J Biomed Opt (2013) 18(2):26024. doi:10.1117/1.JBO.18.2.026024.
35. Ciruela F, Vilardaga JP, Fernandez-Duenas V. Lighting up multiprotein complexes: lessons from GPCR oligomerization. Trends Biotechnol (2010) 28(8):407-15. doi:10.1016/j.tibtech.2010.05.002.
36. Madiraju C, Welsh K, Cuddy MP, Godoi PH, Pass I, Ngo T, et al. TR-FRET-based high-throughput screening assay for identification of UBC13 inhibitors. J Biomol Screen (2012) 17(2):163-76. doi:10.1177/1087057111423417.
37. Ward RJ, Pediani JD, Milligan G. Heteromultimerization of cannabinoid CB1 receptor and orexin OX1 receptor generates a unique complex in which both protomers are regulated by orexin A. J Biol Chem (2011) 286(43):37414-28. doi:10.1074/jbc. M111.287649.
38. Doumazane E, Scholler P, Zwier JM, Trinquet E, Rondard P, Pin JP. A new approach to analyze cell surface protein complexes reveals specific heterodimeric metabotropic glutamate receptors. FASEB J (2011) 25(1):66-77. doi:10.1096/fj.10-163147.
39. Pou C, Mannoury la Cour C, Stoddart LA, Millan MJ, Milligan G. Functional homomers and heteromers of dopamine D2L and D3 receptors co-exist at the cell surface. J Biol Chem (2012) 287(12):8864-78. doi:10.1074/jbc. M111.326678.
40. Kuder K, Kiec-Kononowicz K. Fluorescent GPCR ligands as new tools in pharmacology. Curr Med Chem (2008) 15(21):2132-43. doi:10.2174/092986708785747599.
41. Cottet M, Faklaris O, Falco A, Trinquet E, Pin JP, Mouillac B, et al. Fluorescent ligands to investigate GPCR binding properties and oligomerization. Biochem Soc Trans (2013) 41(1):148-53. doi:10.1042/bst20120237.
42. May LT, Bridge LJ, Stoddart LA, Briddon SJ, Hill SJ. Allosteric interactions across native adenosine-A3 receptor homodimers: quantification using single-cell ligand-binding kinetics. FASEB J (2011) 25(10):3465-76. doi:10.1096/fj.11-186296.
43. Albizu L, Cottet M, Kralikova M, Stoev S, Seyer R, Brabet I, et al. Time-resolved FRET between GPCR ligands reveals oligomers in native tissues. Nat Chem Biol (2010) 6(8):587-94. doi:10.1038/nchembio.396.
44. Cottet M, Faklaris O, Maurel D, Scholler P, Doumazane E, Trinquet E, et al. BRET and Time-resolved FRET strategy to study GPCR oligomerization: from cell lines toward native tissues. Front Endocrinol (Lausanne) (2012) 3:92. doi:10.3389/fendo.2012.00092.
45. Gaborit N, Larbouret C, Vallaghe J, Peyrusson F, Bascoul-Mollevi C, Crapez E, et al. Time-resolved fluorescence resonance energy transfer (TR-FRET) to analyze the disruption of EGFR/HER2 dimers: a new method to evaluate the efficiency of targeted therapy using monoclonal antibodies. J Biol Chem (2011) 286(13):11337-45. doi:10.1074/jbc. M111.223503.
46. Watts AO, van Lipzig MM, Jaeger WC, Seeber RM, van Zwam M, Vinet J, et al. Identification and profiling of CXCR3-CXCR4 chemokine receptor heteromer complexes. Br J Pharmacol (2013) 168(7):1662-74. doi:10.1111/bph.12064.
47. Pfleger KD, Seeber RM, Eidne KA. Bioluminescence resonance energy transfer (BRET) for the real-time detection of protein-protein interactions. Nat Protoc (2006) 1(1):337-45. doi:10.1038/nprot.2006.52.
48. Kocan M, Pfleger KD. Study of GPCR-protein interactions by BRET. Methods Mol Biol (2011) 746:357-71. doi:10.1007/978-1-61779-126-0_20.
49. Pfleger KD, Eidne KA. New technologies: bioluminescence resonance energy transfer (BRET) for the detection of real time interactions involving G-protein coupled receptors. Pituitary (2003) 6(3):141-51. doi:10.1023/B:PITU.0000011175.41760.5d.
50. Xu Y, Piston DW, Johnson CH. A bioluminescence resonance energy transfer (BRET) system: application to interacting circadian clock proteins. Proc Natl Acad Sci U S A (1999) 96(1):151-6. doi:10.1073/pnas.96.1.151.
51. Kocan M, Pfleger KD. Detection of GPCR/beta-arrestin interactions in live cells using bioluminescence resonance energy transfer technology. Methods Mol Biol (2009) 552:305-17. doi:10.1007/978-1-60327-317-6_22.
52. Mercier JF, Salahpour A, Angers S, Breit A, Bouvier M. Quantitative assessment of beta 1-and beta 2-adrenergic receptor homo-and heterodimerization by bioluminescence resonance energy transfer. J Biol Chem (2002) 277(47):44925-31. doi:10.1074/jbc. M205767200.
53. Gales C, Rebois RV, Hogue M, Trieu P, Breit A, Hebert TE, et al. Real-time monitoring of receptor and G-protein interactions in living cells. Nat Methods (2005) 2(3):177-84. doi:10.1038/nmeth743.
54. Kocan M, See HB, Sampaio NG, Eidne KA, Feldman BJ, Pfleger KD. Agonist-independent interactions between beta-arrestins and mutant vasopressin type II receptors associated with nephrogenic syndrome of inappropriate antidiuresis. Mol Endocrinol (2009) 23(4):559-71. doi:10.1210/me.2008-0321.
55. Kocan M, Dalrymple MB, Seeber RM, Feldman BJ, Pfleger KD. Enhanced BRET technology for the monitoring of agonist-induced and agonist-independent interactions between GPCRs and beta-Arrestins. Front Endocrinol (Lausanne) (2011) 1:12. doi:10.3389/fendo.2010.00012.
56. Hamdan FF, Audet M, Garneau P, Pelletier J, Bouvier M. High-throughput screening of G protein-coupled receptor antagonists using a bioluminescence resonance energy transfer 1-based beta-arrestin2 recruitment assay. J Biomol Screen (2005) 10(5):463-75. doi:10.1177/1087057105275344.
57. Kocan M, See HB, Seeber RM, Eidne KA, Pfleger KD. Demonstration of improvements to the bioluminescence resonance energy transfer (BRET) technology for the monitoring of G protein-coupled receptors in live cells. J Biomol Screen (2008) 13(9):888-98. doi:10.1177/1087057108324032.
58. Dacres H, Michie M, Wang J, Pfleger KD, Trowell SC. Effect of enhanced Renilla luciferase and fluorescent protein variants on the Förster distance of Bioluminescence resonance energy transfer (BRET). Biochem Biophys Res Commun (2012) 425(3):625-9. doi:10.1016/j.bbrc.2012.07.133.
59. Pfleger KD, Dromey JR, Dalrymple MB, Lim EM, Thomas WG, Eidne KA. Extended bioluminescence resonance energy transfer (eBRET) for monitoring prolonged protein-protein interactions in live cells. Cell Signal (2006) 18(10):1664-70. doi:10.1016/j.cellsig.2006.01.004.
60. Pfleger KD. Analysis of protein-protein interactions using bioluminescence resonance energy transfer. Methods Mol Biol (2009) 574:173-83. doi:10.1007/978-1-60327-321-3_14.
61. Armstrong SP, Seeber RM, Ayoub MA, Feldman BJ, Pfleger KD. Characterization of three vasopressin receptor 2 variants: an apparent polymorphism (V266A) and two loss-of-function mutations (R181C and M311V). PLoS One (2013) 8(6):e65885. doi:10.1371/journal.pone.0065885.
62. Jaeger WC, Seeber RM, Eidne KA, Pfleger KDG. Molecular determinants of orexin receptor-arrestin-ubiquitin complex formation. Br J Pharmacol (2014) 171(2):364-74. doi:10.1111/bph.12481.
63. Levi J, De A, Cheng Z, Gambhir SS. Bisdeoxycoelenterazine derivatives for improvement of bioluminescence resonance energy transfer assays. J Am Chem Soc (2007) 129(39):11900-1. doi:10.1021/ja073936h.
64. Dragulescu-Andrasi A, Chan CT, De A, Massoud TF, Gambhir SS. Bioluminescence resonance energy transfer (BRET) imaging of protein-protein interactions within deep tissues of living subjects. Proc Natl Acad Sci U S A (2011) 108(29):12060-5. doi:10.1073/pnas.1100923108.
65. De A, Ray P, Loening AM, Gambhir SS. BRET3: a red-shifted bioluminescence resonance energy transfer (BRET)-based integrated platform for imaging protein-protein interactions from single live cells and living animals. FASEB J (2009) 23(8):2702-9. doi:10.1096/fj.08-118919.
66. Breton B, Sauvageau E, Zhou J, Bonin H, Le Gouill C, Bouvier M. Multiplexing of multicolor bioluminescence resonance energy transfer. Biophys J (2010) 99(12):4037-46. doi:10.1016/j.bpj.2010.10.025.
67. Breton B, Lagace M, Bouvier M. Combining resonance energy transfer methods reveals a complex between the alpha2A-adrenergic receptor, Gai1β1γ2, and GRK2. FASEB J (2010) 24(12):4733-43. doi:10.1096/fj.10-164061.
68. Kiyokawa E, Aoki K, Nakamura T, Matsuda M. Spatiotemporal regulation of small GTPases as revealed by probes based on the principle of Forster Resonance Energy Transfer (FRET): implications for signaling and pharmacology. Annu Rev Pharmacol Toxicol (2011) 51:337-58. doi:10.1146/annurev-pharmtox-010510-100234.
69. Komatsu N, Aoki K, Yamada M, Yukinaga H, Fujita Y, Kamioka Y, et al. Development of an optimized backbone of FRET biosensors for kinases and GTPases. Mol Biol Cell (2011) 22(23):4647-56. doi:10.1091/mbc. E11-01-0072.
70. Balla A, Erdelyi LS, Soltesz-Katona E, Balla T, Varnai P, Hunyady L. Demonstration of angiotensin II-induced Ras activation in the trans-Golgi network and endoplasmic reticulum using bioluminescence resonance energy transfer-based biosensors. J Biol Chem (2011) 286(7):5319-27. doi:10.1074/jbc. M110.176933.
71. Pfeffer SR. Rab GTPases: specifying and deciphering organelle identity and function. Trends Cell Biol (2001) 11(12):487-91. doi:10.1016/S0962-8924(01)02147-X.
72. Xu C, Peter M, Bouquier N, OllendorffV, Villamil I, Liu J, et al. REV, A BRET-based sensor of ERK activity. Front Endocrinol (Lausanne) (2013) 4:95. doi:10.3389/fendo.2013.00095.
73. Ayoub MA, Damian M, Gespach C, Ferrandis E, Lavergne O, De Wever O, et al. Inhibition of heterotrimeric G protein signaling by a small molecule acting on Galpha subunit. J Biol Chem (2009) 284(42):29136-45. doi:10.1074/jbc. M109.042333.
74. Ayoub MA, Maurel D, Binet V, Fink M, Prezeau L, Ansanay H, 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(5):1329-40. doi:10.1124/mol.106.030304.
75. 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(9):3522-35. doi:10.1096/fj.10-154997.
76. Jiang LI, Collins J, Davis R, Lin K-M, DeCamp D, Roach T, et al. Use of a cAMP BRET sensor to characterize a novel regulation of cAMP by the sphingosine 1-phosphate/G13 pathway. J Biol Chem (2007) 282(14):10576-84. doi:10.1074/jbc. M609695200.
77. Prinz A, Diskar M, Erlbruch A, Herberg FW. Novel, isotype-specific sensors for protein kinase A subunit interaction based on bioluminescence resonance energy transfer (BRET). Cell Signal (2006) 18(10):1616-25. doi:10.1016/j.cellsig.2006.01.013.
78. Salahpour A, Espinoza S, Masri B, Lam V, Barak L, Gainetdinov Raul R. BRET biosensors to study GPCR biology, pharmacology and signal transduction. Front Endocrinol (Lausanne) (2012) 3:105. doi:10.3389/fendo.2012.00105.
79. Dacres H, Wang J, Leitch V, Horne I, Anderson AR, Trowell SC. Greatly enhanced detection of a volatile ligand at femtomolar levels using bioluminescence resonance energy transfer (BRET). Biosens Bioelectron (2011) 29(1):119-24. doi:10.1016/j.bios.2011.08.004.
80. Degorce F, Card A, Soh S, Trinquet E, Knapik GP, Xie B. HTRF: a technology tailored for drug discovery-a review of theoretical aspects and recent applications. Curr Chem Genomics (2009) 3:22-32. doi:10.2174/1875397300903010022.
81. Trinquet E, Bouhelal R, Dietz M. Monitoring Gq-coupled receptor response through inositol phosphate quantification with the IP-One assay. Expert Opin Drug Discov (2011) 6(10):981-94. doi:10.1517/17460441.2011.608658.
82. Trinquet E, Fink M, Bazin H, Grillet F, Maurin F, Bourrier E, 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(1):126-35. doi:10.1016/j.ab.2006.08.002.
83. Perroy J, Pontier S, Charest PG, Aubry M, Bouvier M. Real-time monitoring of ubiquitination in living cells by BRET. Nat Methods (2004) 1(3):203-8. doi:10.1038/nmeth722.
84. Dalrymple MB, Jaeger WC, Eidne KA, Pfleger KD. Temporal profiling of orexin receptor-arrestin-ubiquitin complexes reveals differences between receptor subtypes. J Biol Chem (2011) 286(19):16726-33. doi:10.1074/jbc. M111.223537.
85. Ferre S, Baler R, Bouvier M, Caron MG, Devi LA, Durroux T, et al. Building a new conceptual framework for receptor heteromers. Nat Chem Biol (2009) 5(3):131-4. doi:10.1038/nchembio0309-131.
86. See HB, Seeber RM, Kocan M, Eidne KA, Pfleger KD. Application of G protein-coupled receptor-heteromer identification technology to monitor beta-arrestin recruitment to G protein-coupled receptor heteromers. Assay Drug Dev Technol (2011) 9(1):21-30. doi:10.1089/adt.2010.0336.
87. Johnstone EKM, Pfleger K. Receptor-Heteromer Investigation Technology and its application using BRET. Front Endocrinol (Lausanne) (2012) 3:101. doi:10.3389/fendo.2012.00101.
88. Ayoub MA, See HB, Seeber RM, Armstrong SP, Pfleger KD. Profiling epidermal growth factor receptor and heregulin receptor 3 heteromerization using receptor tyrosine kinase heteromer investigation technology. PLoS One (2013) 8(5):e64672. doi:10.1371/journal.pone.0064672.
89. Mustafa S, Ayoub MA, Pfleger KDG. Uncovering GPCR heteromer-biased ligands. Drug Discov Today Technol (2010) 7(1):e77-85. doi:10.1016/j.ddtec.2010.06.003.
90. Porrello ER, Pfleger KDG, Seeber RM, Qian H, Oro C, Abogadie F, et al. Heteromerization of angiotensin receptors changes trafficking and arrestin recruitment profiles. Cell Signal (2011) 23(11):1767-76. doi:10.1016/j.cellsig.2011.06.011.
91. Mustafa S, Pfleger KDG. G protein-coupled receptor heteromer identification technology: identification and profiling of GPCR heteromers. J Lab Autom (2011) 16(4):285-91. doi:10.1016/j.jala.2011.03.002.
92. Mustafa S, See HB, Seeber RM, Armstrong SP, White CW, Ventura S, et al. Identification and profiling of a novel a1A-adrenoceptor-CXC chemokine receptor 2 heteromer. J Biol Chem (2012) 287(16):12952-65. doi:10.1074/jbc. M111.322834.
93. Michel MC, Vrydag W. a1-, a2-and β-adrenoceptors in the urinary bladder, urethra and prostate. Br J Pharmacol (2006) 147(S2):S88-119. doi:10.1038/sj.bjp.0706619.
94. Stanasila L, Abuin L, Dey J, Cotecchia S. Different internalization properties of the alpha1a-and alpha1b-adrenergic receptor subtypes: the potential role of receptor interaction with beta-arrestins and AP50. Mol Pharmacol (2008) 74(3):562-73. doi:10.1124/mol.107.043422.
95. Hennenberg M, Schlenker B, Roosen A, Strittmatter F, Walther S, Stief C, et al. Beta-arrestin-2 is expressed in human prostate smooth muscle and a binding partner of alpha1A-adrenoceptors. World J Urol (2011) 29(2):157-63. doi:10.1007/s00345-010-0634-3.
96. Morell M, Ventura S, Aviles FX. Protein complementation assays: approaches for the in vivo analysis of protein interactions. FEBS Lett (2009) 583(11):1684-91. doi:10.1016/j.febslet.2009.03.002.
97. Remy I, Michnick SW. A highly sensitive protein-protein interaction assay based on Gaussia luciferase. Nat Methods (2006) 3(12):977-9. doi:10.1038/nmeth979.
98. Michnick SW, Ear PH, Manderson EN, Remy I, Stefan E. Universal strategies in research and drug discovery based on protein-fragment complementation assays. Nat Rev Drug Discov (2007) 6(7):569-82. doi:10.1038/nrd2311.
99. Rose RH, Briddon SJ, Holliday ND. Bimolecular fluorescence complementation: lighting up seven transmembrane domain receptor signalling networks. Br J Pharmacol (2010) 159(4):738-50. doi:10.1111/j.1476-5381.2009.00480.x.
100. Remy I, Michnick SW. Application of protein-fragment complementation assays in cell biology. Biotechniques (2007) 42(2):137. doi:10.2144/000112396 139, 141 passim,.
101. Morell M, Espargaro A, Aviles FX, Ventura S. Study and selection of in vivo protein interactions by coupling bimolecular fluorescence complementation and flow cytometry. Nat Protoc (2008) 3(1):22-33. doi:10.1038/nprot.2007.496.
102. Gandia J, Galino J, Amaral OB, Soriano A, Lluís C, Franco R, et al. Detection of higher-order G protein-coupled receptor oligomers by a combined BRET-BiFC technique. FEBS Lett (2008) 582(20):2979-84. doi:10.1016/j.febslet.2008.07.045.
103. Urizar E, Yano H, Kolster R, Gales C, Lambert N, Javitch JA. CODA-RET reveals functional selectivity as a result of GPCR heteromerization. Nat Chem Biol (2011) 7(9):624-30. doi:10.1038/nchembio.623.
104. Guo W, Urizar E, Kralikova M, Mobarec JC, Shi L, Filizola M, et al. Dopamine D2 receptors form higher order oligomers at physiological expression levels. EMBO J (2008) 27(17):2293-304. doi:10.1038/emboj.2008.153.
105. Carriba P, Navarro G, Ciruela F, Ferre S, Casado V, Agnati L, et al. Detection of heteromerization of more than two proteins by sequential BRET-FRET. Nat Methods (2008) 5(8):727-33. doi:10.1038/nmeth.1229.
106. Cabello N, Gandía J, Bertarelli DCG, Watanabe M, Lluís C, Franco R, et al. Metabotropic glutamate type 5, dopamine D2 and adenosine A2a receptors form higher-order oligomers in living cells. J Neurochem (2009) 109(5):1497-507. doi:10.1111/j.1471-4159.2009.06078.x.
107. Soderberg O, Gullberg M, Jarvius M, Ridderstrale K, Leuchowius KJ, Jarvius J, et al. Direct observation of individual endogenous protein complexes in situ by proximity ligation. Nat Methods (2006) 3(12):995-1000. doi:10.1038/nmeth947.
108. Weibrecht I, Leuchowius KJ, Clausson CM, Conze T, Jarvius M, Howell WM, et al. Proximity ligation assays: a recent addition to the proteomics toolbox. Expert Rev Proteomics (2010) 7(3):401-9. doi:10.1586/epr.10.10.
109. TrifilieffP, Rives ML, Urizar E, Piskorowski RA, Vishwasrao HD, Castrillon J, et al. Detection of antigen interactions ex vivo by proximity ligation assay: endogenous dopamine D2-adenosine A2A receptor complexes in the striatum. Biotechniques (2011) 51(2):111-8. doi:10.2144/000113719.
110. Borroto-Escuela DO, Craenenbroeck KV, Romero-Fernandez W, Guidolin D, Woods AS, Rivera A, et al. Dopamine D2 and D4 receptor heteromerization and its allosteric receptor-receptor interactions. Biochem Biophys Res Commun (2011) 404(4):928-34. doi:10.1016/j.bbrc.2010.12.083.
111. Parhamifar L, Sime W, Yudina Y, Vilhardt F, Mörgelin M, Sjölander A. Ligand-induced tyrosine phosphorylation of cysteinyl leukotriene receptor 1 triggers internalization and signaling in intestinal epithelial cells. PLoS One (2010) 5(12):e14439. doi:10.1371/journal.pone.0014439.
112. Kenakin T, Miller LJ. Seven transmembrane receptors as shapeshifting proteins: the impact of allosteric modulation and functional selectivity on new drug discovery. Pharmacol Rev (2010) 62(2):265-304. doi:10.1124/pr.108.000992.
113. Kenakin TP. Biased signalling and allosteric machines: new vistas and challenges for drug discovery. Br J Pharmacol (2012) 165(6):1659-69. doi:10.1111/j.1476-5381.2011.01749.x.
114. Williams C, Hill SJ. GPCR signaling: understanding the pathway to successful drug discovery. Methods Mol Biol (2009) 552:39-50. doi:10.1007/978-1-60327-317-6_3.
115. Baker JG, Adams LA, Salchow K, Mistry SN, Middleton RJ, Hill SJ, et al. Synthesis and characterization of high-affinity 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene-labeled fluorescent ligands for human beta-adrenoceptors. J Med Chem (2011) 54(19):6874-87. doi:10.1021/jm2008562.
116. Baker JG, Hall IP, Hill SJ. Pharmacology and direct visualisation of BODIPY-TMR-CGP: a long-acting fluorescent beta2-adrenoceptor agonist. Br J Pharmacol (2003) 139(2):232-42. doi:10.1038/sj.bjp.0705287.
117. Briddon SJ, Middleton RJ, Yates AS, George MW, Kellam B, Hill SJ. Application of fluorescence correlation spectroscopy to the measurement of agonist binding to a G-protein coupled receptor at the single cell level. Faraday Discuss (2004) 126:197-207. doi:10.1039/b307407b discussion 45-54,.
118. Daly CJ, Parmryd I, McGrath JC. Visualization and analysis of vascular receptors using confocal laser scanning microscopy and fluorescent ligands. Methods Mol Biol (2012) 897:95-107. doi:10.1007/978-1-61779-909-9_5.
119. Middleton RJ, Briddon SJ, Cordeaux Y, Yates AS, Dale CL, George MW, et al. New fluorescent adenosine A1-receptor agonists that allow quantification of ligand-receptor interactions in microdomains of single living cells. J Med Chem (2007) 50(4):782-93. doi:10.1021/jm061279i.
120. Briddon SJ, Middleton RJ, Cordeaux Y, Flavin FM, Weinstein JA, George MW, et al. Quantitative analysis of the formation and diffusion of A1-adenosine receptor-antagonist complexes in single living cells. Proc Natl Acad Sci U S A (2004) 101(13):4673-8. doi:10.1073/pnas.0400420101.
121. Corriden R, Self T, Akong-Moore K, Nizet V, Kellam B, Briddon SJ, et al. Adenosine-A3 receptors in neutrophil microdomains promote the formation of bacteria-tethering cytonemes. EMBO Rep (2013) 14(8):726-32. doi:10.1038/embor.2013.89.
122. Vernall AJ, Stoddart LA, Briddon SJ, Hill SJ, Kellam B. Highly potent and selective fluorescent antagonists of the human adenosine A(3) receptor based on the 1,2,4-triazolo[4,3-a]quinoxalin-1-one scaffold. J Med Chem (2012) 55(4):1771-82. doi:10.1021/jm201722y.
123. Stoddart LA, Vernall AJ, Denman JL, Briddon SJ, Kellam B, Hill SJ. Fragment screening at adenosine-A(3) receptors in living cells using a fluorescence-based binding assay. Chem Biol (2012) 19(9):1105-15. doi:10.1016/j.chembiol.2012.07.014.
124. May LT, Briddon SJ, Hill SJ. Antagonist selective modulation of adenosine A1 and A3 receptor pharmacology by the food dye Brilliant Black BN: evidence for allosteric interactions. Mol Pharmacol (2010) 77(4):678-86. doi:10.1124/mol.109.063065.
125. May LT, Self TJ, Briddon SJ, Hill SJ. The effect of allosteric modulators on the kinetics of agonist-G protein-coupled receptor interactions in single living cells. Mol Pharmacol (2010) 78(3):511-23. doi:10.1124/mol.110.064493.
126. Hern JA, Baig AH, Mashanov GI, Birdsall B, Corrie JET, Lazareno S, et al. Formation and dissociation of M1 muscarinic receptor dimers seen by total internal reflection fluorescence imaging of single molecules. Proc Natl Acad Sci U S A (2010) 107(6):2693-8. doi:10.1073/pnas.0907915107.
127. Kasai RS, Suzuki KGN, Prossnitz ER, Koyama-Honda I, Nakada C, Fujiwara TK, et al. Full characterization of GPCR monomer-dimer dynamic equilibrium by single molecule imaging. J Cell Biol (2011) 192(3):463-80. doi:10.1083/jcb.201009128.
128. Azzi M, Charest PG, Angers S, Rousseau G, Kohout T, Bouvier M, et al. 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) 100(20):11406-11. doi:10.1073/pnas.1936664100.
129. Baker JG, Hall IP, Hill SJ. Agonist and inverse agonist actions of beta-blockers at the human beta 2-adrenoceptor provide evidence for agonist-directed signaling. Mol Pharmacol (2003) 64(6):1357-69. doi:10.1124/mol.64.6.1357.
130. Whalen EJ, Rajagopal S, Lefkowitz RJ. Therapeutic potential of beta-arrestin-and G protein-biased agonists. Trends Mol Med (2011) 17(3):126-39. doi:10.1016/j.molmed.2010.11.004.
131. Hill SJ, May LT, Kellam B, Woolard J. Allosteric interactions at adenosine A1 and A3 receptors: new insights into the role of small molecules and receptor dimerization. Br J Pharmacol (2014) 171(5):1102-13. doi:10.1111/bph.12345.
132. Keov P, Sexton PM, Christopoulos A. Allosteric modulation of G protein-coupled receptors: a pharmacological perspective. Neuropharmacology (2011) 60(1):24-35. doi:10.1016/j.neuropharm.2010.07.010.
133. 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.
134. Cordeaux Y, Briddon SJ, Alexander SP, Kellam B, Hill SJ. Agonist-occupied A3 adenosine receptors exist within heterogeneous complexes in membrane microdomains of individual living cells. FASEB J (2008) 22(3):850-60. doi:10.1096/fj.07-8180com.
135. Gines S, Ciruela F, Burgueno J, Casado V, Canela EI, Mallol J, et al. Involvement of caveolin in ligand-induced recruitment and internalization of A1 adenosine receptor and adenosine deaminase in an epithelial cell line. Mol Pharmacol (2001) 59(5):1314-23. doi:10.1124/mol.59.5.1314.
136. Insel PA, Head BP, Ostrom RS, Patel HH, Swaney JS, Tang CM, et al. Caveolae and lipid rafts: G protein-coupled receptor signaling microdomains in cardiac myocytes. Ann N Y Acad Sci (2005) 1047:166-72. doi:10.1196/annals.1341.015.
137. Ostrom RS, Insel PA. The evolving role of lipid rafts and caveolae in G protein-coupled receptor signaling: implications for molecular pharmacology. Br J Pharmacol (2004) 143(2):235-45. doi:10.1038/sj.bjp.0705930.
138. Feinstein TN, Wehbi VL, Ardura JA, Wheeler DS, Ferrandon S, Gardella TJ, et al. Retromer terminates the generation of cAMP by internalized PTH receptors. Nat Chem Biol (2011) 7(5):278-84. doi:10.1038/nchembio.545.
139. Irannejad R, Tomshine JC, Tomshine JR, Chevalier M, Mahoney JP, Steyaert J, et al. Conformational biosensors reveal GPCR signalling from endosomes. Nature (2013) 495(7442):534-8. doi:10.1038/nature12000.
140. Mullershausen F, Zecri F, Cetin C, Billich A, Guerini D, Seuwen K. Persistent signaling induced by FTY720-phosphate is mediated by internalized S1P1 receptors. Nat Chem Biol (2009) 5(6):428-34. doi:10.1038/nchembio.173.
141. Werthmann RC, Volpe S, Lohse MJ, Calebiro D. Persistent cAMP signaling by internalized TSH receptors occurs in thyroid but not in HEK293 cells. FASEB J (2012) 26(5):2043-8. doi:10.1096/fj.11-195248.
142. Briddon SJ, Hill SJ. Pharmacology under the microscope: the use of fluorescence correlation spectroscopy to determine the properties of ligand-receptor complexes. Trends Pharmacol Sci (2007) 28(12):637-45. doi:10.1016/j.tips.2007.09.008.
143. Ayling LJ, Briddon SJ, Halls ML, Hammond GR, Vaca L, Pacheco J, et al. Adenylyl cyclase AC8 directly controls its micro-environment by recruiting the actin cytoskeleton in a cholesterol-rich milieu. J Cell Sci (2012) 125(Pt 4):869-86. doi:10.1242/jcs.091090.
144. Briddon SJ, Gandia J, Amaral OB, Ferre S, Lluis C, Franco R, et al. Plasma membrane diffusion of G protein-coupled receptor oligomers. Biochim Biophys Acta (2008) 1783(12):2262-8. doi:10.1016/j.bbamcr.2008.07.006.
145. Herrick-Davis K, Grinde E, Cowan A, Mazurkiewicz JE. Fluorescence correlation spectroscopy analysis of serotonin, adrenergic, muscarinic, and dopamine receptor dimerization: the oligomer number puzzle. Mol Pharmacol (2013) 84(4):630-42. doi:10.1124/mol.113.087072.
146. Kilpatrick LE, Briddon SJ, Holliday ND. Fluorescence correlation spectroscopy, combined with bimolecular fluorescence complementation, reveals the effects of beta-arrestin complexes and endocytic targeting on the membrane mobility of neuropeptide Y receptors. Biochim Biophys Acta (2012) 1823(6):1068-81. doi:10.1016/j.bbamcr.2012.03.002.
147. Whorton MR, Bokoch MP, Rasmussen SG, Huang B, Zare RN, Kobilka B, et al. A monomeric G protein-coupled receptor isolated in a high-density lipoprotein particle efficiently activates its G protein. Proc Natl Acad Sci U S A (2007) 104(18):7682-7. doi:10.1073/pnas.0611448104.
148. Gao T, Petrlova J, He W, Huser T, Kudlick W, Voss J, et al. Characterization of de novo synthesized GPCRs supported in nanolipoprotein discs. PLoS One (2012) 7(9):e44911. doi:10.1371/journal.pone.0044911.
149. Kuszak AJ, Pitchiaya S, Anand JP, Mosberg HI, Walter NG, Sunahara RK. Purification and functional reconstitution of monomeric mu-opioid receptors: allosteric modulation of agonist binding by Gi2. J Biol Chem (2009) 284(39):26732-41. doi:10.1074/jbc. M109.026922.