G protein–coupled receptors (GPCRs) compose one of the largest families of membrane proteins involved in intracellular signaling. They are involved in numerous physiological and pathological processes and are prime candidates for drug development. Over the past decade, an increasing number of studies have reported heteromerization between GPCRs. Many investigations in heterologous systems have provided important indications of potential novel pharmacology; however, the physiological relevance of these findings has yet to be established with endogenous receptors in native tissues. In this review, we focus on family A GPCRs and describe the techniques and criteria to assess their heteromerization. We conclude that advances in approaches to study receptor complex functionality in heterologous systems, coupled with techniques that enable specific examination of native receptor heteromers in vivo, are likely to establish GPCR heteromers as novel therapeutic targets.


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Literature Cited

  1. Milligan G, Bouvier M. 1.  2005. Methods to monitor the quaternary structure of G protein–coupled receptors. FEBS J. 272:2914–25 [Google Scholar]
  2. Pin JP, Neubig R, Bouvier M, Devi L, Filizola M. 2.  et al. 2007. International Union of Basic and Clinical Pharmacology. LXVII. Recommendations for the recognition and nomenclature of G protein–coupled receptor heteromultimers. Pharmacol. Rev. 59:5–13 [Google Scholar]
  3. Lohse MJ. 3.  2010. Dimerization in GPCR mobility and signaling. Curr. Opin. Pharmacol. 10:53–58 [Google Scholar]
  4. Gomes I, Fujita W, Chandrakala MV, Devi LA. 4.  2013. Disease-specific heteromerization of G-protein-coupled receptors that target drugs of abuse. Prog. Mol. Biol. Transl. Sci. 117:207–65 [Google Scholar]
  5. Ferré S, Baler R, Bouvier M, Caron MG, Devi LA. 5.  et al. 2009. Building a new conceptual framework for receptor heteromers. Nat. Chem. Biol. 5:131–34 [Google Scholar]
  6. Ciruela F, Vilardaga JP, Fernandez-Duenas V. 6.  2010. Lighting up multiprotein complexes: lessons from GPCR oligomerization. Trends Biotechnol. 28:407–15 [Google Scholar]
  7. Kaczor AA, Selent J. 7.  2011. Oligomerization of G protein–coupled receptors: biochemical and biophysical methods. Curr. Med. Chem. 18:4606–34 [Google Scholar]
  8. Fernandez-Duenas V, Taura JJ, Cottet M, Gomez-Soler M, Lopez-Cano M. 8.  et al. 2015. Untangling dopamine-adenosine receptor-receptor assembly in experimental parkinsonism in rats. Dis. Model. Mech. 8:57–63 [Google Scholar]
  9. He SQ, Zhang ZN, Guan JS, Liu HR, Zhao B. 9.  et al. 2011. Facilitation of μ-opioid receptor activity by preventing δ-opioid receptor-mediated codegradation. Neuron 69:120–31 [Google Scholar]
  10. Kabli N, Nguyen T, Balboni G, O'Dowd BF, George SR. 10.  2014. Antidepressant-like and anxiolytic-like effects following activation of the μ-δ opioid receptor heteromer in the nucleus accumbens. Mol. Psychiatry 19:986–94 [Google Scholar]
  11. O'Dowd BF, Ji X, O'Dowd PB, Nguyen T, George SR. 11.  2012. Disruption of the μ-δ opioid receptor heteromer. Biochem. Biophys. Res. Commun. 422:556–60 [Google Scholar]
  12. Liu XY, Liu ZC, Sun YG, Ross M, Kim S. 12.  et al. 2011. Unidirectional cross-activation of GRPR by MOR1D uncouples itch and analgesia induced by opioids. Cell 147:447–58 [Google Scholar]
  13. Gupta A, Mulder J, Gomes I, Rozenfeld R, Bushlin I. 13.  et al. 2010. Increased abundance of opioid receptor heteromers after chronic morphine administration. Sci. Signal. 3ra54
  14. Berg KA, Rowan MP, Gupta A, Sanchez TA, Silva M. 14.  et al. 2012. Allosteric interactions between δ and κ opioid receptors in peripheral sensory neurons. Mol. Pharmacol. 81:264–72 [Google Scholar]
  15. Bushlin I, Gupta A, Stockton SD Jr, Miller LK, Devi LA. 15.  2012. Dimerization with cannabinoid receptors allosterically modulates δ opioid receptor activity during neuropathic pain. PLOS ONE 7:e49789 [Google Scholar]
  16. Rozenfeld R, Gupta A, Gagnidze K, Lim MP, Gomes I. 16.  et al. 2011. AT1R-CB1R heteromerization reveals a new mechanism for the pathogenic properties of angiotensin II. EMBO J. 30:2350–63 [Google Scholar]
  17. Hansen JL, Hansen JT, Speerschneider T, Lyngso C, Erikstrup N. 17.  et al. 2009. Lack of evidence for AT1R/B2R heterodimerization in COS-7, HEK293, and NIH3T3 cells: How common is the AT1R/B2R heterodimer?. J. Biol. Chem. 284:1831–39 [Google Scholar]
  18. Frederick AL, Yano H, Trifilieff P, Vishwasrao HD, Biezonski D. 18.  et al. 2015. Evidence against dopamine D1/D2 receptor heteromers. Mol. Psychiatry. 201373–85
  19. Levsky JM, Singer RH. 19.  2003. Fluorescence in situ hybridization: past, present and future. J. Cell Sci. 116:2833–38 [Google Scholar]
  20. Chabot JG, Kar S, Quirion R. 20.  1996. Autoradiographical and immunohistochemical analysis of receptor localization in the central nervous system. Histochem. J. 28:729–45 [Google Scholar]
  21. Weibrecht I, Leuchowius KJ, Clausson CM, Conze T, Jarvius M. 21.  et al. 2010. Proximity ligation assays: a recent addition to the proteomics toolbox. Expert Rev. Proteomics 7:401–9 [Google Scholar]
  22. Jonas KC, Fanelli F, Huhtaniemi IT, Hanyaloglu AC. 22.  2015. Single molecule analysis of functionally asymmetric G protein–coupled receptor (GPCR) oligomers reveals diverse spatial and structural assemblies. J. Biol. Chem. 290:3875–92 [Google Scholar]
  23. Jaeger WC, Armstrong SP, Hill SJ, Pfleger KDG. 23.  2014. Biophysical detection of diversity and bias in GPCR function. Front. Endocrinol. 5:26 [Google Scholar]
  24. Hebert TE, Gales C, Rebois RV. 24.  2006. Detecting and imaging protein-protein interactions during G protein-mediated signal transduction in vivo and in situ by using fluorescence-based techniques. Cell Biochem. Biophys. 45:85–109 [Google Scholar]
  25. Ayoub M, Zhang Y, Kelly R, See H, Johnstone E. 25.  et al. 2015. Functional interaction between angiotensin II receptor type 1 and chemokine (C-C motif) receptor 2 with implications for chronic kidney disease. PLOS ONE 10:e0119803 [Google Scholar]
  26. Kocan M, Pfleger KDG. 26.  2011. Study of GPCR-protein interactions by BRET. Methods Mol. Biol. 746:357–71 [Google Scholar]
  27. Mercier JF, Salahpour A, Angers S, Breit A, Bouvier M. 27.  2002. Quantitative assessment of β1- and β2-adrenergic receptor homo- and heterodimerization by bioluminescence resonance energy transfer. J. Biol. Chem. 277:44925–31 [Google Scholar]
  28. Pfleger KDG, Eidne KA. 28.  2006. Illuminating insights into protein-protein interactions using bioluminescence resonance energy transfer (BRET). Nat. Methods 3:165–74 [Google Scholar]
  29. Lohse MJ, Nuber S, Hoffmann C. 29.  2012. Fluorescence/bioluminescence resonance energy transfer techniques to study G-protein-coupled receptor activation and signaling. Pharmacol. Rev. 64:299–336 [Google Scholar]
  30. Albizu L, Cottet M, Kralikova M, Stoev S, Seyer R. 30.  et al. 2010. Time-resolved FRET between GPCR ligands reveals oligomers in native tissues. Nat. Chem. Biol. 6:587–94 [Google Scholar]
  31. Comps-Agrar L, Kniazeff J, Nørskov-Lauritsen L, Maurel D, Gassmann M. 31.  et al. 2011. The oligomeric state sets GABAB receptor signalling efficacy. EMBO J. 30:2336–49 [Google Scholar]
  32. Cottet M, Faklaris O, Falco A, Trinquet E, Pin JP. 32.  et al. 2013. Fluorescent ligands to investigate GPCR binding properties and oligomerization. Biochem. Soc. Trans. 41:148–53 [Google Scholar]
  33. Hounsou C, Margathe J, Oueslati N, Belhocine A, Dupuis E. 33.  et al. 2015. Time-resolved FRET binding assay to investigate hetero-oligomer binding properties: proof of concept with dopamine D1/D3 heterodimer. ACS Chem. Biol. 10:466–74 [Google Scholar]
  34. Callén L, Moreno E, Barroso-Chinea P, Moreno-Delgado D, Cortés A. 34.  et al. 2012. Cannabinoid receptors CB1 and CB2 form functional heteromers in brain. J. Biol. Chem. 287:20851–65 [Google Scholar]
  35. Trifilieff P, Rives ML, Urizar E, Piskorowski RA, Vishwasrao HD. 35.  et al. 2011. Detection of antigen interactions ex vivo by proximity ligation assay: endogenous dopamine D2-adenosine A2A receptor complexes in the striatum. BioTechniques 51:111–18 [Google Scholar]
  36. Fuxe K, Borroto-Escuela D, Ciruela F, Guidolin D, Agnati L. 36.  2014. Receptor-receptor interactions in heteroreceptor complexes: a new principle in biology. Focus on their role in learning and memory. Neurosci. Discov. 2:6 [Google Scholar]
  37. Koos B, Andersson L, Clausson CM, Grannas K, Klaesson A. 37.  et al. 2014. Analysis of protein interactions in situ by proximity ligation assays. Curr. Top. Microbiol. Immunol. 377:111–26 [Google Scholar]
  38. Sierra S, Luquin N, Rico AJ, Gómez-Bautista V, Roda E. 38.  et al. 2015. Detection of cannabinoid receptors CB1 and CB2 within basal ganglia output neurons in macaques: changes following experimental parkinsonism. Brain Struct. Funct. 220:2721–38 [Google Scholar]
  39. Berggard T, Linse S, James P. 39.  2007. Methods for the detection and analysis of protein-protein interactions. Proteomics 7:2833–42 [Google Scholar]
  40. Gomes I, Gupta A, Devi LA. 40.  2013. G-protein-coupled heteromers: regulation in disease. Methods Enzymol. 521:219–38 [Google Scholar]
  41. Erbs E, Faget L, Scherrer G, Matifas A, Filliol D. 41.  et al. 2014. A μ-δ opioid receptor brain atlas reveals neuronal co-occurrence in subcortical networks. Brain Struct. Funct. 220:677–702 [Google Scholar]
  42. George SR, Fan T, Xie Z, Tse R, Tam V. 42.  et al. 2000. Oligomerization of μ- and δ-opioid receptors. Generation of novel functional properties. J. Biol. Chem. 275:26128–35 [Google Scholar]
  43. Kabli N, Martin N, Fan T, Nguyen T, Hasbi A. 43.  et al. 2010. Agonists at the δ-opioid receptor modify the binding of μ-receptor agonists to the μ-δ receptor hetero-oligomer. Br. J. Pharmacol. 161:1122–36 [Google Scholar]
  44. Baragli A, Alturaihi H, Watt HL, Abdallah A, Kumar U. 44.  2007. Heterooligomerization of human dopamine receptor 2 and somatostatin receptor 2 co-immunoprecipitation and fluorescence resonance energy transfer analysis. Cell Signal. 19:2304–16 [Google Scholar]
  45. Rocheville M, Lange DC, Kumar U, Patel SC, Patel RC, Patel YC. 45.  2000. Receptors for dopamine and somatostatin: formation of hetero-oligomers with enhanced functional activity. Science 288:154–57 [Google Scholar]
  46. Wang D, Sun X, Bohn LM, Sadee W. 46.  2005. Opioid receptor homo- and heterodimerization in living cells by quantitative bioluminescence resonance energy transfer. Mol. Pharmacol. 67:2173–84 [Google Scholar]
  47. Pfeiffer M, Kirscht S, Stumm R, Koch T, Wu D. 47.  et al. 2003. Heterodimerization of substance P and μ-opioid receptors regulates receptor trafficking and resensitization. J. Biol. Chem. 278:51630–37 [Google Scholar]
  48. Dasgupta S, Ferré S, Kull B, Hedlund PB, Finnman UB. 48.  et al. 1996. Adenosine A2A receptors modulate the binding characteristics of dopamine D2 receptors in stably cotransfected fibroblast cells. Eur. J. Pharmacol. 316:325–31 [Google Scholar]
  49. Ferré S, von Euler G, Johansson B, Fredholm BB, Fuxe K. 49.  1991. Stimulation of high-affinity adenosine A2 receptors decreases the affinity of dopamine D2 receptors in rat striatal membranes. PNAS 88:7238–41 [Google Scholar]
  50. Albizu L, Holloway T, Gonzalez-Maeso J, Sealfon SC. 50.  2011. Functional crosstalk and heteromerization of serotonin 5-HT2A and dopamine D2 receptors. Neuropharmacology 61:770–77 [Google Scholar]
  51. Jordan BA, Devi LA. 51.  1999. G-protein-coupled receptor heterodimerization modulates receptor function. Nature 399:697–700 [Google Scholar]
  52. Gonzalez S, Moreno-Delgado D, Moreno E, Perez-Capote K, Franco R. 52.  et al. 2012. Circadian-related heteromerization of adrenergic and dopamine D4 receptors modulates melatonin synthesis and release in the pineal gland. PLOS Biol. 10:e1001347 [Google Scholar]
  53. Sohy D, Yano H, de Nadai P, Urizar E, Guillabert A. 53.  et al. 2009. Hetero-oligomerization of CCR2, CCR5, and CXCR4 and the protean effects of “selective” antagonists. J. Biol. Chem. 284:31270–79 [Google Scholar]
  54. Gomes I, Ijzerman AP, Ye K, Maillet EL, Devi LA. 54.  2011. G protein–coupled receptor heteromerization: a role in allosteric modulation of ligand binding. Mol. Pharmacol. 79:1044–52 [Google Scholar]
  55. Gonzalez-Maeso J, Ang RL, Yuen T, Chan P, Weisstaub NV. 55.  et al. 2008. Identification of a serotonin/glutamate receptor complex implicated in psychosis. Nature 452:93–97 [Google Scholar]
  56. Rozenfeld R, Bushlin I, Gomes I, Tzavaras N, Gupta A. 56.  et al. 2012. Receptor heteromerization expands the repertoire of cannabinoid signaling in rodent neurons. PLOS ONE 7:e29239 [Google Scholar]
  57. Zhu WZ, Chakir K, Zhang S, Yang D, Lavoie C. 57.  et al. 2005. Heterodimerization of β1- and β2-adrenergic receptor subtypes optimizes β-adrenergic modulation of cardiac contractility. Circ. Res. 97:244–51 [Google Scholar]
  58. McGraw DW, Mihlbachler KA, Schwarb MR, Rahman FF, Small KM. 58.  et al. 2006. Airway smooth muscle prostaglandin-EP1 receptors directly modulate β2-adrenergic receptors within a unique heterodimeric complex. J. Clin. Investig. 116:1400–9 [Google Scholar]
  59. Fan T, Varghese G, Nguyen T, Tse R, O'Dowd BF, George SR. 59.  2005. A role for the distal carboxyl tails in generating the novel pharmacology and G protein activation profile of μ and δ opioid receptor hetero-oligomers. J. Biol. Chem. 280:38478–88 [Google Scholar]
  60. Kabli N, Fan T, O'Dowd BF, George SR. 60.  2014. μ-δ Opioid receptor heteromer-specific signaling in the striatum and hippocampus. Biochem. Biophys. Res. Commun. 450:906–11 [Google Scholar]
  61. Kern A, Albarran-Zeckler R, Walsh HE, Smith RG. 61.  2012. Apo-ghrelin receptor forms heteromers with DRD2 in hypothalamic neurons and is essential for anorexigenic effects of DRD2 agonism. Neuron 73:317–32 [Google Scholar]
  62. Charles AC, Mostovskaya N, Asas K, Evans CJ, Dankovich ML, Hales TG. 62.  2003. Coexpression of δ-opioid receptors with μ receptors in GH3 cells changes the functional response to mu agonists from inhibitory to excitatory. Mol. Pharmacol. 63:89–95 [Google Scholar]
  63. Rozenfeld R, Devi LA. 63.  2007. Receptor heterodimerization leads to a switch in signaling: β-arrestin2-mediated ERK activation by μ-δ opioid receptor heterodimers. FASEB J. 21:2455–65 [Google Scholar]
  64. Lin H, Trejo J. 64.  2013. Transactivation of the PAR1-PAR2 heterodimer by thrombin elicits β-arrestin-mediated endosomal signaling. J. Biol. Chem. 288:11203–15 [Google Scholar]
  65. Bellot M, Galandrin S, Boularan C, Matthies HJ, Despas F. 65.  et al. 2015. Dual agonist occupancy of AT1-R-α2C-AR heterodimers results in atypical Gs-PKA signaling. Nat. Chem. Biol. 11:271–79 [Google Scholar]
  66. Wang HL, Hsu CY, Huang PC, Kuo YL, Li AH. 66.  et al. 2005. Heterodimerization of opioid receptor-like 1 and μ-opioid receptors impairs the potency of μ receptor agonist. J. Neurochem. 92:1285–94 [Google Scholar]
  67. Rios C, Gomes I, Devi LA. 67.  2006. μ Opioid and CB1 cannabinoid receptor interactions: reciprocal inhibition of receptor signaling and neuritogenesis. Br. J. Pharmacol. 148:387–95 [Google Scholar]
  68. Pello OM, Martinez-Muñoz L, Parrillas V, Serrano A, Rodríguez-Frade JM. 68.  et al. 2008. Ligand stabilization of CXCR4/δ-opioid receptor heterodimers reveals a mechanism for immune response regulation. Eur. J. Immunol. 38:537–49 [Google Scholar]
  69. Carriba P, Ortiz O, Patkar K, Justinova Z, Stroik J. 69.  et al. 2007. Striatal adenosine A2A and cannabinoid CB1 receptors form functional heteromeric complexes that mediate the motor effects of cannabinoids. Neuropsychopharmacology 32:2249–59 [Google Scholar]
  70. Moreno JL, Holloway T, Gonzalez-Maeso J. 70.  2013. G protein–coupled receptor heterocomplexes in neuropsychiatric disorders. Prog. Mol. Biol. Trans. Sci. 117:187–205 [Google Scholar]
  71. Sohy D, Parmentier M, Springael JY. 71.  2007. Allosteric transinhibition by specific antagonists in CCR2/CXCR4 heterodimers. J. Biol. Chem. 282:30062–69 [Google Scholar]
  72. Chow BS, Kocan M, Bosnyak S, Sarwar M, Wigg B. 72.  et al. 2014. Relaxin requires the angiotensin II type 2 receptor to abrogate renal interstitial fibrosis. Kidney Int. 86:75–85 [Google Scholar]
  73. Leger AJ, Jacques SL, Badar J, Kaneider NC, Derian CK. 73.  et al. 2006. Blocking the protease-activated receptor 1–4 heterodimer in platelet-mediated thrombosis. Circulation 113:1244–54 [Google Scholar]
  74. Gomes I, Jordan BA, Gupta A, Trapaidze N, Nagy V, Devi LA. 74.  2000. Heterodimerization of μ and δ opioid receptors: a role in opiate synergy. J. Neurosci. 20RC110
  75. Gomes I, Gupta A, Filipovska J, Szeto HH, Pintar JE, Devi LA. 75.  2004. A role for heterodimerization of μ and δ opiate receptors in enhancing morphine analgesia. PNAS 101:5135–39 [Google Scholar]
  76. Hasbi A, Nguyen T, Fan T, Cheng R, Rashid A. 76.  et al. 2007. Trafficking of preassembled opioid μ-δ heterooligomer-Gz signaling complexes to the plasma membrane: coregulation by agonists. Biochemistry 46:12997–3009 [Google Scholar]
  77. Law PY, Erickson-Herbrandson LJ, Zha QQ, Solberg J, Chu J. 77.  et al. 2005. Heterodimerization of μ- and δ-opioid receptors occurs at the cell surface only and requires receptor-G protein interactions. J. Biol. Chem. 280:11152–64 [Google Scholar]
  78. Pfeiffer M, Koch T, Schroder H, Laugsch M, Hollt V, Schulz S. 78.  2002. Heterodimerization of somatostatin and opioid receptors cross-modulates phosphorylation, internalization, and desensitization. J. Biol. Chem. 277:19762–72 [Google Scholar]
  79. Hillion J, Canals M, Torvinen M, Casadó V, Scott R. 79.  et al. 2002. Coaggregation, cointernalization, and codesensitization of adenosine A2A receptors and dopamine D2 receptors. J. Biol. Chem. 277:18091–97 [Google Scholar]
  80. Torvinen M, Torri C, Tombesi A, Marcellino D, Watson S. 80.  et al. 2005. Trafficking of adenosine A2A and dopamine D2 receptors. J. Mol. Neurosci. 25:191–200 [Google Scholar]
  81. Milan-Lobo L, Whistler JL. 81.  2011. Heteromerization of the μ- and δ-opioid receptors produces ligand-biased antagonism and alters μ-receptor trafficking. J. Pharmacol. Exp. Ther. 337:868–75 [Google Scholar]
  82. Terrillon S, Barberis C, Bouvier M. 82.  2004. Heterodimerization of V1a and V2 vasopressin receptors determines the interaction with β-arrestin and their trafficking patterns. PNAS 101:1548–53 [Google Scholar]
  83. Mustafa S, See HB, Seeber RM, Armstrong SP, White CW. 83.  et al. 2012. Identification and profiling of novel α1A-adrenoceptor-CXC chemokine receptor 2 heteromer. J. Biol. Chem. 287:12952–65 [Google Scholar]
  84. Decaillot FM, Kazmi MA, Lin Y, Ray-Saha S, Sakmar TP, Sachdev P. 84.  2011. CXCR7/CXCR4 heterodimer constitutively recruits β-arrestin to enhance cell migration. J. Biol. Chem. 286:32188–97 [Google Scholar]
  85. Bulenger S, Marullo S, Bouvier M. 85.  2005. Emerging role of homo- and heterodimerization in G-protein-coupled receptor biosynthesis and maturation. Trends Pharmacol. Sci. 26:131–37 [Google Scholar]
  86. Hammad MM, Dupré DJ. 86.  2010. Chaperones contribute to G protein–coupled receptor oligomerization, but do not participate in assembly of the G protein with the receptor signaling complex. J. Mol. Signal. 5:16 [Google Scholar]
  87. Abd Alla J, Reeck K, Langer A, Streichert T, Quitterer U. 87.  2009. Calreticulin enhances B2 bradykinin receptor maturation and heterodimerization. Biochem. Biophys. Res. Commun. 387:186–90 [Google Scholar]
  88. Decaillot FM, Rozenfeld R, Gupta A, Devi LA. 88.  2008. Cell surface targeting of μ-δ opioid receptor heterodimers by RTP4. PNAS 105:16045–50 [Google Scholar]
  89. Ayoub MA, Pfleger KDG. 89.  2010. Recent advances in bioluminescence resonance energy transfer technologies to study GPCR heteromerization. Curr. Opin. Pharmacol. 10:44–52 [Google Scholar]
  90. Mustafa S, Ayoub MA, Pfleger KDG. 90.  2010. Uncovering GPCR heteromer-biased ligands. Drug Discov. Today Technol. 7:e77–85 [Google Scholar]
  91. Mustafa S, Pfleger. 91.  2011. G protein–coupled receptor heteromer identification technology: identification and profiling of GPCR heteromers. J. Lab. Autom. 16:285–91 [Google Scholar]
  92. Johnstone EK, Pfleger. 92.  2012. Receptor-heteromer investigation technology and its application using BRET. Front. Endocrinol. 3:101 [Google Scholar]
  93. See HB, Seeber RM, Kocan M, Eidne KA, Pfleger KDG. 93.  2011. Application of G protein–coupled receptor-heteromer identification technology to monitor β-arrestin recruitment to G protein–coupled receptor heteromers. Assay Drug Dev. Technol. 9:21–30 [Google Scholar]
  94. Porrello ER, Pfleger KDG, Seeber RM, Qian H, Oro C. 94.  et al. 2011. Heteromerization of angiotensin receptors changes trafficking and arrestin recruitment profiles. Cell Signal. 23:1767–76 [Google Scholar]
  95. Watts AO, van Lipzig MM, Jaeger WC, Seeber RM, van Zwam M. 95.  et al. 2013. Identification and profiling of CXCR3-CXCR4 chemokine receptor heteromer complexes. Br. J. Pharmacol. 168:1662–74 [Google Scholar]
  96. Schelshorn D, Joly F, Mutel S, Hampe C, Breton B. 96.  et al. 2012. Lateral allosterism in the glucagon receptor family: Glucagon-like peptide 1 induces G-protein-coupled receptor heteromer formation. Mol. Pharmacol. 81:309–18 [Google Scholar]
  97. Armando S, Quoyer J, Lukashova V, Maiga A, Percherancier Y. 97.  et al. 2014. The chemokine CXC4 and CC2 receptors form homo- and heterooligomers that can engage their signaling G-protein effectors and β-arrestin. FASEB J. 28:4509–23 [Google Scholar]
  98. Gomes I, Fujita W, Gupta A, Saldanha SA, Negri A. 98.  et al. 2013. Identification of a μ-δ opioid receptor heteromer-biased agonist with antinociceptive activity. PNAS 110:12072–77 [Google Scholar]
  99. Stoddart LA, Johnstone EKM, Wheal AJ, Goulding J, Robers MB. 99.  et al. 2015. Application of BRET to monitor ligand binding to GPCRs. Nat. Methods 12:661–63 [Google Scholar]
  100. Daniels DJ, Lenard NR, Etienne CL, Law PY, Roerig SC, Portoghese PS. 100.  2005. Opioid-induced tolerance and dependence in mice is modulated by the distance between pharmacophores in a bivalent ligand series. PNAS 102:19208–13 [Google Scholar]
  101. Lenard NR, Daniels DJ, Portoghese PS, Roerig SC. 101.  2007. Absence of conditioned place preference or reinstatement with bivalent ligands containing μ-opioid receptor agonist and δ-opioid receptor antagonist pharmacophores. Eur. J. Pharmacol. 566:75–82 [Google Scholar]
  102. Le Naour M, Akgün E, Yekkirala A, Lunzer MM, Powers MD. 102.  et al. 2013. Bivalent ligands that target μ opioid (MOP) and cannabinoid1 (CB1) receptors are potent analgesics devoid of tolerance. J. Med. Chem. 56:5505–13 [Google Scholar]
  103. Yuan Y, Arnatt CK, El-Hage N, Dever SM, Jacob JC. 103.  et al. 2013. A bivalent ligand targeting the putative mu opioid receptor and chemokine receptor CCR5 heterodimers: binding affinity versus functional activities. Med. Chem. Commun. 4:847–51 [Google Scholar]
  104. Akgün E, Javed MI, Lunzer MM, Smeester BA, Beitz AJ, Portoghese PS. 104.  2013. Ligands that interact with putative MOR-mGluR5 heteromer in mice with inflammatory pain produce potent antinociception. PNAS 110:11595–99 [Google Scholar]
  105. Bhushan RG, Sharma SK, Xie Z, Daniels DJ, Portoghese PS. 105.  2004. A bivalent ligand (KDN-21) reveals spinal δ and κ opioid receptors are organized as heterodimers that give rise to δ1 and κ2 phenotypes. Selective targeting of δ-κ heterodimers. J. Med. Chem. 47:2969–72 [Google Scholar]
  106. Yamamoto T, Nair P, Davis P, Ma SW, Navratilova E. 106.  et al. 2007. Design, synthesis, and biological evaluation of novel bifunctional C-terminal-modified peptides for δ/μ opioid receptor agonists and neurokinin-1 receptor antagonists. J. Med. Chem. 50:2779–86 [Google Scholar]
  107. Journé A, Habib S, Dodda B, Morcos M, Sadek M. 107.  et al. 2014. N1-linked melatonin dimers as bivalent ligands targeting dimeric melatonin receptors. Med. Chem. Commun. 5792–96
  108. Vardanyan R, Kumirov VK, Nichol GS, Davis P, Liktor-Busa E. 108.  et al. 2011. Synthesis and biological evaluation of new opioid agonist and neurokinin-1 antagonist bivalent ligands. Bioorg. Med. Chem. 19:6135–42 [Google Scholar]
  109. Largent-Milnes TM, Brookshire SW, Skinner DP Jr, Hanlon KE, Giuvelis D. 109.  2013. Building a better analgesic: multifunctional compounds that address injury-induced pathology to enhance analgesic efficacy while eliminating unwanted side effects. J. Pharmacol. Exp. Ther. 347:7–19 [Google Scholar]
  110. Yekkirala AS, Lunzer MM, McCurdy CR, Powers MD, Kalyuzhny AE. 110.  et al. 2011. N-naphthoyl-β-naltrexamine (NNTA), a highly selective and potent activator of μ/κ-opioid heteromers. PNAS 108:5098–103 [Google Scholar]
  111. Sevigny LM, Austin KM, Zhang P, Kasuda S, Koukos G. 111.  et al. 2011. Protease-activated receptor-2 modulates protease-activated receptor-1-driven neointimal hyperplasia. Arterioscler. Thromb. Vasc. Biol. 31:e100–6 [Google Scholar]
  112. González S, Rangel-Barajas C, Peper M, Lorenzo R, Moreno E. 112.  et al. 2012. Dopamine D4 receptor, but not the ADHD-associated D4.7 variant, forms functional heteromers with the dopamine D2S receptor in the brain. Mol. Psychiatry 17:650–62 [Google Scholar]
  113. Moreno JL, Muguruza C, Umali A, Mortillo S, Holloway T. 113.  et al. 2012. Identification of three residues essential for 5-hydroxytryptamine 2A-metabotropic glutamate 2 (5-HT2A·mGlu2) receptor heteromerization and its psychoactive behavioral function. J. Biol. Chem. 287:44301–19 [Google Scholar]
  114. Baba K, Benleulmi-Chaachoua A, Journé AS, Kamal M, Guillaume JL. 114.  et al. 2013. Heteromeric MT1/MT2 melatonin receptors modulate photoreceptor function. Sci. Signal. 6:ra89 [Google Scholar]
  115. Fujita W, Gomes I, Devi LA. 115.  2015. Heteromers of μ-δ opioid receptors: new pharmacology and novel therapeutic possibilities. Br. J. Pharmacol. 172:375–87 [Google Scholar]
  116. Fujita W, Gomes I, Devi LA. 116.  2014. Revolution in GPCR signalling: opioid receptor heteromers as novel therapeutic targets: IUPHAR review 10. Br. J. Pharmacol. 171:4155–76 [Google Scholar]
  117. Gomes I, Gupta A, Bushlin I, Devi LA. 117.  2014. Antibodies to probe endogenous G protein–coupled receptor heteromer expression, regulation, and function. Front. Pharmacol. 5:268 [Google Scholar]
  118. Fink JS, Weaver DR, Rivkees SA, Peterfreund RA, Pollack AE. 118.  et al. 1992. Molecular cloning of the rat A2 adenosine receptor: selective co-expression with D2 dopamine receptors in rat striatum. Brain Res. Mol. Brain Res. 14:186–95 [Google Scholar]
  119. Bonaventura J, Rico AJ, Moreno E, Sierra S, Sánchez M. 119.  et al. 2014. L-DOPA-treatment in primates disrupts the expression of A2A adenosine–CB1 cannabinoid–D2 dopamine receptor heteromers in the caudate nucleus. Neuropharmacology 79:90–100 [Google Scholar]
  120. Fuxe K, Ferré S, Canals M, Torvinen M, Terasmaa A. 120.  et al. 2005. Adenosine A2A and dopamine D2 heteromeric receptor complexes and their function. J. Mol. Neurosci. 26:209–20 [Google Scholar]
  121. Cabello N, Gandía J, Bertarelli DCG, Watanabe M, Lluís C. 121.  et al. 2009. Metabotropic glutamate type 5, dopamine D2 and adenosine A2a receptors form higher-order oligomers in living cells. J. Neurochem. 109:1497–507 [Google Scholar]
  122. Soriano A, Ventura R, Molero A, Hoen R, Casadó V. 122.  et al. 2009. Adenosine A2A receptor-antagonist/dopamine D2 receptor-agonist bivalent ligands as pharmacological tools to detect A2A-D2 receptor heteromers. J. Med. Chem. 52:5590–602 [Google Scholar]
  123. Scholten DJ, Canals M, Maussang D, Roumen L, Smit MJ. 123.  et al. 2012. Pharmacological modulation of chemokine receptor function. Br. J. Pharmacol. 165:1617–43 [Google Scholar]
  124. Tripathi A, Vana PG, Chavan TS, Brueggemann LI, Byron KL. 124.  et al. 2015. Heteromerization of chemokine (C-X-C motif) receptor 4 with α1A/B-adrenergic receptors controls α1-adrenergic receptor function. PNAS 112:13E1659–68 [Google Scholar]
  125. Rashid AJ, So CH, Kong MM, Furtak T, El-Ghundi M. 125.  et al. 2007. D1-D2 dopamine receptor heterooligomers with unique pharmacology are coupled to rapid activation of Gq/11 in the striatum. PNAS 104:654–59 [Google Scholar]
  126. Ng J, Rashid AJ, So CH, O'Dowd BF, George SR. 126.  2010. Activation of calcium/calmodulin-dependent protein kinase IIα in the striatum by the heteromeric D1-D2 dopamine receptor complex. Neuroscience 165:535–41 [Google Scholar]
  127. Pei L, Li S, Wang M, Diwan M, Anisman H. 127.  et al. 2010. Uncoupling the dopamine D1-D2 receptor complex exerts antidepressant-like effects. Nat. Med. 16:1393–95 [Google Scholar]
  128. Vilar M, Sung TC, Chen Z, Garcia-Carpio I, Fernandez EM. 128.  et al. 2014. Heterodimerization of p45-p75 modulates p75 signaling: structural basis and mechanism of action. PLOS Biol. 12:e1001918 [Google Scholar]
  129. Ludtke SJ, Serysheva II. 129.  2013. Single-particle cryo-EM of calcium release channels: structural validation. Curr. Opin. Struct. Biol. 23:755–62 [Google Scholar]
  130. Bai XC, McMullan G, Scheres SHW. 130.  2015. How cryo-EM is revolutionizing structural biology. Trends Biochem. Sci. 40:49–57 [Google Scholar]
  131. Christopoulos A, Kenakin T. 131.  2002. G protein–coupled receptor allosterism and complexing. Pharmacol. Rev. 54:323–74 [Google Scholar]
  132. Haack KVV, McCarty NA. 132.  2011. Functional consequences of GPCR heterodimerization: GPCRs as allosteric modulators. Pharmaceuticals 4:509–23 [Google Scholar]
  133. Urban JD, Clarke WP, von Zastrow M, Nichols DE, Kobilka B. 133.  et al. 2007. Functional selectivity and classical concepts of quantitative pharmacology. J. Pharmacol. Exp. Ther. 320:1–13 [Google Scholar]
  134. Fujita W, Gomes I, Dove LS, Prohaska D, McIntyre G, Devi LA. 134.  2014. Molecular characterization of eluxadoline as a potential ligand targeting μ-δ opioid receptor heteromers. Biochem. Pharmacol. 92:448–56 [Google Scholar]

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