Oligomerization of G protein-coupled receptors: Biochemical and biophysical methods

Current Medicinal Chemistry

Volumn 18, Issue 30, 2011, Pages 4606-4634

  Kaczor, A A ^a,b   Selent, J ^a  

^a UNIVERSITAT POMPEU FABRA   (Spain)

^b MEDICAL UNIVERSITY OF LUBLIN   (Poland)

Author keywords

BiFC; BRET; Co immunoprecipitation; FRAP; FRET; GPCR oligomers; TIRF

Indexed keywords

4 AMINOBUTYRIC ACID B RECEPTOR; CANNABINOID 1 RECEPTOR; CHEMOKINE RECEPTOR CCR2; CHEMOKINE RECEPTOR CCR5; CHEMOKINE RECEPTOR CXCR1; CHEMOKINE RECEPTOR CXCR2; CHOLECYSTOKININ RECEPTOR; CORTICOTROPIN RELEASING FACTOR RECEPTOR; FOLLITROPIN RECEPTOR BINDING INHIBITOR; G PROTEIN COUPLED RECEPTOR; KAPPA OPIATE RECEPTOR; LUTEINIZING HORMONE RECEPTOR; MELANOCORTIN 1 RECEPTOR; MELATONIN 1 RECEPTOR; MELATONIN 2 RECEPTOR; METHYLSCOPOLAMINE; MU OPIATE RECEPTOR; NEUROKININ 1 RECEPTOR; PROSTAGLANDIN E RECEPTOR 1; PROTIRELIN RECEPTOR; QUINUCLIDINYL BENZILATE; RHODOPSIN; SEROTONIN 1A RECEPTOR; SEROTONIN 1B RECEPTOR; SEROTONIN 1C RECEPTOR; SEROTONIN 1D RECEPTOR; SEROTONIN 4 RECEPTOR; THYROTROPIN RECEPTOR; UNINDEXED DRUG; VASOPRESSIN V2 RECEPTOR;

ATOMIC FORCE MICROSCOPY; BIOLUMINESCENCE RESONANCE ENERGY TRANSFER; BLEACHING; CHIMERA; CONFOCAL MICROSCOPY; DIMERIZATION; DRUG TARGETING; FLUORESCENCE MICROSCOPY; FLUORESCENCE RECOVERY AFTER PHOTOBLEACHING; FLUORESCENCE RESONANCE ENERGY TRANSFER; HUMAN; IMMUNOBLOTTING; IMMUNOELECTRON MICROSCOPY; IMMUNOFLUORESCENCE MICROSCOPY; IMMUNOPRECIPITATION; MUTANT; OLFACTORY RECEPTOR; OLIGOMERIZATION; PROTEIN CROSS LINKING; PROTEIN EXPRESSION; REVIEW; TRANSMISSION ELECTRON MICROSCOPY; X RAY CRYSTALLOGRAPHY;

EID: 80053511695     PISSN: 09298673     EISSN: 1875533X     Source Type: Journal    
DOI: 10.2174/092986711797379285     Document Type: Review

References (314)

1. Fuxe, K.; Marcellino, D.; Leo, G.; Agnati, L.F. Molecular integration viaallosteric interactions in receptor heteromers. A working hypothesis. Curr.Opin. Pharmacol., 2010, 10, 14-22.
2. Fuxe, K.; Canals, M.; Torvinen, M.; Marcellino, D.; Terasmaa, A.;Genedani, S.; Leo, G.; Guidolin, D.; Diaz-Cabiale, Z.; Rivera, A.;Lundstrom, L.; Langel, U.; Narvaez, J.; Tanganelli, S.; Lluis, C.; Ferré, S.;Woods, A.; Franco, R.; Agnati, L.F. Intramembrane receptor-receptorinteractions: a novel principle in molecular medicine. J. Neural Transm., 2007, 114, 49-75. (Pubitemid 46018675)
3. Agnati, L.F.; Fuxe, K.; Zini, I.; Lenzi, P.; Hökfelt, T. Aspects on receptorregulation and isoreceptor identification. Med. Biol., 1980, 58, 182-187.
4. Fuxe, K.; Agnati, L.F.; Benfenati, F.; Cimmino, M.; Algeri, S.; Hökfelt, T.;Mutt, V. Modulation by cholecystokinins of 3H-spiroperidol binding in ratstriatum: evidence for increased affinity and reduction in the number ofbinding sites. Acta Physiol. Scand., 1981, 113, 567-569. (Pubitemid 12183362)
5. Fuxe, K.; Agnati, L.F.; Benfenati, F.; Celani, M.; Zini, I.; Zoli, M.; Mutt, V.Evidence for the existence of receptor-receptor interactions in the centralnervous system. Studies on the regulation of monoamine receptors byneuropeptides. J. Neural Transm., 1983, 18, 165-179.
6. Agnati, L.F.; Ferré, S.; Lluis, C.; Franco, R.; Fuxe, K. Molecularmechanisms and therapeutical implications of intramembranereceptor/ receptor interactions among heptahelical receptors with examplesfrom the striatopallidal GABA neurons. Pharmacol. Rev., 2003, 55, 509-550. (Pubitemid 37013214)
7. Limbird, L.E.; Meyts, P.D.; Lefkowitz, R.J. Beta-adrenergic receptors:evidence for negative cooperativity. Biochem. Biophys. Res. Commun., 1975, 64, 1160-1168.
8. Zoli, M.; Agnati, L.F.; Hedlund, P.B.; Li, X.M.; Ferré, S.; Fuxe, K.Receptor-receptor interactions as an integrative mechanism in nerve cells.Mol. Neurobiol., 1993, 7, 293-334.
9. Fotiadis, D.; Liang, Y.; Filipek, S.; Saperstein, D.A.; Engel, A.; Palczewski, K. Atomic-force microscopy: Rhodopsin dimers in native disc membranes.Nature, 2003, 421, 127-128. (Pubitemid 36090969)
10. Fotiadis, D.; Liang, Y.; Filipek, S.; Saperstein, D.A.; Engel, A.; Palczewski, K. The G protein-coupled receptor rhodopsin in the native membrane. FEBS Lett., 2004, 564, 281-288. (Pubitemid 38520934)
11. Liang, Y.; Fotiadis, D.; Filipek, S.; Saperstein, D.A.; Palczewski, K.; Engel, A. Organization of the G protein-coupled receptors rhodopsin and opsin innative membranes. J. Biol. Chem., 2003, 278, 21655-21662. (Pubitemid 36792566)
12. Wu, B.; Chien, E.Y.T.; Mol, C.D.; Fenalti, G.; Liu, W.; Katritch, V.;Abagyan, R.; Brooun, A.; Wells, P.; Bi, F.C.; Hamel, D.J.; Kuhn, P.; Handel, T.M.; Cherezov, V.; Stevens, R. . Structures of the CXCR4 chemokineGPCR with small-molecule and cyclic peptide antagonists. Science, 2010, 330, 1066-1071.
13. Saxena, R.; Chattopadhyay, A. Membrane organization and dynamics of theserotonin(1A) receptor in live cells. J. Neurochem., 2011, 116, 726-733.
14. Lambert, N.A. GPCR dimers fall apart. Sci. Signal., 2010, 3, 12.
15. Kasai, R.S.; Suzuki, K.G.N.; Prossnitz, E.R.; Koyama-Honda, I.; Nakada, C.;Fujiwara, T.K.; Kusumi, A. Full characterization of GPCR monomer-dimerdynamic equilibrium by single molecule imaging. J. Cell Biol., 2011, 192, 463-480.
16. George, S.R.; O'Dowd, B.F.; Lee, S.P. G-protein-coupled receptoroligomerization and its potential for drug discovery. Nat. Rev. Drug Discov., 2002, 1, 808-820. (Pubitemid 37361564)
17. Filizola, M.; Weinstein, H. The structure and dynamics of GPCR oligomers:a new focus in models of cell-signaling mechanisms and drug design. Curr.Opin. Drug Discov. Devel., 2005, 8, 577-584. (Pubitemid 41224120)
18. Panetta, R.; Greenwood, M.T. Physiological relevance of GPCRoligomerization and its impact on drug discovery. Drug Discov. Today, 2008, 13, 1059-1066.
19. González-Maeso, J. GPCR oligomers in pharmacology and signaling. Mol.Brain, 2011, 4, 20.
20. Ayoub, M.A.; Pfleger, K.D.G. Recent advances in bioluminescenceresonance energy transfer technologies to study GPCR heteromerization.Curr. Opin. Pharmacol., 2010, 10, 44-52.
21. Kent, T.; McAlpine, C.; Sabetnia, S.; Presland, J. G-protein-coupled receptorheterodimerization: assay technologies to clinical significance. Curr. Opin.Drug Discov. Devel., 2007, 10, 580-589. (Pubitemid 47367773)
22. Kroeger, K.M.; Pfleger, K.D.G. ; Eidne, K.A. In: Contemporary ClinicalNeuroscience: The G Protein-Coupled Receptors Handbook; Devi, L.A., Ed.;Humana Press Inc.: Totowa, NJ, 2005.
23. Rios, C.D.; Jordan, B.A.; Gomes, I.; Devi, L.A. G-protein-coupled receptordimerization: modulation of receptor function. Pharmacol. Ther., 2001, 92, 71-87. (Pubitemid 34251127)
24. Limbird, L.E.; Meyts, P.D.; Lefkowitz, R.J. [beta]-Adrenergic receptors:Evidence for negative cooperativity. Biochem. Biophys. Res. Commun., 1975, 64, 1160-1168.
25. Hirschberg, B.T.; Schimerlik, M.I. A kinetic model for oxotremorine Mbinding to recombinant porcine m2 muscarinic receptors expressed in Chinese hamster ovary cells. J. Biol. Chem., 1994, 269, 26127-26135. (Pubitemid 24328422)
26. Wreggett, K.A.; Wells, J.W. Cooperativity manifest in the binding properties of purified cardiac muscarinic receptors. J. Biol. Chem., 1995, 270, 22488-22499.
27. Mattera, R.; Pitts, B.J.; Entman, M.L.; Birnbaumer, L. Guanine nucleotideregulation of a mammalian myocardial muscarinic receptor system. Evidencefor homo- and heterotropic cooperativity in ligand binding analyzed bycomputer-assisted curve fitting. J. Biol. Chem., 1985, 260, 7410-7421. (Pubitemid 15063016)
28. Potter, L.T.; Ballesteros, L.A.; Bichajian, L.H.; Ferrendelli, C.A.; Fisher, A.;Hanchett, H.E.; Zhang, R. Evidence of paired M2 muscarinic receptors. Mol. Pharmacol., 1991, 39, 211-221.
29. Hazum, E.; Chang, K.J.; Leighton, H.J.; Lever, O.W.; Cuatrecasas, P.Increased biological activity of dimers of oxymorphone and enkephalin:possible role of receptor crosslinking. Biochem. Biophys. Res. Commun., 1982, 104, 347-353. (Pubitemid 12146313)
30. Conn, P.M.; Rogers, D.C.; Stewart, J.M.; Niedel, J.; Sheffield, T. Conversionof a gonadotropin-releasing hormone antagonist to an agonist. Nature, 1982, 296, 653-655. (Pubitemid 12089067)
31. Haack, K.K.V.; McCarty, N.A. Functional consequences of GPCRheterodimerization: GPCRs as allosteric modulators. Pharmaceuticals, 2011, 4, 509-523.
32. Kempner, E.S. Novel predictions from radiation target analysis. Trends Biochem. Sci., 1993, 18, 236-239. (Pubitemid 23186850)
33. Ness, G.C.; Pendleton, L.C.; McCreery, M.J. Target size analysis byradiation inactivation: the use of free radical scavengers. Exp. Biol. Med. (Maywood), 2005, 230, 455-463. (Pubitemid 40923422)
34. Osbornejr, J. Molecular mass and volume in radiation target theory. Biophys. J., 2000, 78, 1698-1702.
35. Dawson, G.; Ellory, J.C. Functional lysosomal hydrolase size as determined by radiation inactivation analysis. Biochem. J., 1985, 226, 283-288.
36. Fraser, C.M.; Venter, J.C. The size of the mammalian lung beta 2-adrenergicreceptor as determined by target size analysis and immunoaffinitychromatography. Biochem. Biophys. Res. Commun., 1982, 109, 21-29. (Pubitemid 13072668)
37. Venter, J.C.; Schaber, J.S.; U'Prichard, D.C.; Fraser, C.M. Molecular size ofthe human platelet alpha 2-adrenergic receptor as determined by radiationinactivation. Biochem. Biophys. Res. Commun., 1983, 116, 1070-1075. (Pubitemid 14202689)
38. Gredal, O.; Nielsen, M. Binding of [3H]SKF 38393 to dopamine D-1receptors in rat striatum in vitro; estimation of receptor molecular size byradiation inactivation. J. Neurochem., 1987, 48, 370-375. (Pubitemid 17005142)
39. Lilly, L.; Fraser, C.M.; Jung, C.Y.; Seeman, P.; Venter, J.C. Molecular sizeof the canine and human brain D2 dopamine receptor as determined byradiation inactivation. Mol. Pharmacol., 1983, 24, 10-14. (Pubitemid 13075099)
40. Shirakawa, O.; Tanaka, C. Molecular characterization of muscarinic receptorsubtypes in bovine cerebral cortex by radiation inactivation and molecularexclusion h.p.l.c. Br. J. Pharmacol., 1985, 86, 375-383. (Pubitemid 15241107)
41. Collins, S.M.; Jung, C.Y.; Grover, A.K. Muscarinic receptor size on smoothmuscle cells and membranes. Am. J. Physiol., 1986, 251, G195-200.
42. Ott, S.; Costa, T.; Wüster, M.; Hietel, B.; Herz, A. Target size analysis ofopioid receptors. No difference between receptor types, but discriminationbetween two receptor states. Eur. J. Biochem., 1986, 155, 621-630. (Pubitemid 16077833)
43. McLawhon, R.W.; Ellory, J.C.; Dawson, G. Molecular size of opiate(enkephalin) receptors in neuroblastoma-glioma hybrid cells as determined by radiation inactivation analysis. J. Biol. Chem., 1983, 258, 2102-2105. (Pubitemid 13118408)
44. Conn, P.M.; Venter, J.C. Radiation inactivation (target size analysis) of thegonadotropin-releasing hormone receptor: evidence for a high molecularweight complex. Endocrinology, 1985, 116, 1324-1326. (Pubitemid 15078145)
45. Nielsen, T.B.; Totsuka, Y.; Kempner, E.S.; Field, J.B. Structure of thethyrotropin receptor and thyroid adenylate cyclase system as determined bytarget analysis. Biochemistry, 1984, 23, 6009-6016. (Pubitemid 15153474)
46. Gennick, S.E.; Thomas, C.G.; Nayfeh, S.N. Characterization of the subunitstructure of the thyrotropin receptor in the FRTL-5 rat thyroid cell line.Endocrinology, 1987, 121, 2119-2130. (Pubitemid 18016984)
47. Frame, L.T.; Yeung, S.M.; Venter, J.C.; Cooper, D.M. Target size of theadenosine Ri receptor. Biochem. J., 1986, 235, 621-624.
48. Vassilatis, D.K.; Hohmann, J.G.; Zeng, H.; Li, F.; Ranchalis, J.E.; Mortrud, M.T.; Brown, A.; Rodriguez, S.S.; Weller, J.R.; Wright, A.C.; Bergmann, J.E.; Gaitanaris, G.A. The G protein-coupled receptor repertoires of humanand mouse. Proc. Natl. Acad. Sci. U. S. A., 2003, 100, 4903-4908. (Pubitemid 36457826)
49. Hakak, Y.; Shrestha, D.; Goegel, M.C.; Behan, D.P.; Chalmers, D.T. Globalanalysis of G-protein-coupled receptor signaling in human tissues. FEBS Lett., 2003, 550, 11-17. (Pubitemid 37281349)
50. Maggio, R.; Vogel, Z.; Wess, J. Coexpression studies with mutantmuscarinic/adrenergic receptors provide evidence for intermolecular "crosstalk"between G-protein-linked receptors. Proc. Natl. Acad. Sci. U. S. A., 1993, 90, 3103-3107. (Pubitemid 23113566)
51. Scarselli, M.; Novi, F.; Schallmach, E.; Lin, R.; Baragli, A.; Colzi, A.;Griffon, N.; Corsini, G.U.; Sokoloff, P.; Levenson, R.; Vogel, Z.; Maggio, R.D2/D3 dopamine receptor heterodimers exhibit unique functional properties.J. Biol. Chem., 2001, 276, 30308-30314.
52. Monnot, C.; Bihoreau, C.; Conchon, S.; Curnow, K.M.; Corvol, P.; Clauser, E. Polar residues in the transmembrane domains of the type 1 angiotensin IIreceptor are required for binding and coupling. Reconstitution of the bindingsite by co-expression of two deficient mutants. J. Biol. Chem., 1996, 271, 1507-1513.
53. Rocheville, M.; Lange, D.C.; Kumar, U.; Sasi, R.; Patel, R.C.; Patel, Y.C.Subtypes of the somatostatin receptor assemble as functional homo- andheterodimers. J. Biol. Chem., 2000, 275, 7862-7869. (Pubitemid 30159693)
54. Gazi, L.; López-Giménez, J.F.; Strange, P.G. Formation of oligomers by Gprotein-coupled receptors. Curr. Opin. Drug Discov. Devel., 2002, 5, 756-763.
55. Grosse, R.; Schöneberg, T.; Schultz, G.; Gudermann, T. Inhibition ofgonadotropin-releasing hormone receptor signaling by expression of a splicevariant of the human receptor. Mol. Endocrinol., 1997, 11, 1305-1318. (Pubitemid 28041337)
56. Zhu, X.; Wess, J. Truncated V2 vasopressin receptors as negative regulatorsof wild-type V2 receptor function. Biochemistry, 1998, 37, 15773-15784. (Pubitemid 28524748)
57. Benkirane, M.; Jin, D.Y.; Chun, R.F.; Koup, R.A.; Jeang, K.T. Mechanismof transdominant inhibition of CCR5-mediated HIV-1 infection byccr5delta32. J. Biol. Chem., 1997, 272, 30603-30606. (Pubitemid 27527488)
58. Hebert, T.E.; Loisel, T.P.; Adam, L.; Ethier, N.; Onge, S.S.; Bouvier, M.Functional rescue of a constitutively desensitized beta2AR through receptordimerization. Biochem. J., 1998, 330, 287-293. (Pubitemid 28075752)
59. Leaños-Miranda, A.; Ulloa-Aguirre, A.; Ji, T.H.; Janovick, J.A.; Conn, P.M.Dominant-negative action of disease-causing gonadotropin- releasinghormone receptor (GnRHR) mutants: a trait that potentially coevolved withdecreased plasma membrane expression of GnRHR in humans. J. Clin. Endocrinol. Metab., 2003, 88, 3360-3367. (Pubitemid 36877517)
60. Karpa, K.D.; Lin, R.; Kabbani, N.; Levenson, R. The dopamine D3 receptorinteracts with itself and the truncated D3 splice variant d3nf: D3-D3nfinteraction causes mislocalization of D3 receptors. Mol. Pharmacol., 2000, 58, 677-683.
61. Bai, M.; Trivedi, S.; Brown, E.M. Dimerization of the extracellular calciumsensingreceptor (CaR) on the cell surface of CaR-transfected HEK293 cells.J. Biol. Chem., 1998, 273, 23605-23610. (Pubitemid 28417555)
62. Rodríguez-Frade, J.M.; Vila-Coro, A.J.; de Ana, A.M.; Albar, J.P.; Martínez A. C.; Mellado, M. The chemokine monocyte chemoattractant protein-1induces functional responses through dimerization of its receptor CCR2.Proc. Natl. Acad. Sci. U. S. A., 1999, 96, 3628-3633. (Pubitemid 29168961)
63. Angers, S.; Salahpour, A.; Joly, E.; Hilairet, S.; Chelsky, D.; Dennis, M.;Bouvier, M. Detection of beta 2-adrenergic receptor dimerization in livingcells using bioluminescence resonance energy transfer (BRET). Proc. Natl. Acad. Sci. U. S. A., 2000, 97, 3684-3689. (Pubitemid 30183363)
64. Rogers, T.B. High affinity angiotensin II receptors in myocardialsarcolemmal membranes. Characterization of receptors and covalent linkageof 125I-angiotensin II to a membrane component of 116, 000 daltons. J. Biol. Chem., 1984, 259, 8106-8114. (Pubitemid 14090553)
65. AbdAlla, S.; Zaki, E.; Lother, H.; Quitterer, U. Involvement of the aminoterminus of the B(2) receptor in agonist-induced receptor dimerization. J. Biol. Chem., 1999, 274, 26079-26084.
66. Zawarynski, P.; Tallerico, T.; Seeman, P.; Lee, S.P.; O'Dowd, B.F.; George, S.R. Dopamine D2 receptor dimers in human and rat brain. FEBS Lett., 1998, 441, 383-386. (Pubitemid 29065320)
67. Capponi, A.M.; Catt, K.J. Solubilization and characterization of adrenal anduterine angiotensin II receptors after photoaffinity labeling. J. Biol. Chem., 1980, 255, 12081-12086. (Pubitemid 11128442)
68. Paglin, S.; Jamieson, J.D. Covalent crosslinking of angiotensin II to itsbinding sites in rat adrenal membranes. Proc. Natl. Acad. Sci. U. S. A., 1982, 79, 3739-3743. (Pubitemid 12013541)
69. Guillemette, G.; Escher, E. Analysis of the adrenal angiotensin II receptorwith the photoaffinity labeling method. Biochemistry, 1983, 22, 5591-5596. (Pubitemid 14212081)
70. Carson, M.C.; Harper, C.M.; Baukal, A.J.; Aguilera, G.; Catt, K.J.Physicochemical characterization of photoaffinity-labeled angiotensin IIreceptors. Mol. Endocrinol., 1987, 1, 147-153.
71. Rondeau, J.J.; McNicoll, N.; Escher, E.; Meloche, S.; Ong, H.; De Léan, A.Hydrodynamic properties of the angiotensin II receptor from bovine adrenalzona glomerulosa. Biochem. J., 1990, 268, 443-448. (Pubitemid 20193986)
72. Skrabanek, L.; Murcia, M.; Bouvier, M.; Devi, L.; George, S.R.; Lohse, M.J.; Milligan, G.; Neubig, R.; Palczewski, K.; Parmentier, M.; Pin, J.-P.;Vriend, G.; Javitch, J.A.; Campagne, F.; Filizola, M. Requirements andontology for a G protein-coupled receptor oligomerization knowledge base.BMC Bioinformatics, 2007, 8, 177.
73. Khelashvili, G.; Dorff, K.; Shan, J.; Camacho-Artacho, M.; Skrabanek, L.;Vroling, B.; Bouvier, M.; Devi, L.A.; George, S.R.; Javitch, J.A.; Lohse, M.J.; Milligan, G.; Neubig, R.R.; Palczewski, K.; Parmentier, M.; Pin, J.-P.;Vriend, G.; Campagne, F.; Filizola, M. GPCR-OKB: the G Protein Coupled Receptor Oligomer Knowledge Base. Bioinformatics, 2010, 26, 1804-1805.
74. Jastrzebska, B.; Maeda, T.; Zhu, L.; Fotiadis, D.; Filipek, S.; Engel, A.;Stenkamp, R.E.; Palczewski, K. Functional characterization of rhodopsinmonomers and dimers in detergents. J. Biol. Chem., 2004, 279, 54663-54675. (Pubitemid 40053210)
75. Mancia, F.; Assur, Z.; Herman, A.G.; Siegel, R.; Hendrickson, W.A. Ligandsensitivity in dimeric associations of the serotonin 5HT2c receptor. EMBO Rep., 2008, 9, 363-369.
76. Guo, W.; Urizar, E.; Kralikova, M.; Mobarec, J.C.; Shi, L.; Filizola, M.;Javitch, J.A. Dopamine D2 receptors form higher order oligomers atphysiological expression levels. EMBO J., 2008, 27, 2293-2304.
77. Guo, W.; Shi, L.; Javitch, J.A. The fourth transmembrane segment forms theinterface of the dopamine D2 receptor homodimer. J. Biol. Chem., 2003, 278, 4385-4388. (Pubitemid 36800928)
78. Guo, W.; Shi, L.; Filizola, M.; Weinstein, H.; Javitch, J.A. Crosstalk in Gprotein-coupled receptors: changes at the transmembrane homodimerinterface determine activation. Proc. Natl. Acad. Sci. U. S. A., 2005, 102, 17495-17500. (Pubitemid 41740894)
79. Klco, J.M.; Lassere, T.B.; Baranski, T.J. C5a receptor oligomerization. I.Disulfide trapping reveals oligomers and potential contact surfaces in a Gprotein-coupled receptor. J. Biol. Chem., 2003, 278, 35345-35353. (Pubitemid 37102303)
80. Banères, J.-L.; Parello, J. Structure-based analysis of GPCR function:evidence for a novel pentameric assembly between the dimeric leukotrieneB4 receptor BLT1 and the G-protein. J. Mol. Biol., 2003, 329, 815-829. (Pubitemid 36629373)
81. Gao, F.; Harikumar, K.G.; Dong, M.; Lam, P.C.-H.; Sexton, P.M.Christopoulos, A.; Bordner, A.; Abagyan, R.; Miller, L.J. Functionalimportance of a structurally distinct homodimeric complex of the family B Gprotein-coupled secretin receptor. Mol. Pharmacol., 2009, 76, 264-274.
82. Johnston, J.M.; Aburi, M.; Provasi, D.; Bortolato, A.; Urizar, E.; Lambert, N.A.; Javitch, J.A.; Filizola, M. Making structural sense of dimerizationinterfaces of delta opioid receptor homodimers. Biochemistry, 2011, 50, 1682-1690.
83. Ng, G.Y.; Clark, J.; Coulombe, N.; Ethier, N.; Hebert, T.E.; Sullivan, R.;Kargman, S.; Chateauneuf, A.; Tsukamoto, N.; McDonald, T.; Whiting, P.;Mezey, E.; Johnson, M.P.; Liu, Q.; Kolakowski, L.F.; Evans, J.F.; Bonner, T.I.; O'Neill, G.P. Identification of a GABAB receptor subunit, gb2, requiredfor functional GABAB receptor activity. J. Biol. Chem., 1999, 274, 7607-7610.
84. Harrison, C.; van der Graaf, P.H. Current methods used to investigate Gprotein coupled receptor oligomerisation. J. Pharmacol. Toxicol. Methods, 2006, 54, 26-35. (Pubitemid 43996847)
85. Satake, H.; Sakai, T. Recent advances and perceptions in studies ofheterodimerization between G protein-coupled receptors. Protein Pept. Lett., 2008, 15, 300-308. (Pubitemid 351457381)
86. Promega Protein Interaction Guide, www.promega.com.
87. Kroeger, K.M.; Pfleger, K.D.G.; Eidne, K.A. G-protein coupled receptoroligomerization in neuroendocrine pathways. Front. Neuroendocrinol., 2003, 24, 254-278. (Pubitemid 38064318)
88. Breitwieser, G.E. G protein-coupled receptor oligomerization: implicationsfor G protein activation and cell signaling. Circ. Res., 2004, 94, 17-27. (Pubitemid 38064094)
89. Maggio, R.; Novi, F.; Scarselli, M.; Corsini, G.U. The impact of G-proteincoupledreceptor hetero-oligomerization on function and pharmacology.FEBS J., 2005, 272, 2939-2946. (Pubitemid 40904682)
90. Prinster, S.C.; Hague, C.; Hall, R.A. Heterodimerization of g protein-coupledreceptors: specificity and functional significance. Pharmacol. Rev., 2005, 57, 289-298. (Pubitemid 41196951)
91. Kieffer, B.L. Opioids: first lessons from knockout mice. Trends Pharmacol.Sci., 1999, 20, 19-26. (Pubitemid 29304521)
92. Salim, K.; Fenton, T.; Bacha, J.; Urien-Rodriguez, H.; Bonnert, T.; Skynner, H.A.; Watts, E.; Kerby, J.; Heald, A.; Beer, M.; McAllister, G.; Guest, P.C.Oligomerization of G-protein-coupled receptors shown by selective coimmunoprecipitation.J. Biol. Chem., 2002, 277, 15482-15485. (Pubitemid 34967814)
93. Brea, J.; Castro, M.; Giraldo, J.; López-Giménez, J.F.; Padín, J.F.; Quintián, F.; Cadavid, M.I.; Vilaró, M.T.; Mengod, G.; Berg, K.A.; Clarke, W.P.;Vilardaga, J.-P.; Milligan, G.; Loza, M.I. Evidence for distinct antagonistrevealedfunctional states of 5-hydroxytryptamine(2A) receptor homodimers.Mol. Pharmacol., 2009, 75, 1380-1391.
94. Franco, R.; Casadó, V.; Mallol, J.; Ferrada, C.; Ferré, S.; Fuxe, K.; Cortés, A.; Ciruela, F.; Lluis, C.; Canela, E.I. The two-state dimer receptor model: ageneral model for receptor dimers. Mol. Pharmacol., 2006, 69, 1905-1912. (Pubitemid 43894307)
95. Leff, P.; Scaramellini, C.; Law, C.; McKechnie, K. A three-state receptormodel of agonist action. Trends Pharmacol. Sci., 1997, 18, 355-362.
96. Herrick-Davis, K.; Weaver, B.A.; Grinde, E.; Mazurkiewicz, J.E. Serotonin5-HT2C receptor homodimer biogenesis in the endoplasmic reticulum: realtimevisualization with confocal fluorescence resonance energy transfer. J. Biol. Chem., 2006, 281, 27109-27116. (Pubitemid 44401740)
97. Berthouze, M.; Rivail, L.; Lucas, A.; Ayoub, M.A.; Russo, O.; Sicsic, S.;Fischmeister, R.; Berque-Bestel, I.; Jockers, R.; Lezoualc'h, F. Twotransmembrane Cys residues are involved in 5-HT4 receptor dimerization.Biochem. Biophys. Res. Commun., 2007, 356, 642-647. (Pubitemid 46509766)
98. Selent, J.; Kaczor A.A. Oligomerization of G protein-coupled receptors:computational methods. Curr. Med. Chem., 2011, in press.
99. Ballesteros, J. A.; Weinstein, H. In: Receptor Molecular Biology; Sealfon, S.C., Ed.; Academic Press: New York, 1995; Vol. 25, pp. 366-428.
100. Pellissier, L.P.; Barthet, G.; Gaven, F.; Cassier, E.; Trinquet, E.; Pin, J.-P.;Marin, P.; Dumuis, A.; Bockaert, J.; Baneres, J.-L.; Claeysen, S. G proteinactivation by serotonin type 4 receptor dimers: evidence that turning on twoprotomers is more efficient. J. Biol. Chem., 2011, 286, 9985-9997.
101. Stanasila, L.; Perez, J.-B.; Vogel, H.; Cotecchia, S. Oligomerization of thealpha 1a- and alpha 1b-adrenergic receptor subtypes. Potential implicationsin receptor internalization. J. Biol. Chem., 2003, 278, 40239-40251. (Pubitemid 37248592)
102. Carrillo, J.J.; Pediani, J.; Milligan, G. Dimers of class A G protein-coupledreceptors function via agonist-mediated trans-activation of associated Gproteins. J. Biol. Chem., 2003, 278, 42578-42587. (Pubitemid 37310531)
103. Carrillo, J.J.; López-Giménez, J.F.; Milligan, G. Multiple interactionsbetween transmembrane helices generate the oligomeric alpha1badrenoceptor.Mol. Pharmacol., 2004, 66, 1123-1137. (Pubitemid 39411053)
104. Hebert, T.E.; Moffett, S.; Morello, J.P.; Loisel, T.P.; Bichet, D.G.; Barret, C.;Bouvier, M. A peptide derived from a beta2-adrenergic receptortransmembrane domain inhibits both receptor dimerization and activation. J. Biol. Chem., 1996, 271, 16384-16392. (Pubitemid 26236264)
105. Sartania, N.; Appelbe, S.; Pediani, J.D.; Milligan, G. Agonist occupancy of asingle monomeric element is sufficient to cause internalization of the dimericbeta2-adrenoceptor. Cell. Signal., 2007, 19, 1928-1938. (Pubitemid 47081383)
106. Cvejic, S.; Devi, L.A. Dimerization of the delta opioid receptor: implicationfor a role in receptor internalization. J. Biol. Chem., 1997, 272, 26959-26964. (Pubitemid 27452648)
107. Trettel, F.; Di Bartolomeo, S.; Lauro, C.; Catalano, M.; Ciotti, M.T.;Limatola, C. Ligand-independent CXCR2 dimerization. J. Biol. Chem., 2003, 278, 40980-40988. (Pubitemid 37280920)
108. Vila-Coro, A.J.; Mellado, M.; Martín de Ana, A.; Lucas, P.; del Real, G.;Martínez A. C.; Rodríguez-Frade, J.M. HIV-1 infection through the CCR5receptor is blocked by receptor dimerization. Proc. Natl. Acad. Sci. U. S. A., 2000, 97, 3388-3393. (Pubitemid 30183312)
109. Berglund, M.M.; Schober, D.A.; Esterman, M.A.; Gehlert, D.R.Neuropeptide Y Y4 receptor homodimers dissociate upon agoniststimulation. J. Pharmacol. Exp. Ther., 2003, 307, 1120-1126. (Pubitemid 37494232)
110. Terrillon, S.; Durroux, T.; Mouillac, B.; Breit, A.; Ayoub, M.A.; Taulan, M.;Jockers, R.; Barberis, C.; Bouvier, M. Oxytocin and vasopressin V1a and V2receptors form constitutive homo- and heterodimers during biosynthesis.Mol. Endocrinol., 2003, 17, 677-691. (Pubitemid 36403579)
111. Laroche, G.; Lépine, M.-C; Thériault, C.; Giguère, P.; Giguère, V.; Gallant, M.A.; de Brum-Fernandes, A.; Parent, J.-L. Oligomerization of the alpha andbeta isoforms of the thromboxane A2 receptor: relevance to receptorsignaling and endocytosis. Cell. Signal., 2005, 17, 1373-1383. (Pubitemid 41206647)
112. Young, S.F.; Griffante, C.; Aguilera, G. Dimerization between vasopressinV1b and corticotropin releasing hormone type 1 receptors. Cell. Mol.Neurobiol., 2007, 27, 439-461. (Pubitemid 46763890)
113. Robbins, M.J.; Ciruela, F.; Rhodes, A.; McIlhinney, R.A. Characterization ofthe dimerization of metabotropic glutamate receptors using an N-terminaltruncation of mGluR1alpha. J. Neurochem., 1999, 72, 2539-2547. (Pubitemid 29242206)
114. Romano, C.; Yang, W.L.; O'Malley, K.L. Metabotropic glutamate receptor 5 is a disulfide-linked dimer. J. Biol. Chem., 1996, 271, 28612-28616. (Pubitemid 26374686)
115. Uberti, M.A.; Hague, C.; Oller, H.; Minneman, K.P.; Hall, R.A.Heterodimerization with beta2-adrenergic receptors promotes surfaceexpression and functional activity of alpha1D-adrenergic receptors. J.Pharmacol. Exp. Ther., 2005, 313, 16-23. (Pubitemid 40411323)
116. Lee, S.P.; So, C.H.; Rashid, A.J.; Varghese, G.; Cheng, R.; Lança, A.J.;O'Dowd, B.F.; George, S.R. Dopamine D1 and D2 receptor co-activationgenerates a novel phospholipase C-mediated calcium signal. J. Biol. Chem., 2004, 279, 35671-35678. (Pubitemid 39100570)
117. Pei, L.; Li, S.; Wang, M.; Diwan, M.; Anisman, H.; Fletcher, P.J.; Nobrega, J.N.; Liu, F. Uncoupling the dopamine D1-D2 receptor complex exertsantidepressant-like effects. Nat. Med., 2010, 16, 1393-1395.
118. Jordan, B.A.; Trapaidze, N.; Gomes, I.; Nivarthi, R.; Devi, L.A.Oligomerization of opioid receptors with beta 2-adrenergic receptors: a rolein trafficking and mitogen-activated protein kinase activation. Proc. Natl. Acad. Sci. U. S. A., 2001, 98, 343-348. (Pubitemid 32095911)
119. George, S.R.; Lee, S.P.; Varghese, G.; Zeman, P.R.; Seeman, P.; Ng, G.Y.;O'Dowd, B.F. A transmembrane domain-derived peptide inhibits D1dopamine receptor function without affecting receptor oligomerization. J. Biol. Chem., 1998, 273, 30244-30248. (Pubitemid 28545490)
120. Lee, S.P.; O'Dowd, B.F.; Ng, G.Y.; Varghese, G.; Akil, H.; Mansour, A.;Nguyen, T.; George, S.R. Inhibition of cell surface expression by mutantreceptors demonstrates that D2 dopamine receptors exist as oligomers in thecell. Mol. Pharmacol., 2000, 58, 120-128. (Pubitemid 30452534)
121. George, S.R.; Fan, T.; Xie, Z.; Tse, R.; Tam, V.; Varghese, G.; O'Dowd, B.F. Oligomerization of mu- and delta-opioid receptors. Generation of novelfunctional properties. J. Biol. Chem., 2000, 275, 26128-26135.
122. Gomes, I.; Filipovska, J.; Jordan, B.A.; Devi, L.A. Oligomerization of opioidreceptors. Methods, 2002, 27, 358-365.
123. Wilson, S.; Wilkinson, G.; Milligan, G. The CXCR1 and CXCR2 receptorsform constitutive homo- and heterodimers selectively and with equalapparent affinities. J. Biol. Chem., 2005, 280, 28663-28674. (Pubitemid 41105767)
124. El-Asmar, L.; Springael, J.-Y.; Ballet, S.; Andrieu, E.U.; Vassart, G.;Parmentier, M. Evidence for negative binding cooperativity within CCR5-CCR2b heterodimers. Mol. Pharmacol., 2005, 67, 460-469. (Pubitemid 40216739)
125. Michineau, S.; Alhenc-Gelas, F.; Rajerison, R.M. Human bradykinin B2receptor sialylation and N-glycosylation participate with disulfide bonding insurface receptor dimerization. Biochemistry, 2006, 45, 2699-2707.
126. Cheng, Z.J.; Miller, L.J. Agonist-dependent dissociation of oligomericcomplexes of G protein-coupled cholecystokinin receptors demonstrated inliving cells using bioluminescence resonance energy transfer. J. Biol. Chem., 2001, 276, 48040-48047.
127. Sánchez-Laorden, B.L.; Sánchez-Más, J.; Martínez-Alonso, E.; Martínez-Menárguez, J.A.; García-Borrón, J.C.; Jiménez-Cervantes, C. Dimerizationof the human melanocortin 1 receptor: functional consequences anddominant-negative effects. J. Invest. Dermatol., 2006, 126, 172-181. (Pubitemid 43336110)
128. Ayoub, M.A.; Couturier, C.; Lucas-Meunier, E.; Angers, S.; Fossier, P.;Bouvier, M.; Jockers, R. Monitoring of ligand-independent dimerization andligand-induced conformational changes of melatonin receptors in living cellsby bioluminescence resonance energy transfer. J. Biol. Chem., 2002, 277, 21522-21528. (Pubitemid 34952296)
129. Thomas, R.M.; Nechamen, C.A.; Mazurkiewicz, J.E.; Muda, M.; Palmer, S.;Dias, J.A. Follice-stimulating hormone receptor forms oligomers and showsevidence of carboxyl-terminal proteolytic processing. Endocrinology, 2007, 148, 1987-1995. (Pubitemid 46997064)
130. Latif, R.; Michalek, K.; Morshed, S.A.; Davies, T.F. A tyrosine residue onthe TSH receptor stabilizes multimer formation. PLoS ONE, 2010, 5, e9449.
131. Suzuki, T.; Namba, K.; Yamagishi, R.; Kaneko, H.; Haga, T.; Nakata, H. Ahighly conserved tryptophan residue in the fourth transmembrane domain ofthe A adenosine receptor is essential for ligand binding but not receptorhomodimerization. J. Neurochem., 2009, 110, 1352-1362.
132. Zhu, C.-C.; Cook, L.B.; Hinkle, P.M. Dimerization and phosphorylation ofthyrotropin-releasing hormone receptors are modulated by agoniststimulation. J. Biol. Chem., 2002, 277, 28228-28237. (Pubitemid 34966777)
133. Héroux, M.; Hogue, M.; Lemieux, S.; Bouvier, M. Functional calcitoningene-related peptide receptors are formed by the asymmetric assembly of acalcitonin receptor-like receptor homo-oligomer and a monomer of receptoractivity-modifying protein-1. J. Biol. Chem., 2007, 282, 31610-31620. (Pubitemid 350044900)
134. Xie, Z.; Lee, S.P.; O'Dowd, B.F.; George, S.R. Serotonin 5-HT1B and 5-HT1D receptors form homodimers when expressed alone and heterodimerswhen co-expressed. FEBS Lett., 1999, 456, 63-67. (Pubitemid 29339042)
135. Xu, J.; He, J.; Castleberry, A.M.; Balasubramanian, S.; Lau, A.G.; Hall, R.A.Heterodimerization of alpha 2A- and beta 1-adrenergic receptors. J. Biol. Chem., 2003, 278, 10770-10777. (Pubitemid 36800349)
136. Mercier, J.-F.; Salahpour, A.; Angers, S;. Breit, A.; Bouvier, M. Quantitativeassessment of beta 1- and beta 2-adrenergic receptor homo- andheterodimerization by bioluminescence resonance energy transfer. J. Biol. Chem., 2002, 277, 44925-44931. (Pubitemid 36159089)
137. Lavoie, C.; Mercier, J.-F.; Salahpour, A.; Umapathy, D.; Breit, A.;Villeneuve, L.-R.; Zhu, W.-Z.; Xiao, R.-P.; Lakatta, E.G.; Bouvier, M.;Hébert, T.E. Beta 1/beta 2-adrenergic receptor heterodimerization regulatesbeta 2-adrenergic receptor internalization and ERK signaling efficacy. J. Biol. Chem., 2002, 277, 35402-35410.
138. Barki-Harrington, L.; Luttrell, L.M.; Rockman, H.A. Dual inhibition of betaadrenergicand angiotensin II receptors by a single antagonist: a functionalrole for receptor-receptor interaction in vivo. Circulation, 2003, 108, 1611-1618. (Pubitemid 37187789)
139. LaRocca, T.J.; Schwarzkopf, M.; Altman, P.; Zhang, S.; Gupta, A.; Gomes, I.; Alvin, Z.; Champion, H.C.; Haddad, G.; Hajjar, R.J.; Devi, L.A.; Schecter, A.D.; Tarzami, S.T. 2-Adrenergic receptor signaling in the cardiac myocyteis modulated by interactions with CXCR4. J. Cardiovasc. Pharmacol., 2010, 56, 548-559.
140. McGraw, D.W.; Mihlbachler, K.A.; Schwarb, M.R.; Rahman, F.F.; Small, K.M.; Almoosa, K.F.; Liggett, S.B. Airway smooth muscle prostaglandin-EP1 receptors directly modulate beta2-adrenergic receptors within a uniqueheterodimeric complex. J. Clin. Invest., 2006, 116, 1400-1409.
141. Hague, C.; Uberti, M.A.; Chen, Z.; Bush, C.F.; Jones, S.V.; Ressler, K.J.;Hall, R.A.; Minneman, K.P. Olfactory receptor surface expression is drivenby association with the beta2-adrenergic receptor. Proc. Natl. Acad. Sci. U.S. A., 2004, 101, 13672-13676. (Pubitemid 39238461)
142. Borroto-Escuela, D.O.; Craenenbroeck, K.V.; Romero-Fernandez, W.;Guidolin, D.; Woods, A.S.; Rivera, A.; Haegeman, G.; Agnati, L.F.;Tarakanov, A.O.; Fuxe, K. Dopamine D2 and D4 receptor heteromerizationand its allosteric receptor-receptor interactions. Biochem. Biophys. Res.Commun., 2011, 404, 928-934.
143. Dunham, J.H.; Meyer, R.C.; Garcia, E.L.; Hall, R.A. GPR37 surfaceexpression enhancement via N-terminal truncation or protein- proteininteractions. Biochemistry, 2009, 48, 10286-10297.
144. Ginés, S.; Hillion, J.; Torvinen, M.; Le Crom, S; Casadó, V.; Canela, E.I.;Rondin, S.; Lew, J.Y.; Watson, S.; Zoli, M.; Agnati, L.F.; Verniera, P.; Lluis, C.; Ferré, S.; Fuxe, K.; Franco, R. Dopamine D1 and adenosine A1 receptorsform functionally interacting heteromeric complexes. Proc. Natl. Acad. Sci.U. S. A., 2000, 97, 8606-8611. (Pubitemid 30639720)
145. Hillion, J.; Canals, M.; Torvinen, M.; Casado, V.; Scott, R.; Terasmaa, A.;Hansson, A.; Watson, S.; Olah, M.E.; Mallol, J.; Canela, E.I.; Zoli, M.;Agnati, L.F.; Ibanez, C.F.; Lluis, C.; Franco, R.; Ferre, S.; Fuxe, K.Coaggregation, cointernalization, and codesensitization of adenosine A2Areceptors and dopamine D2 receptors. J. Biol. Chem., 2002, 277, 18091-18097. (Pubitemid 34967623)
146. Cabello, N.; Gandía, J.; Bertarelli, D.C.G.; Watanabe, M.; Lluís, C.; Franco, R;. Ferré, S.; Luján, R.; Ciruela, F. Metabotropic glutamate type 5, dopamineD2 and adenosine A2a receptors form higher-order oligomers in living cells.J. Neurochem., 2009, 109, 1497-1507.
147. Jordan, B.A.; Devi, L.A. G-protein-coupled receptor heterodimerizationmodulates receptor function. Nature, 1999, 399, 697-700.
148. Gomes, I.; Jordan, B.A.; Gupta, A.; Trapaidze, N.; Nagy, V.; Devi, L.A.Heterodimerization of mu and delta opioid receptors: A role in opiatesynergy. J. Neurosci., 2000, 20, RC110.
149. Waldhoer, M.; Fong, J.; Jones, R.M.; Lunzer, M.M.; Sharma, S.K.; Kostenis, E.; Portoghese, P.S.; Whistler, J.L. A heterodimer-selective agonist shows invivo relevance of G protein-coupled receptor dimers. Proc. Natl. Acad. Sci.U. S. A., 2005, 102, 9050-9055. (Pubitemid 40881076)
150. Wang, D.; Sun, X.; Bohn, L.M.; Sadée, W. Opioid receptor homo- andheterodimerization in living cells by quantitative bioluminescence resonanceenergy transfer. Mol. Pharmacol., 2005, 67, 2173-2184. (Pubitemid 41007796)
151. Hasbi, A.; Nguyen, T.; Fan, T.; Cheng, R.; Rashid, A.; Alijaniaram, M.;Rasenick, M.M.; O'Dowd, B.F.; George, S.R. Trafficking of preassembledopioid mu-delta heterooligomer-Gz signaling complexes to the plasmamembrane: coregulation by agonists. Biochemistry, 2007, 46, 12997-13009. (Pubitemid 350086219)
152. Pfeiffer, M.; Kirscht, S.; Stumm, R.; Koch, T.; Wu, D.; Laugsch, M.;Schröder, H.; Höllt, V.; Schulz, S. Heterodimerization of substance P andmu-opioid receptors regulates receptor trafficking and resensitization. J. Biol. Chem., 2003, 278, 51630-51637. (Pubitemid 38020408)
153. Pfeiffer, M.; Koch, T.; Schröder, H.; Laugsch, M.; Höllt, V.; Schulz, S.Heterodimerization of somatostatin and opioid receptors cross-modulatesphosphorylation, internalization, and desensitization. J. Biol. Chem., 2002, 277, 19762-19772. (Pubitemid 34967492)
154. Pfeiffer, M.; Koch, T.; Schröder, H.; Klutzny, M.; Kirscht, S.; Kreienkamp, H.J.; Höllt, V.; Schulz, S. Homo- and heterodimerization of somatostatinreceptor subtypes. Inactivation of sst(3) receptor function byheterodimerization with sst(2A). J. Biol. Chem., 2001, 276, 14027-14036.
155. AbdAlla, S.; Lother, H.; Abdel-tawab, A.M.; Quitterer, U. The angiotensin IIAT2 receptor is an AT1 receptor antagonist. J. Biol. Chem., 2001, 276, 39721-39726.
156. AbdAlla, S.; Lother, H.; el Massiery, A.; Quitterer, U. Increased AT(1)receptor heterodimers in preeclampsia mediate enhanced angiotensin IIresponsiveness. Nat. Med., 2001, 7, 1003-1009. (Pubitemid 32937379)
157. Mellado, M.; Rodríguez-Frade, J.M.; Vila-Coro, A.J.; Fernández, S.; Martínde Ana, A.; Jones, D.R.; Torán, J.L.; Martínez A. C. Chemokine receptorhomo- or heterodimerization activates distinct signaling pathways. EMBO J., 2001, 20, 2497-2507. (Pubitemid 32452868)
158. Parenty, G.; Appelbe, S.; Milligan, G. CXCR2 chemokine receptorantagonism enhances DOP opioid receptor function via allosteric regulationof the CXCR2-DOP receptor heterodimer. Biochem. J., 2008, 412, 245-256. (Pubitemid 351758230)
159. Cheng, Z.-J.; Harikumar, K.G.; Holicky, E.L.; Miller, L.J.Heterodimerization of type A and B cholecystokinin receptors enhancesignaling and promote cell growth. J. Biol. Chem., 2003, 278, 52972-52979. (Pubitemid 38035899)
160. Rozenfeld, R.; Gupta, A.; Gagnidze, K.; Lim, M.P.; Gomes, I.; Lee-Ramos, D.; Nieto, N.; Devi, L.A. AT1R-CB1R heteromerization reveals a newmechanism for the pathogenic properties of angiotensin II. EMBO J., 2011, 30, 2350-2363.
161. Ciruela, F.; Casadó, V.; Rodrigues, R.J.; Luján, R.; Burgueño, J.; Canals, M.;Borycz, J.; Rebola, N.; Goldberg, S.R.; Mallol, J.; Cortés, A.; Canela, E.I.;López-Giménez, J.F.; Milligan, G.; Lluis, C.; Cunha, R.A.; Ferré, S.; Franco, R. Presynaptic control of striatal glutamatergic neurotransmission byadenosine A1-A2A receptor heteromers. J. Neurosci., 2006, 26, 2080-2087.
162. Yoshioka, K.; Hosoda, R.; Kuroda, Y.; Nakata, H. Hetero-oligomerization ofadenosine A1 receptors with P2Y1 receptors in rat brains. FEBS Lett., 2002, 531, 299-303. (Pubitemid 35341212)
163. Carriba, P.; Ortiz, O.; Patkar, K.; Justinova, Z.; Stroik, J.; Themann, A.;Müller, C.; Woods, A.S.; Hope, B.T.; Ciruela, F.; Casadó, V.; Canela, E.I.;Lluis, C.; Goldberg, S.R.; Moratalla, R.; Franco, R.; Ferré, S. Striataladenosine A2A and cannabinoid CB1 receptors form functional heteromericcomplexes that mediate the motor effects of cannabinoids. Neuropsychopharmacology, 2007, 32, 2249-2259. (Pubitemid 47587686)
164. Levoye, A.; Dam, J.; Ayoub, M.A.; Guillaume, J.-L.; Couturier, C.;Delagrange, P.; Jockers, R. The orphan GPR50 receptor specifically inhibitsMT1 melatonin receptor function through heterodimerization. EMBO J., 2006, 25, 3012-3023. (Pubitemid 44106754)
165. Wilson, S.J.; McGinley, K.; Huang, A.J.; Smyth, E.M. Heterodimerization ofthe alpha and beta isoforms of the human thromboxane receptor enhancesisoprostane signaling. Biochem. Biophys. Res. Commun., 2007, 352, 397-403. (Pubitemid 44838501)
166. Jones, K.A.; Borowsky, B.; Tamm, J.A.; Craig, D.A.; Durkin, M.M.; Dai, M.; Yao, W.J.; Johnson, M.; Gunwaldsen, C.; Huang, L.Y.; Tang, C.; Shen, Q.; Salon, J.A.; Morse, K.; Laz, T.; Smith, K.E.; Nagarathnam, D.; Noble, S.A.; Branchek, T.A.; Gerald, C. GABA(B) receptors function as aheteromeric assembly of the subunits GABA(B)R1 and GABA(B)R2.Nature, 1998, 396, 674-679. (Pubitemid 29003945)
167. Kaupmann, K.; Malitschek, B.; Schuler, V.; Heid, J.; Froestl, W.; Beck, P.;Mosbacher, J.; Bischoff, S.; Kulik, A.; Shigemoto, R.; Karschin, A.; Bettler, B. GABA(B)-receptor subtypes assemble into functional heteromericcomplexes. Nature, 1998, 396, 683-687. (Pubitemid 29003947)
168. White, J.H.; Wise, A.; Main, M.J.; Green, A.; Fraser, N.J.; Disney, G.H.;Barnes, A.A.; Emson, P.; Foord, S.M.; Marshall, F.H. Heterodimerization isrequired for the formation of a functional GABA(B) receptor. Nature, 1998, 396, 679-682. (Pubitemid 29003946)
169. Kumpost, J.; Syrova, Z.; Kulihova, L.; Frankova, D.; Bologna, J.-C.;Hlavackova, V.; Prezeau, L.; Kralikova, M.; Hruskova, B.; Pin, J.-P.; Blahos, J. Surface expression of metabotropic glutamate receptor variants mGluR1aand mGluR1b in transfected HEK293 cells. Neuropharmacology, 2008, 55, 409-418.
170. Gama, L.; Wilt, S.G.; Breitwieser, G.E. Heterodimerization of calciumsensing receptors with metabotropic glutamate receptors in neurons. J. Biol. Chem., 2001, 276, 39053-39059.
171. González-Maeso, J.; Ang, R.L.; Yuen, T.; Chan, P.; Weisstaub, N.V.; López-Giménez, J.F.; Zhou, M.; Okawa, Y.; Callado, L.F.; Milligan, G.; Gingrich, J.A.; Filizola, M.; Meana, J.J.; Sealfon, S.C. Identification of aserotonin/glutamate receptor complex implicated in psychosis. Nature, 2008, 452, 93-97. (Pubitemid 351355090)
172. Popoli, P.; Pèzzola, A.; Torvinen, M.; Reggio, R.; Pintor, A.; Scarchilli, L.;Fuxe, K.; Ferré, S. The selective mGlu(5) receptor agonist CHPG inhibitsquinpirole-induced turning in 6-hydroxydopamine-lesioned rats andmodulates the binding characteristics of dopamine D(2) receptors in the ratstriatum: interactions with adenosine A(2a) receptors. Neuropsychopharmacology, 2001, 25, 505-513. (Pubitemid 32830955)
173. Díaz-Cabiale, Z.; Vivó, M.; Del Arco, A.; O'Connor, W.T.; Harte, M.K.;Müller, C.E.; Martínez, E.; Popoli, P.; Fuxe, K.; Ferré, S. Metabotropicglutamate mGlu5 receptor-mediated modulation of the ventral striopallidalGABA pathway in rats. Interactions with adenosine A(2A) and dopamineD(2) receptors. Neurosci. Lett., 2002, 324, 154-158. (Pubitemid 34457827)
174. Coccurello, R.; Breysse, N.; Amalric, M. Simultaneous blockade ofadenosine A2A and metabotropic glutamate mGlu5 receptors increase theirefficacy in reversing Parkinsonian deficits in rats. Neuropsychopharmacology, 2004, 29, 1451-1461. (Pubitemid 38982237)
175. Ciruela, F.; Escriche, M.; Burgueno, J.; Angulo, E.; Casado, V.; Soloviev, M.M.; Canela, E.I.; Mallol, J.; Chan, W.Y.; Lluis, C.; McIlhinney, R.A.;Franco, R. Metabotropic glutamate 1alpha and adenosine A1 receptorsassemble into functionally interacting complexes. J. Biol. Chem., 2001, 276, 18345-18351.
176. Ferré, S.; Karcz-Kubicha, M.; Hope, B.T.; Popoli, P.; Burgueño, J.;Gutiérrez, M.A.; Casadó, V.; Fuxe, K.; Goldberg, S.R.; Lluis, C.; Franco, R.;Ciruela, F. Synergistic interaction between adenosine A2A and glutamatemGlu5 receptors: implications for striatal neuronal function. Proc. Natl. Acad. Sci. U. S. A., 2002, 99, 11940-11945. (Pubitemid 34994503)
177. Adams, C.L.; Cowen, M.S.; Short, J.L.; Lawrence, A.J. Combinedantagonism of glutamate mGlu5 and adenosine A2A receptors interact toregulate alcohol-seeking in rats. Int. J. Neuropsychopharmacol., 2008, 11, 229-241. (Pubitemid 351231820)
178. Canals, M.; Lopez-Gimenez, J.F.; Milligan, G. Cell surface delivery andstructural re-organization by pharmacological chaperones of anoligomerization-defective alpha(1b)-adrenoceptor mutant demonstratesmembrane targeting of GPCR oligomers. Biochem. J., 2009, 417, 161-172.
179. Lopez-Gimenez, J.F.; Canals, M.; Pediani, J.D.; Milligan, G. The alpha1badrenoceptorexists as a higher-order oligomer: effective oligomerization isrequired for receptor maturation, surface delivery, and function. Mol. Pharmacol., 2007, 71, 1015-1029. (Pubitemid 46457006)
180. Milligan, G.; Pediani, J.D.; Canals, M.; Lopez-Gimenez, J.F. Oligomericstructure of the alpha1b-adrenoceptor: comparisons with rhodopsin. Vision Res., 2006, 46, 4434-4441.
181. Kobayashi, H.; Ogawa, K.; Yao, R.; Lichtarge, O.; Bouvier, M. Functionalrescue of beta-adrenoceptor dimerization and trafficking by pharmacologicalchaperones. Traffic, 2009, 10, 1019-1033.
182. Łukasiewicz, S.; Faron-Górecka, A.; Dobrucki, J.; Polit, A.; Dziedzicka-Wasylewska, M. Studies on the role of the receptor protein motifs possiblyinvolved in electrostatic interactions on the dopamine D1 and D2 receptoroligomerization. FEBS J., 2009, 276, 760-775.
183. Łukasiewicz, S.; Polit, A.; Kȩdracka-Krok, S.; Wȩdzony, K.; Maćkowiak, M.; Dziedzicka-Wasylewska, M. Hetero-dimerization of serotonin 5-HT(2A)and dopamine D(2) receptors. Biochim. Biophys. Acta, 2010, 1803, 1347-1358.
184. Harikumar, K.G.; Ball, A.M.; Sexton, P.M.; Miller, L.J. Importance of lipidexposedresidues in transmembrane segment four for family B calcitoninreceptor homo-dimerization. Regul. Pept., 2010, 164, 113-119.
185. Damian, M.; Mary, S.; Martin, A.; Pin, J.-P.; Banères, J.-L. G proteinactivation by the leukotriene B4 receptor dimer. Evidence for an absence oftrans-activation. J. Biol. Chem., 2008, 283, 21084-21092.
186. Grymek, K.; Łukasiewicz, S.; Faron-Górecka, A.; Tworzydło, M.; Polit, A.;Dziedzicka-Wasylewska, M. Role of silent polymorphisms within thedopamine D1 receptor associated with schizophrenia on D1-D2 receptorhetero-dimerization. Pharmacol. Rep., 2009, 61, 1024-1033.
187. Hernanz-Falcón, P.; Rodríguez-Frade, J.M.; Serrano, A.; Juan, D.; del Sol, A.; Soriano, S.F.; Roncal, F.; Gómez, L.; Valencia, A.; Martínez A. C.;Mellado, M. Identification of amino acid residues crucial for chemokinereceptor dimerization. Nat. Immunol., 2004, 5, 216-223. (Pubitemid 38208364)
188. Guan, R.; Wu, X.; Feng, X.; Zhang, M.; Hébert, T.E.; Segaloff, D.L.Structural determinants underlying constitutive dimerization of unoccupiedhuman follitropin receptors. Cell. Signal., 2010, 22, 247-256.
189. Hlavackova, V.; Goudet, C.; Kniazeff, J.; Zikova, A.; Maurel, D.; Vol, C.;Trojanova, J.; Prézeau, L.; Pin, J.-P.; Blahos, J. Evidence for a singleheptahelical domain being turned on upon activation of a dimeric GPCR.EMBO J., 2005, 24, 499-509. (Pubitemid 40343252)
190. Pfleger, K.D.G.; Eidne, K.A. Monitoring the formation of dynamic Gprotein-coupled receptor-protein complexes in living cells. Biochem. J., 2005, 385, 625-637. (Pubitemid 40208822)
191. Gregan, B.; Jürgensen, J.; Papsdorf, G.; Furkert, J.; Schaefer, M.;Beyermann, M.; Rosenthal, W.; Oksche, A. Ligand-dependent differences inthe internalization of endothelin A and endothelin B receptor heterodimers. J. Biol. Chem., 2004, 279, 27679-27687. (Pubitemid 38812609)
192. Floyd, D.H.; Geva, A.; Bruinsma, S.P.; Overton, M.C.; Blumer, K.J.;Baranski, T.J. C5a receptor oligomerization. II. Fluorescence resonanceenergy transfer studies of a human G protein-coupled receptor expressed inyeast. J. Biol. Chem., 2003, 278, 35354-35361. (Pubitemid 37102304)
193. Toth, P.T.; Ren, D.; Miller, R.J. Regulation of CXCR4 receptor dimerizationby the chemokine SDF-1alpha and the HIV-1 coat protein gp120: afluorescence resonance energy transfer (FRET) study. J. Pharmacol. Exp.Ther., 2004, 310, 8-17. (Pubitemid 38812689)
194. Vilardaga, J.-P.; Bünemann, M.; Krasel, C.; Castro, M.; Lohse, M.J.Measurement of the millisecond activation switch of G protein- coupledreceptors in living cells. Nat. Biotechnol., 2003, 21, 807-812. (Pubitemid 36791401)
195. Overton, M.C.; Blumer, K.J. The extracellular N-terminal domain andtransmembrane domains 1 and 2 mediate oligomerization of a yeast Gprotein-coupled receptor. J. Biol. Chem., 2002, 277, 41463-41472. (Pubitemid 35257448)
196. Wurch, T.; Matsumoto, A.; Pauwels, P.J. Agonist-independent and -dependent oligomerization of dopamine D(2) receptors by fusion tofluorescent proteins. FEBS Lett., 2001, 507, 109-113. (Pubitemid 33000307)
197. Dinger, M.C.; Bader, J.E.; Kobor, A.D.; Kretzschmar, A K.; Beck-Sickinger, A.G. Homodimerization of neuropeptide y receptors investigated byfluorescence resonance energy transfer in living cells. J. Biol. Chem., 2003, 278, 10562-10571. (Pubitemid 36800325)
198. Overton, M.C.; Blumer, K.J. G-protein-coupled receptors function asoligomers in vivo. Curr. Biol., 2000, 10, 341-344. (Pubitemid 30186140)
199. Harding, P.J.; Attrill, H.; Boehringer, J.; Ross, S.; Wadhams, G.H.; Smith, E.; Armitage, J.P.; Watts, A. Constitutive dimerization of the G-proteincoupled receptor, neurotensin receptor 1, reconstituted into phospholipidbilayers. Biophys. J., 2009, 96, 964-973.
200. Łukasiewicz, S.; Błasiak, E.; Faron-Górecka, A.; Polit, A.; Tworzydło, M.;Górecki, A.; Wasylewski, Z.; Dziedzicka-Wasylewska, M. Fluorescencestudies of homooligomerization of adenosine A2A and serotonin 5-HT1Areceptors reveal the specificity of receptor interactions in the plasmamembrane. Pharmacol. Rep., 2007, 59, 379-392.
201. Cornea, A.; Janovick, J.A.; Maya-Núñez, G.; Conn, P.M. Gonadotropinreleasinghormone receptor microaggregation. Rate monitored byfluorescence resonance energy transfer. J. Biol. Chem., 2001, 276, 2153-2158. (Pubitemid 32109697)
202. Canals, M.; Burgueño, J.; Marcellino, D.; Cabello, N.; Canela, E.I.; Mallol, J.; Agnati, L.; Ferré, S.; Bouvier, M.; Fuxe, K.; Ciruela, F.; Lluis, C.; Franco, R. Homodimerization of adenosine A2A receptors: qualitative andquantitative assessment by fluorescence and bioluminescence energytransfer. J. Neurochem., 2004, 88, 726-734. (Pubitemid 38140216)
203. Canals, M.; Marcellino, D.; Fanelli, F.; Ciruela, F.; de Benedetti, P.;Goldberg, S.R.; Neve, K.; Fuxe, K.; Agnati, L.F.; Woods, A.S.; Ferré, S.;Lluis, C.; Bouvier, M.; Franco, R. Adenosine A2A-dopamine D2 receptorreceptorheteromerization: qualitative and quantitative assessment byfluorescence and bioluminescence energy transfer. J. Biol. Chem., 2003, 278, 46741-46749. (Pubitemid 37452253)
204. Cheung, T.C.; Hearn, J.P. Development of a baculovirus-based fluorescenceresonance energy transfer assay for measuring protein-protein interaction.Eur. J. Biochem., 2003, 270, 4973-4981. (Pubitemid 38021578)
205. Horvat, R.D.; Roess, D.A.; Nelson, S.E.; Barisas, B.G.; Clay, C.M. Bindingof agonist but not antagonist leads to fluorescence resonance energy transferbetween intrinsically fluorescent gonadotropin-releasing hormone receptors.Mol. Endocrinol., 2001, 15, 695-703. (Pubitemid 32411310)
206. Latif, R.; Graves, P.; Davies, T.F. Oligomerization of the human thyrotropinreceptor: fluorescent protein-tagged hTSHR reveals post-translationalcomplexes. J. Biol. Chem., 2001, 276, 45217-45224.
207. McVey, M.; Ramsay, D.; Kellett, E.; Rees, S.; Wilson, S.; Pope, A.J.;Milligan, G. Monitoring receptor oligomerization using time- resolvedfluorescence resonance energy transfer and bioluminescence resonanceenergy transfer. The human delta -opioid receptor displays constitutiveoligomerization at the cell surface, which is not regulated by receptoroccupancy. J. Biol. Chem., 2001, 276, 14092-14099.
208. Bakker, R.A.; Dees, G. Carrillo, J.J.; Booth, R.G.; López-Gimenez, J.F.;Milligan, G.; Strange, P.G.; Leurs, R. Domain swapping in the humanhistamine H1 receptor. J. Pharmacol. Exp. Ther., 2004, 311, 131-138.
209. Liu, J.; Maurel, D.; Etzol, S.; Brabet, I.; Ansanay, H.; Pin, J.-P.; Rondard, P.Molecular determinants involved in the allosteric control of agonist affinityin the GABAB receptor by the GABAB2 subunit. J. Biol. Chem., 2004, 279, 15824-15830. (Pubitemid 38509269)
210. Maurel, D.; Kniazeff, J.; Mathis, G.; Trinquet, E.; Pin, J.-P.; Ansanay, H.Cell surface detection of membrane protein interaction with homogeneoustime-resolved fluorescence resonance energy transfer technology. Anal.Biochem., 2004, 329, 253-262. (Pubitemid 38680506)
211. Albizu, L.; Cottet, M.; Kralikova, M.; Stoev, S.; Seyer, R.; Brabet, I.; Roux, T.; Bazin, H.; Bourrier, E; Lamarque, L.; Breton, C.; Rives, M.-L.; Newman, A.; Javitch, J.; Trinquet, E.; Manning, M.; Pin, J.-P.; Mouillac, B.; Durroux, T. Time-resolved FRET between GPCR ligands reveals oligomers in nativetissues. Nat. Chem. Biol., 2010, 6, 587-594.
212. Rocheville, M.; Lange, D.C.; Kumar, U.; Patel, S.C.; Patel, R.C.; Patel, Y.C.Receptors for dopamine and somatostatin: formation of hetero-oligomerswith enhanced functional activity. Science, 2000, 288, 154-157. (Pubitemid 30203051)
213. Patel, R.C.; Kumar, U.; Lamb, D.C.; Eid, J.S.; Rocheville, M.; Grant, M.;Rani, A.; Hazlett, T.; Patel, S.C.; Gratton, E.; Patel, Y.C. Ligand binding tosomatostatin receptors induces receptor-specific oligomer formation in livecells. Proc. Natl. Acad. Sci. U. S. A., 2002, 99, 3294-3299. (Pubitemid 34240625)
214. Grant, M.; Collier, B.; Kumar, U. Agonist-dependent dissociation of humansomatostatin receptor 2 dimers: a role in receptor trafficking. J. Biol. Chem., 2004, 279, 36179-36183. (Pubitemid 39128952)
215. Latif, R.; Graves, P.; Davies, T.F. Ligand-dependent inhibition ofoligomerization at the human thyrotropin receptor. J. Biol. Chem., 2002, 277, 45059-45067. (Pubitemid 36159106)
216. Roess, D.A.; Horvat, R.D.; Munnelly, H.; Barisas, B.G. Luteinizing hormonereceptors are self-associated in the plasma membrane. Endocrinology, 2000, 141, 4518-4523. (Pubitemid 32055129)
217. Gandía, J.; Lluís, C.; Ferré, S.; Franco, R.; Ciruela, F. Light resonanceenergy transfer-based methods in the study of G protein-coupled receptoroligomerization. Bioessays, 2008, 30, 82-89.
218. Mayor, S.; Bilgrami, S. In: Evaluating Techniques in Biochemical Research;Cell Press: Cambridge, MA, 2007.
219. Patel, R.C.; Lange, D.C.; Patel, Y.C. Photobleaching fluorescence resonanceenergy transfer reveals ligand-induced oligomer formation of humansomatostatin receptor subtypes. Methods, 2002, 27, 340-348.
220. Cottet, M.; Albizu, L.; Comps-Agrar, L;. Trinquet, E.; Pin, J.-P.; Mouillac, B.; Durroux, T. Time resolved FRET strategy with fluorescent ligands toanalyze receptor interactions in native tissues: application to GPCRoligomerization. Methods Mol. Biol., 2011, 746, 373-387.
221. Ganguly, S.; Clayton, A.H.A.; Chattopadhyay, A. Organization of higherorderoligomers of the serotonin(1A) receptor explored utilizing Homo-FRET in live cells. Biophys. J., 2011, 100, 361-368.
222. Herrick-Davis, K.; Grinde, E.; Harrigan, T.J.; Mazurkiewicz, J.E. Inhibitionof serotonin 5-hydroxytryptamine2c receptor function throughheterodimerization: receptor dimers bind two molecules of ligand and one Gprotein.J. Biol. Chem., 2005, 280, 40144-40151. (Pubitemid 41779150)
223. Kong, M.M.C.; Fan, T.; Varghese, G.; O'Dowd, B.F.; George, S.R. Agonistinducedcell surface trafficking of an intracellularly sequestered D1dopamine receptor homo-oligomer. Mol. Pharmacol., 2006, 70, 78-89.
224. Albizu, L.; Balestre, M.-N.; Breton, C.; Pin, J.-P.; Manning, M.; Mouillac, B.; Barberis, C.; Durroux, T. Probing the existence of G protein-coupledreceptor dimers by positive and negative ligand-dependent cooperativebinding. Mol. Pharmacol., 2006, 70, 1783-1791.
225. Vidi, P.-A.; Chen, J.; Irudayaraj, J.M.K.; Watts, V.J. Adenosine A(2A)receptors assemble into higher-order oligomers at the plasma membrane.FEBS Lett., 2008, 582, 3985-3990.
226. Overton, M.C.; Blumer, K.J. Use of fluorescence resonance energy transferto analyze oligomerization of G-protein-coupled receptors expressed inyeast. Methods, 2002, 27, 324-332.
227. Vilardaga, J.-P.; Nikolaev, V.O.; Lorenz, K.; Ferrandon, S.; Zhuang, Z.;Lohse, M.J. Conformational cross-talk between alpha2A-adrenergic and muopioidreceptors controls cell signaling. Nat. Chem. Biol., 2008, 4, 126-131.
228. Marcellino, D.; Ferré, S.; Casadó, V.; Cortés, A.; Le Foll, B.; Mazzola, C.;Drago, F.; Saur, O.; Stark, H.; Soriano, A.; Barnes, C.; Goldberg, S.R.; Lluis, C.; Fuxe, K.; Franco, R. Identification of dopamine D1-D3 receptorheteromers. Indications for a role of synergistic D1-D3 receptor interactionsin the striatum. J. Biol. Chem., 2008, 283, 26016-26025.
229. So, C.H.; Verma, V.; Alijaniaram, M.; Cheng, R.; Rashid, A.J.; O'Dowd, B.F.; George, S.R. Calcium signaling by dopamine D5 receptor and D5-D2receptor hetero-oligomers occurs by a mechanism distinct from that fordopamine D1-D2 receptor hetero-oligomers. Mol. Pharmacol., 2009, 75, 843-854.
230. Kota, P.; Reeves, P.J.; Rajbhandary, U.L.; Khorana, H.G. Opsin is present asdimers in COS1 cells: identification of amino acids at the dimeric interface.Proc. Natl. Acad. Sci. U. S. A., 2006, 103, 3054-3059. (Pubitemid 43346423)
231. Mansoor, S.E.; Palczewski, K.; Farrens, D.L. Rhodopsin self-associates inasolectin liposomes. Proc. Natl. Acad. Sci. U. S. A., 2006, 103, 3060-3065.
232. Tateyama, M.; Abe, H.; Nakata, H.; Saito, O.; Kubo, Y. Ligand-inducedrearrangement of the dimeric metabotropic glutamate receptor 1alpha. Nat.Struct. Mol. Biol., 2004, 11, 637-642. (Pubitemid 38823530)
233. Maurel, D.; Comps-Agrar, L.; Brock, C.; Rives, M.-L.; Bourrier, E.; Ayoub, M.A.; Bazin, H.; Tinel, N.; Durroux, T.; Prézeau, L.; Trinquet, E.; Pin, J.-P.Cell-surface protein-protein interaction analysis with time-resolved FRETand snap-tag technologies: application to GPCR oligomerization. Nat. Methods, 2008, 5, 561-567. (Pubitemid 351761765)
234. Brock, C.; Oueslati, N.; Soler, S.; Boudier, L; Rondard, P.; Pin, J.-P.Activation of a dimeric metabotropic glutamate receptor by intersubunitrearrangement. J. Biol. Chem., 2007, 282, 33000-33008. (Pubitemid 350161742)
235. Marcellino, D.; Carriba, P.; Filip, M.; Borgkvist, A.; Frankowska, M.;Bellido, I.; Tanganelli, S.; Müller, C.E.; Fisone, G.; Lluis, C.; Agnati, L.F.;Franco, R.; Fuxe, K. Antagonistic cannabinoid CB1/dopamine D2 receptorinteractions in striatal CB1/D2 heteromers. A combined neurochemical andbehavioral analysis. Neuropharmacology, 2008, 54, 815-823.
236. Pello, O.M.; Martínez-Muñoz, L.; Parrillas, V.; Serrano, A.; Rodríguez-Frade, J.M.; Toro, M.J.; Lucas, P.; Monterrubio, M.; Martínez A. C.;Mellado, M. Ligand stabilization of CXCR4/delta-opioid receptorheterodimers reveals a mechanism for immune response regulation. Eur. J.Immunol., 2008, 38, 537-549.
237. Rediger, A.; Tarnow, P.; Bickenbach, A.; Schaefer, M.; Krude, H.; Gruters, A.; Biebermann, H. Heterodimerization of hypothalamic G-protein-coupledreceptors involved in weight regulation. Obes. Facts, 2009, 2, 80-86.
238. Ellis, J.; Pediani, J.D.; Canals, M.; Milasta, S.; Milligan, G. Orexin-1receptor-cannabinoid CB1 receptor heterodimerization results in both liganddependentand -independent coordinated alterations of receptor localizationand function. J. Biol. Chem., 2006, 281, 38812-38824. (Pubitemid 46042008)
239. Goudet, C.; Kniazeff, J.; Hlavackova, V.; Malhaire, F.; Maurel, D.; Acher, F.; Blahos, J.; Prézeau, L.; Pin, J.-P. Asymmetric functioning of dimericmetabotropic glutamate receptors disclosed by positive allosteric modulators.J. Biol. Chem., 2005, 280, 24380-24385. (Pubitemid 40934521)
240. Boyer, S.B.; Clancy, S.M.; Terunuma, M.; Revilla-Sanchez, R.; Thomas, S.M.; Moss, S.J.; Slesinger, P.A. Direct interaction of GABAB receptorswith M2 muscarinic receptors enhances muscarinic signaling. J. Neurosci., 2009, 29, 15796-15809.
241. Kroeger, K.M.; Hanyaloglu, A.C.; Seeber, R.M.; Miles, L.E.; Eidne, K.A.Constitutive and agonist-dependent homo-oligomerization of the thyrotropinreleasinghormone receptor. Detection in living cells using bioluminescenceresonance energy transfer. J. Biol. Chem., 2001, 276, 12736-12743.
242. Lemay, J.; Marullo, S.; Jockers, R.; Alizon, M.; Brelot, A. On thedimerization of CCR5. Nat. Immunol., 2005, 6, 535; author reply 535-536.
243. Bergendahl, V.; Heyduk, T.; Burgess, R.R. Luminescence Resonance EnergyTransfer-based high-throughput screening assay for inhibitors of essentialprotein-protein interactions in bacterial RNA polymerase. Appl. Environ.Microbiol., 2003, 69, 1492-1498. (Pubitemid 36314286)
244. Salahpour, A.; Angers, S.; Mercier, J.-F.; Lagacé, M.; Marullo, S.; Bouvier, M. Homodimerization of the beta2-adrenergic receptor as a prerequisite forcell surface targeting. J. Biol. Chem., 2004, 279, 33390-33397. (Pubitemid 39062987)
245. Breit, A.; Gagnidze, K.; Devi, L.A.; Lagacé, M.; Bouvier, M. Simultaneousactivation of the delta opioid receptor (deltaOR)/sensory neuron-specificreceptor-4 (SNSR-4) hetero-oligomer by the mixed bivalent agonist bovineadrenal medulla peptide 22 activates SNSR-4 but inhibits deltaOR signaling.Mol. Pharmacol., 2006, 70, 686-696. (Pubitemid 44092329)
246. Ramsay, D.; Kellett, E.; McVey, M.; Rees, S.; Milligan, G. Homo- andhetero-oligomeric interactions between G-protein-coupled receptors in livingcells monitored by two variants of bioluminescence resonance energytransfer (BRET): hetero-oligomers between receptor subtypes form moreefficiently than between less closely related sequences. Biochem. J., 2002, 365, 429-440. (Pubitemid 36135314)
247. Issafras, H.; Angers, S.; Bulenger, S.; Blanpain, C.; Parmentier, M.; Labbé-Jullié, C.; Bouvier, M.; Marullo, S. Constitutive agonist-independent CCR5oligomerization and antibody-mediated clustering occurring at physiologicallevels of receptors. J. Biol. Chem., 2002, 277, 34666-34673.
248. Babcock, G.J.; Farzan, M.; Sodroski, J. Ligand-independent dimerization ofCXCR4, a principal HIV-1 coreceptor. J. Biol. Chem., 2003, 278, 3378-3385. (Pubitemid 36801253)
249. Svendsen, A.M.; Vrecl, M.; Ellis, T.M.; Heding, A.; Kristensen, J.B.; Wade, J.D.; Bathgate, R.A.D.; De Meyts, P.; Nøhr, J. Cooperative binding ofinsulin-like Peptide 3 to a dimeric relaxin family peptide receptor 2.Endocrinology, 2008, 149, 1113-1120. (Pubitemid 351397932)
250. Mandrika, I.; Petrovska, R.; Klovins, J. Evidence for constitutivedimerization of niacin receptor subtypes. Biochem. Biophys. Res. Commun., 2010, 395, 281-287.
251. Hanyaloglu, A.C.; Seeber, R.M.; Kohout, T.A.; Lefkowitz, R.J.; Eidne, K.A.Homo- and hetero-oligomerization of thyrotropin-releasing hormone (TRH)receptor subtypes. Differential regulation of beta-arrestins 1 and 2. J. Biol. Chem., 2002, 277, 50422-50430. (Pubitemid 36042194)
252. Hague, C.; Uberti, M.A.; Chen, Z.; Hall, R.A.; Minneman, K.P. Cell surfaceexpression of alpha1D-adrenergic receptors is controlled byheterodimerization with alpha1B-adrenergic receptors. J. Biol. Chem., 2004, 279, 15541-15549. (Pubitemid 38618955)
253. Breit, A.; Lagacé, M.; Bouvier, M. Hetero-oligomerization between beta2-and beta3-adrenergic receptors generates a beta-adrenergic signaling unitwith distinct functional properties. J. Biol. Chem., 2004, 279, 28756-28765. (Pubitemid 38900160)
254. 2A) receptors assemble into functionallyinteracting heteromers. Biochem. Biophys. Res. Commun., 2010, 401, 605-610.
255. Jordan, B.A.; Gomes, I.; Rios, C.; Filipovska, J.; Devi, L.A. Functionalinteractions between mu opioid and alpha 2A-adrenergic receptors. Mol. Pharmacol., 2003, 64, 1317-1324. (Pubitemid 37532221)
256. Gomes, I.; Gupta, A.; Filipovska, J.; Szeto, H.H.; Pintar, J.E.; Devi, L.A. Arole for heterodimerization of mu and delta opiate receptors in enhancingmorphine analgesia. Proc. Natl. Acad. Sci. U. S. A., 2004, 101, 5135-5139. (Pubitemid 38469214)
257. Rios, C.; Gomes, I.; Devi, L.A. mu opioid and CB1 cannabinoid receptorinteractions: reciprocal inhibition of receptor signaling and neuritogenesis.Br. J. Pharmacol., 2006, 148, 387-395. (Pubitemid 43882074)
258. James, J.R.; Oliveira, M.I.; Carmo, A.M.; Iaboni, A.; Davis, S.J. A rigorousexperimental framework for detecting protein oligomerization usingbioluminescence resonance energy transfer. Nat. Methods, 2006, 3, 1001-1006. (Pubitemid 44782699)
259. McMillin, S.M.; Heusel, M.; Liu, T.; Costanzi, S.; Wess, J. Structural basisof M3 muscarinic receptor dimer/oligomer formation. J. Biol. Chem., 2011, 286, 28584-28598.
260. Urizar, E.; Montanelli, L.; Loy, T.; Bonomi, M.; Swillens, S.; Gales, C.;Bouvier, M.; Smits, G;. Vassart, G.; Costagliola, S. Glycoprotein hormonereceptors: link between receptor homodimerization and negativecooperativity. EMBO J., 2005, 24, 1954-1964. (Pubitemid 40896167)
261. Kamiya, T.; Saitoh, O.; Yoshioka, K.; Nakata, H. Oligomerization ofadenosine A2A and dopamine D2 receptors in living cells. Biochem. Biophys. Res. Commun., 2003, 306, 544-549. (Pubitemid 36683109)
262. Gandia, J.; Galino, J.; Amaral, O.B.; Soriano, A.; Lluís, C.; Franco, R.;Ciruela, F. Detection of higher-order G protein-coupled receptor oligomersby a combined BRET-BiFC technique. FEBS Lett., 2008, 582, 2979-2984.
263. Héroux, M.; Breton, B.; Hogue, M.; Bouvier, M. Assembly and signaling ofCRLR and RAMP1 complexes assessed by BRET. Biochemistry, 2007, 46, 7022-7033. (Pubitemid 46906431)
264. Jensen, A.A.; Hansen, J.L.; Sheikh, S.P.; Bräuner-Osborne, H. Probingintermolecular protein-protein interactions in the calcium-sensing receptorhomodimer using bioluminescence resonance energy transfer (BRET). Eur. J. Biochem., 2002, 269, 5076-5087. (Pubitemid 35282451)
265. Hudson, B.D.; Hébert, T.E.; Kelly, M.E.M. Physical and functionalinteraction between CB1 cannabinoid receptors and beta2-adrenoceptors. Br.J. Pharmacol., 2010, 160, 627-642.
266. Ferrada, C.; Moreno, E.; Casadó, V.; Bongers, G.; Cortés, A.; Mallol, J.;Canela, E.I.; Leurs, R.; Ferré, S.; Lluís, C.; Franco, R. Marked changes insignal transduction upon heteromerization of dopamine D1 and histamine H3 receptors. Br. J. Pharmacol., 2009, 157, 64-75.
267. Juhasz, J.R.; Hasbi, A.; Rashid, A.J.; So, C.H.; George, S.R.; O'Dowd, B.F.Mu-opioid receptor heterooligomer formation with the dopamine D1 receptoras directly visualized in living cells. Eur. J. Pharmacol., 2008, 581, 235-243.
268. Ferrada, C.; Ferré, S.; Casadó, V.; Cortés, A.; Justinova, Z.; Barnes, C.;Canela, E.I.; Goldberg, S.R.; Leurs, R.; Lluis, C.; Franco, R. Interactionsbetween histamine H3 and dopamine D2 receptors and the implications forstriatal function. Neuropharmacology, 2008, 55, 190-197.
269. Ciruela, F.; Burgueño, J.; Casadó, V.; Canals, M.; Marcellino, D.; Goldberg, S.R.; Bader, M.; Fuxe, K.; Agnati, L.F.; Lluis, C.; Franco, R.; Ferré, S.;Woods, A.S. Combining mass spectrometry and pull-down techniques for thestudy of receptor heteromerization. Direct epitope-epitope electrostaticinteractions between adenosine A2A and dopamine D2 receptors. Anal.Chem., 2004, 76, 5354-5363. (Pubitemid 39249416)
270. Navarro, G.; Carriba, P.; Gandía, J.; Ciruela, F.; Casadó, V.; Cortés, A.;Mallol, J.; Canela, E.I.; Lluis, C.; Franco, R. Detection of heteromers formedby cannabinoid CB1, dopamine D2, and adenosine A2A G-protein-coupledreceptors by combining bimolecular fluorescence complementation andbioluminescence energy transfer. ScientificWorldJournal, 2008, 8, 1088-1097.
271. Navarro, G.; Aymerich, M.S.; Marcellino, D.; Cortés, A.; Casadó, V.;Mallol, J.; Canela, E.I.; Agnati, L.; Woods, A.S.; Fuxe, K.; Lluís, C.;Lanciego, J.L.; Ferré, S.; Franco, R. Interactions between calmodulin, adenosine A2A, and dopamine D2 receptors. J. Biol. Chem., 2009, 284, 28058-28068.
272. Hudson, B.D.; Hébert, T.E.; Kelly, M.E.M. Ligand- and heterodimerdirectedsignaling of the CB(1) cannabinoid receptor. Mol. Pharmacol., 2010, 77, 1-9.
273. Sohy, D.; Parmentier, M.; Springael, J.-Y. Allosteric transinhibition byspecific antagonists in CCR2/CXCR4 heterodimers. J. Biol. Chem., 2007, 282, 30062-30069. (Pubitemid 350035295)
274. Harikumar, K.G.; Morfis, M.M.; Sexton, P.M.; Miller, L.J. Pattern of intrafamilyhetero-oligomerization involving the G-protein-coupled secretinreceptor. J. Mol. Neurosci., 2008, 36, 279-285.
275. Alvarez-Curto, E.; Pediani, J.D.; Milligan, G. Applications of fluorescenceand bioluminescence resonance energy transfer to drug discovery at Gprotein coupled receptors. Anal. Bioanal. Chem., 2010, 398, 167-180.
276. Vidi, P.-A.; Watts, V.J. Fluorescent and bioluminescent protein-fragmentcomplementation assays in the study of G protein-coupled receptoroligomerization and signaling. Mol. Pharmacol., 2009, 75, 733-739.
277. Vidi, P.-A.; Ejendal, K.F.K.; Przybyla, J.A.; Watts, V.J. Fluorescent proteincomplementation assays: new tools to study G protein-coupled receptoroligomerization and GPCR-mediated signaling. Mol. Cell. Endocrinol., 2011, 331, 185-193.
278. Vidi, P.-A.; Chemel, B.R.; Hu, C.-D.; Watts, V.J. Ligand- dependentoligomerization of dopamine D(2) and adenosine A(2A) receptors in livingneuronal cells. Mol. Pharmacol., 2008, 74, 544-551.
279. Ciruela, F.; Vilardaga, J.-P.; Fernández-Dueñas, V. Lighting up multiproteincomplexes: lessons from GPCR oligomerization. Trends Biotechnol., 2010, 28, 407-415.
280. Gautier, A.; Juillerat, A.; Heinis, C.; Corrêa, I.R. Jr; Kindermann, M.;Beaufils, F.; Johnsson, K. An engineered protein tag for multiprotein labelingin living cells. Chem. Biol., 2008, 15, 128-136. (Pubitemid 351253620)
281. Kumar, R.L.; Cruzat, A.; Hamrah, P. Current state of in vivo confocalmicroscopy in management of microbial keratitis. Semin. Ophthalmol., 2010, 25, 166-170.
282. Prinster, S.C.; Holmqvist, T.G.; Hall, R.A. Alpha2C-adrenergic receptorsexhibit enhanced surface expression and signaling upon association withbeta2-adrenergic receptors. J. Pharmacol. Exp. Ther., 2006, 318, 974-981. (Pubitemid 44268302)
283. Rivero-Müller, A.; Chou, Y.-Y.; Ji, I.; Lajic, S.; Hanyaloglu, A.C.; Jonas, K.;Rahman, N.; Ji, T.H.; Huhtaniemi, I. Rescue of defective G protein-coupledreceptor function in vivo by intermolecular cooperation. Proc. Natl. Acad.Sci. U. S. A., 2010, 107, 2319-2324.
284. Braeckmans, K.; Buyens, K.; Naeye, B.; Vercauteren, D.; Deschout, H.;Raemdonck, K.; Remaut, K.; Sanders, N.N.; Demeester, J.; De Smedt, S.C.Advanced fluorescence microscopy methods illuminate the transfectionpathway of nucleic acid nanoparticles. J. Control. Release, 2010, 148, 69-74.
285. Dorsch, S.; Klotz, K.-N.; Engelhardt, S.; Lohse, M.J.; Bünemann, M.Analysis of receptor oligomerization by FRAP microscopy. Nat. Methods, 2009, 6, 225-230.
286. Boyer, S.B.; Slesinger, P.A. Probing novel GPCR interactions using acombination of FRET and TIRF. Commun. Integr. Biol., 2010, 3, 343-346.
287. Hern, J.A.; Baig, A.H.; Mashanov, G.I.; Birdsall, B.; Corrie, J.E.T.;Lazareno, S.; Molloy, J.E.; Birdsall, N.J.M. Formation and dissociation ofM1 muscarinic receptor dimers seen by total internal reflection fluorescenceimaging of single molecules. Proc. Natl. Acad. Sci. U. S. A., 2010, 107, 2693-2698.
288. Pavani, S.R.P.; Thompson, M A.; Biteen, J.S.; Lord, S.J.; Liu, N.; Twieg, R.J.; Piestun, R.; Moerner, W.E. Three-dimensional, single-moleculefluorescence imaging beyond the diffraction limit by using a double-helixpoint spread function. Proc. Natl. Acad. Sci. U. S. A., 2009, 106, 2995-2999.
289. Betzig, E.; Patterson, G.H.; Sougrat, R.; Lindwasser, O.W.; Olenych, S.;Bonifacino, J.S.; Davidson, M.W.; Lippincott-Schwartz, J.; Hess, H.F.Imaging intracellular fluorescent proteins at nanometer resolution. Science, 2006, 313, 1642-1645. (Pubitemid 44414039)
290. Rust, M.J.; Bates, M.; Zhuang, X. Sub-diffraction-limit imaging bystochastic optical reconstruction microscopy (STORM). Nat. Methods, 2006, 3, 793-795. (Pubitemid 44445825)
291. Hess, S.T.; Girirajan, T.P.K.; Mason, M.D. Ultra-high resolution imaging byfluorescence photoactivation localization microscopy. Biophys. J., 2006, 91, 4258-4272. (Pubitemid 44887284)
292. Suda, K.; Filipek, S.; Palczewski, K.; Engel, A.; Fotiadis, D. Thesupramolecular structure of the GPCR rhodopsin in solution and native discmembranes. Mol. Membr. Biol., 2004, 21, 435-446. (Pubitemid 40030219)
293. Mayhew, T.M.; Lucocq, J.M. Developments in cell biology for quantitativeimmunoelectron microscopy based on thin sections: a review. Histochem.Cell Biol., 2008, 130, 299-313.
294. Salom, D.; Lodowski, D.T.; Stenkamp, R.E.; Le Trong, I.; Golczak, M.;Jastrzebska, B.; Harris, T.; Ballesteros, J.A.; Palczewski, K. Crystal structureof a photoactivated deprotonated intermediate of rhodopsin. Proc. Natl. Acad. Sci. U. S. A., 2006, 103, 16123-16128. (Pubitemid 44715162)
295. Essen, L.; Siegert, R.; Lehmann, W.D.; Oesterhelt, D. Lipid patches inmembrane protein oligomers: crystal structure of the bacteriorhodopsin- lipidcomplex. Proc. Natl. Acad. Sci. U. S. A., 1998, 95, 11673-11678. (Pubitemid 28460473)
296. Lee, S.P.; O'Dowd, B.F.; Rajaram, R.D.; Nguyen, T.; George, S.R. D2dopamine receptor homodimerization is mediated by multiple sites ofinteraction, including an intermolecular interaction involving transmembranedomain 4. Biochemistry, 2003, 42, 11023-11031. (Pubitemid 37174394)
297. Lodowski, D.T.; Salom, D.; Le Trong, I.; Teller, D.C.; Ballesteros, J.A.;Palczewski, K.; Stenkamp, R.E. Crystal packing analysis of Rhodopsincrystals. J. Struct. Biol., 2007, 158, 455-462.
298. Przybyla, J.A.; Watts, V.J. Ligand-induced regulation and localization ofcannabinoid CB1 and dopamine D2L receptor heterodimers. J. Pharmacol.Exp. Ther. 2010, 332, 710-719.
299. Berque-Bestel, I.; Lezoualc'h, F.; Jockers, R. Bivalent ligands as specificpharmacological tools for G protein-coupled receptor dimers. Curr. DrugDiscov. Technol., 2008, 5, 312-318.
300. Liu, Z.; Zhang, J.; Zhang, A. Design of multivalent ligand targeting Gprotein-coupled receptors. Curr. Pharm. Des., 2009, 15, 682-718.
301. van Rijn, R.M.; Whistler, J.L.; Waldhoer, M. Opioid-receptor- heteromerspecifictrafficking and pharmacology. Curr. Opin. Pharmacol., 2010, 10, 73-79.
302. Bhushan, R.G.; Sharma, S.K.; Xie, Z.; Daniels, D.J.; Portoghese, P.S. ABivalent ligand (KDN-21) reveals spinal δ and κ opioid receptors areorganized as heterodimers that give rise to δ1 and κ2 phenotypes. Selectivetargeting of δ-κ heterodimers. J. Med. Chem., 2004, 47, 2969-2972. (Pubitemid 38702692)
303. Huber, D.; Hübner, H.; Gmeiner, P. 1, 1'-Disubstituted ferrocenes asmolecular hinges in mono- and bivalent dopamine receptor ligands. J. Med.Chem., 2009, 52, 6860-6870.
304. Soriano, A.; Ventura, R.; Molero, A.; Hoen, R.; Casadó, V.; Cortés, A.;Fanelli, F.; Albericio, F.; Lluís, C.; Franco, R.; Royo, M. Adenosine A2Areceptor-antagonist/dopamine D2 receptor-agonist bivalent ligands aspharmacological tools to detect A2A-D2 receptor heteromers. J. Med. Chem., 2009, 52, 5590-5602.
305. Karellas, P.; McNaughton, M.; Baker, S.P.; Scammells, P.J. Synthesis ofbivalent beta2-adrenergic and adenosine A1 receptor ligands. J. Med. Chem., 2008, 51, 6128-6137.
306. Soulier, J.-L.; Russo, O.; Giner, M.; Rivail, L.; Berthouze, M.; Ongeri, S.;Maigret, B.; Fischmeister, R.; Lezoualc'h, F.; Sicsic, S.; Berque-Bestel, I.Design and synthesis of specific probes for human 5-HT4 receptordimerization studies. J. Med. Chem., 2005, 48, 6220-6228. (Pubitemid 41428977)
307. Russo, O.; Berthouze, M.; Giner, M.; Soulier, J.-L.; Rivail, L.; Sicsic, S.;Lezoualc'h, F.; Jockers, R.; Berque-Bestel, I. Synthesis of specific bivalentprobes that functionally interact with 5-HT(4) receptor dimers. J. Med.Chem., 2007, 50, 4482-4492. (Pubitemid 47378844)
308. Lezoualc'h, F.; Jockers, R.; Berque-Bestel, I. Multivalent-based drug designapplied to serotonin 5-HT(4) receptor oligomers. Curr. Pharm. Des., 2009, 15, 719-729.
309. Tanaka, T.; Nomura, W.; Narumi, T.; Masuda, A.; Tamamura, H. Bivalentligands of CXCR4 with rigid linkers for elucidation of the dimerization statein cells. J. Am. Chem. Soc., 2010, 132, 15899-15901.
310. Zhang, Y.; Gilliam, A.; Maitra, R.; Damaj, M.I.; Tajuba, J.M.; Seltzman, H.H.; Thomas, B.F. Synthesis and biological evaluation of bivalent ligandsfor the cannabinoid 1 receptor. J. Med. Chem., 2010, 53, 7048-7060.
311. Bonger, K.M.; van den Berg, R.J.B.H.N.; Heitman, L.H.; Ijzerman, A.P.;Oosterom, J.; Timmers, C.M.; Overkleeft, H.S.; van der Marel, G.A.Synthesis and evaluation of homo-bivalent GnRHR ligands. Bioorg. Med.Chem., 2007, 15, 4841-4856. (Pubitemid 46836839)
312. Bonger, K.M.; van den Berg, R.J.B.H.N.; Knijnenburg, A.D.; Heitman, L.H.;Ijzerman, A.P.; Oosterom, J.; Timmers, C.M.; Overkleeft, H.S.; van derMarel, G.A. Synthesis and evaluation of homodimeric GnRHR antagonistshaving a rigid bis-propargylated benzene core. Bioorg. Med. Chem., 2008, 16, 3744-3758. (Pubitemid 351484036)
313. Morphy, R.; Rankovic, Z. The physicochemical challenges of designingmultiple ligands. J. Med. Chem., 2006, 49, 4961-4970.
314. Morphy, R.; Rankovic, Z. Designing multiple ligands - medicinal chemistrystrategies and challenges. Curr. Pharm. Des., 2009, 15, 587-600.