489
Views
35
CrossRef citations to date
0
Altmetric
Review

G-protein-coupled receptor type A heteromers as an emerging therapeutic target

, PhD (Assistant Professor) , , MD (Emeritus Professor) , , MD (Assistant Professor) , , PhD (Research Scientist) & , MD (Emeritus Professor)

Bibliography

  • Agnati LF, Fuxe K, Zini I, et al. Aspects on receptor regulation and isoreceptor identification. Med Biol 1980;58:182-7
  • Fuxe K, Agnati LF, Benfenati F, et al. Evidence for the existence of receptor–receptor interactions in the central nervous system. Studies on the regulation of monoamine receptors by neuropeptides. J Neural Transm Suppl 1983;18:165-79
  • Limbird LE, Meyts PD, Lefkowitz RJ. Beta-adrenergic receptors:evidence for negative cooperativity. Biochem Biophys Res Commun 1975;64:1160-8
  • Marshall FH, White J, Main M, et al. GABA(B) receptors function as heterodimers. Biochem Soc Trans 1999;27:530-5
  • Fuxe K, Ferre S, Zoli M, et al. Integrated events in central dopamine transmission as analyzed at multiple levels. Evidence for intramembrane adenosine A2A/dopamine D2 and adenosine A1/dopamine D1 receptor interactions in the basal ganglia. Brain Res Brain Res Rev 1998;26:258-73
  • Franco R, Ferré S, Agnati L, et al. Evidence for adenosine/dopamine receptor interactions: indications for heteromerization. Neuropsychopharmacology 2000;23:S50-9
  • Angers S, Salahpour A, Bouvier M. Biochemical and biophysical demonstration of GPCR oligomerization in mammalian cells. Life Sci 2001;68:2243-50
  • Dean MK, Higgs C, Smith RE, et al. Dimerization of G protein-coupled receptors. J Med Chem 2001;44:4595-614
  • Devi LA. Heterodimerization of G protein-coupled receptors: pharmacology, signaling and trafficking. Trends Pharmacol Sci 2001;22:532-7
  • Kenakin T. Drug efficacy at G protein-coupled receptors. Annu Rev Pharmacol Toxicol 2002;42:349-79
  • Xie Z, Lee SP, O’Dowd BF, et al. Serotonin 5-HT1B and 5-HT1D receptors form homodimers when expressed alone and heterodimers when co-expressed. FEBS Lett 1999;456:63-7
  • Lee SP, Xie Z, Varghese G, et al. Oligomerization of dopamine and serotonin receptors. Neuropsychopharmacology 2000;23:S32-40
  • Zeng F, Wess J. Molecular aspects of muscarinic receptor dimerization. Neuropsychopharmacology 2000;23:S19-31
  • Overton MC, Blumer KJ. G protein-coupled receptors function as oligomers in vivo. Curr Biol 2000;10:341-4
  • Bockaert J, Pin JP. Molecular tinkering of G protein-coupled receptors: an evolutionary success. EMBO J 1999;18:1723-9
  • Waldhoer M, Fong J, Jones RM, et al. A heterodimer-selective agonist shows in vivo relevance of G protein-coupled receptor dimers. Proc Natl Acad Sci USA 2005;102:9050-5
  • Bouvier M, Hébert TE. CrossTalk proposal: weighing the evidence for class A GPCR dimers, the evidence favours dimers. J Physiol 2014;592:2439-41
  • Lambert NA, Javitch JA. CrossTalk opposing view: weighing the evidence for class A GPCR dimers, the jury is still out. J Physiol 2014;592:2443-5
  • Wregget KA, Wells JW. Cooperativity manifest in the binding properties of purified cardiac muscarinic receptors. J Biol Chem 1995;270:22488-99
  • Akgün E, Javed MI, Lunzer MM, et al. Ligands that interact with putative MOR-mGluR5 heteromer in mice with inflammatory pain produce potent atinociception. Proc Natl Acad Sci USA 2013;110:11595-9
  • Pfleger KD, Eidne KA. Illuminating insights into protein–protein interactions using bioluminescence resonance energy transfer (BRET). Nat Methods 2006;3:165-74
  • Marullo S, Bouvier M. Resonance energy transfer approaches in molecular pharmacology and beyond. Trends Pharmacol Sci 2007;28:362-5
  • Patel RC, Kumar U, Lamb DC, et al. Ligand binding to somatostatin receptors induces receptor-specific oligomer formation in live cells. Proc Natl Acad Sci USA 2002;99:3294-9
  • Herrick-Davis K, Grinde E, Cowan A, et al. Fluorescence correlation spectroscopy analysis of serotonin, adrenergic, muscarinic, and dopamine receptor dimerization: the oligomer number puzzle. Mol Pharmacol 2013;84:630-42
  • Skieterska K, Duchou J, Lintermans B, et al. Detection of G protein-coupled receptor (GPCR) dimerization by coimmunoprecipitation. Methods Cell Biol 2013;117:323-40
  • Borroto-Escuela DO, Van Creanenbroek K, Romero-Fernandez W, et al. Dopamine D2 and D4 receptor heteromerization and its allosteric receptor-receptor interactions. Biochem Biophys Res Commun 2011;404:928-34
  • Trifilieff P, Rives ML, Urizar E, et al. Detection of antigen interactions ex vivo by proximity ligation assay: endogenous dopamine D2-adenosine A2A receptor complexes in the striatum. Biotechniques 2011;51:111-18
  • Zoli M, Agnati LF, Hedlund PB, et al. Receptor–receptor interactions as an integrative mechanism in nerve cells. Mol Neurobiol 1993;7:293-334
  • Bulenger S, Marullo S, Bouvier M. Emerging role of homo- and heterodimerization in G-protein-coupled receptor biosynthesis and maturation. Trends Pharmacol Sci 2005;26:131-7
  • Prinster SC, Hague C, Hall RA. Heterodimerization of G protein-coupled receptors: specificity and functional significance. Pharmacol Rev 2005;57:289-98
  • Fuxe K, Canals M, Torvinen M, et al. Intramembrane receptor–receptor interactions: a novel principle in molecular medicine. J Neural Transm 2007;114:49-75
  • Flajolet M, Wang Z, Futter M, et al. FGF acts as a co-trasmitter through adenosine A(2A) receptor to regulate synaptic plasticity. Nat Neurosci 2008;11:1402-9
  • Borroto-Escuela DO, Corrales F, Narvaez M, et al. Dynamic modulation of FGFR1-5-HT1A heteroreceptor complexes. Agonist treatment enhances participation of FGFR1 and 5-HT 1A homodimers and recruitment of beta-arrestin2. Biochem Biophys Res Commun 2013;441:387-92
  • Zoli M, Guidolin D, Fuxe K, et al. The receptor mosaic hypothesis of the engram: possible relevance of Boolean network modeling. Int J Neural Syst 1996;7:363-8
  • Agnati LF, Fuxe K, Ferré S. How receptor mosaics decode transmitter signals. Possible relevance of cooperativity. Trends Biochem Sci 2005;30:188-93
  • Kenakin T, Agnati LF, Caron M, et al. International workshop at the Nobel Forum, Karolinska Institutet on G protein-coupled receptors: finding the words to describe monomers, oligomers, and their molecular mechanisms and defining their meaning. Can a consensus be reached ? J Recept Signal Transduct Res 2010;30:284-6
  • Agnati LF, Fuxe K, Zoli M, et al. New vistas on synaptic plasticity: the receptor mosaic hypothesis of the engram. Med Biol 1982;60:183-90
  • Agnati LF, Guidolin D, Leo G, et al. A boolean network modelling of receptor mosaics relevance of topology and cooperativity. J Neural Transm 2007;114:77-92
  • Fuxe K, Marcellino D, Guidolin D, et al. Brain receptor mosaics and their intramembrane receptor–receptor interactions: molecular integration in transmission and novel target for drug development. J Acupunct Meridian Stud 2009;2:1-25
  • Agnati LF, Guidolin D, Vilardaga JP, et al. On the expanding terminology in the GPCR field: the meaning of receptor mosaics and receptor heteromers. J Recept Signal Transduct Res 2010;30:287-303
  • Kenakin T, Miller LJ. Seven transmembrane receptors as shapeshifting proteins: the impact of allosteric modulation and functional selectivity on new drug discovery. Pharmacol Rev 2010;62:265-304
  • Fuxe K, Marcellino D, Borroto-Escuela DO, et al. Adenosine-dopamine interactions in the pathophysiology and treatment of CNS disorders. CNS Neurosci Ther 2010;16:e18-42
  • Fuxe K, Borroto-Escuela DO, Tarakanov A, et al. Understanding the balance and integration of volume and synaptic transmission. Relevance for psychiatry. Neurol Psychiatry Brain Res 2013;19:141-58
  • Agnati LF, Guidolin D, Leo G, et al. Possible new targets for GPCR modulation: allosteric interactions, plasma membrane domains, intercellular transfer and epigenetic mechanisms. J Recept Signal Transduct Res 2011;31:315-31
  • Gomes I, Fujita W, Chandrakala MV, et al. Disease-specific heteromerization of G-protein-coupled receptors that target drugs of abuse. Prog Mol Biol Transl Sci 2013;117:207-65
  • Linseman DA, Benjamin CW, Jones DA. Convergence of angiotensin II and platelet-derived growth factor receptor signalling cascades in vascular smooth muscle cells. J Biol Chem 1995;270:12563-8
  • Daub H, Weiss FU, Wallasch C, et al. Role of transactivation of the EGF receptor in signaling by G-protein-coupled receptors. Nature 1996;379:557-60
  • Luttrel LM, Daaka Y, Lefkowitz RJ. Regulation of tyrosine kinase cascades by G-protein-coupled receptors. Curr Opin Cell Biol 1999;11:177-83
  • Guidolin D, Albertin G, Spinazzi R, et al. Adrenomedullin stimulates angiogenic response in cultured human vascular endothelial cells: involvement of the vascular endothelial growth factor receptor 2. Peptides 2008;29:2013-23
  • Prezeau L, Rives ML, Comps-Agrar L, et al. Functional crosstalk between GPCRs: with or without oligomerization. Curr Opin Pharmacol 2010;10:6-13
  • Szidonya L, Cserzo M, Hunyady L. Dimerization and oligomerization of G-protein-coupled receptors: debated structures with established and emerging functions. J Endocrinol 2008;196:435-53
  • Tsai CJ, Del Sol A, Nussinov R. Protein allostery, signal transmission and dynamics: a classification scheme of allosteric mechanisms. Mol Biosyst 2009;5:207-16
  • Agnati LF, Guidolin D, Leo G, et al. Receptor-receptor interactions: a novel concept in brain integration. Prog Neurobiol 2010;90:157-75
  • Fuxe K, Borroto-Escuela DO, Marcellino D, et al. GPCR heteromers and their allosteric receptor-receptor interactions. Curr Med Chem 2012;19:356-63
  • Smith NJ, Milligan G. Allostery at G protein-coupled receptor homo- and heteromers: uncharted pharmacological landscapes. Pharmacol Rev 2010;62:701-25
  • Gouldson PR, Higgs C, Smith RE, et al. Dimerization and domain swapping in G protein-coupled receptors: a computational study. Neuropsychopharmacology 2000;23:S60-77
  • Fotiadis D, Liang Y, Filipek S, et al. Atomic force microscopy: rhodopsin dimers in native disc membranes. Nature 2003;421:127-8
  • Tateyama M, Abe H, Nakata H, et al. Ligand-induced rearrangement of the dimeric metabotropic glutamate receptor 1alpha. Nat Struct Mol Biol 2004;11:637-42
  • Hern JA, Baig AH, Mashanov GI, et al. Formation and dissociation of M1 muscarinic receptor dimers seen by total internal reflection fluorescence imaging of single molecules. Proc Natl Acad Sci USA 2010;107:2693-8
  • Kenworthy A. Imaging protein-protein interactions using fluorescence resonance energy transfer microscopy. Methods 2001;24:289-96
  • Fernàndez-Dueñas V, Llorente J, Gandìa J, et al. Fluorescence resonance energy transfer-based technologies in the study of protein-protein interactions at the cell surface. Methods 2012;57:467-72
  • Hamdan FF, Percherancier Y, Breton B, et al. Monitoring protein-protein interactions in living cells by luminescence resonance energy transfer (BRET). Curr Protoc Neurosci 2006;5:5.23
  • Borroto-Escuela DO, Flajolet M, Agnati LF, et al. Bioluminescence resonance energy transfer methods to study G protein-coupled receptor-receptor tyrosine kinase heteroreceptor complexes. Methods Cell Biol 2013;117:141-64
  • Ciruela F, Vilardaga JP, Fernandez-Duenas V. Lighting up multiprotein complexes: lessons from GPCR oligomerization. Trends Biotechnol 2010;28:407-15
  • Padilla-Parra S, Tramier M. FRET microscopy in the living cell: different approaches, strengths and weaknesses. Bioessays 2012;34:369-76
  • Kaczor AA, Selent J. Oligomerization of G protein-coupled receptors: biochemical and biophysical methods. Curr Med Chem 2011;18:4606-34
  • Audet M, Lagacé M, Silversides DW, et al. Protein-protein interactions monitored in cells from transgenic mice, using bioluminescence resonance energy transfer. FASEB J 2010;24:2829-38
  • Borroto-Escuela DO, Romero-Fernandez W, Garriga P, et al. G protein-coupled receptor heterodimerization in the brain. Methods Enzymol 2013;521:181-94
  • Gandia J, Galino J, Amaral OB, et al. Detection of higher-order G protein-coupled receptor oligomers by a combined BRET-BiFC technique. FEBS Lett 2008;582:2979-84
  • Vidi PA, Chen JJ, Irudayaraj JM, et al. Adenosine A(2A) receptors assemble into higher-order oligomers at the plasma membrane. FEBS Lett 2008;582:3985-90
  • Kasai RS, Suzuki KG, Prossnitz ER, et al. Full characterization of GPCR monomer-dimer dynamic equilibrium by single molecule imaging. J Cell Biol 2011;192:463-80
  • Chen Y, Wei LN, Müller JD. Probing protein oligomerization in living cells with fluorescence fluctuation spectroscopy. Proc Natl Acad Sci USA 2003;100:15492-7
  • Agnati LF, Fuxe K, Torvinen M, et al. New methods to evaluate colocalization of fluorophores in immunocytochemical preparations as exemplified by a study on A2A and D2 receptors in Chinese hamster ovary cells. J Histochem Cytochem 2005;53:941-53
  • Albizu L, Cottet M, Kralikova M, et al. Time-resolved FRET between GPCR ligands reveals oligomers in native tissues. Nat Chem Biol 2010;6:587-94
  • Rocheville M, Lange DC, Kumar U, et al. Receptors for dopamine and somatostatin: formation of hetero-oligomers with enhanced functional activity. Science 2000;288:154-7
  • Rozenfeld R, Bushlin I, Gomes I, et al. Receptor heteromerization expands the repertoire of cannabinoid signaling in rodent neurons. PLoS One 2012;7:e29239
  • Yekkirala AS, Kalyuzhni AE, Portoghese PS. An immunocytochemical-derived correlate for evaluating the bridging of heteromeric mu-delta opioid protomers by bivalent ligands. ACS Chem Biol 2013;8:1412-16
  • Pei L, Li S, Wang M, et al. Uncoupling the dopamine D1–D2 receptor complex exerts antidepressant-like effects. Nat Med 2010;16:1393-5
  • Guidolin D, Ciruela F, Genedani S, et al. Bioinformatics and mathematical modelling in the study of receptor-receptor interactions and receptor oligomerization. Focus on adenosine receptors. Biochim Biophys Acta 2011;1808:1267-83
  • Hilser VJ, Thompson EB. Intrinsic disorder as a mechanism to optimize allosteric coupling in proteins. Proc Natl Acad Sci USA 2007;104:8311-15
  • Agnati LF, Leo G, Genedani S, et al. Structural plasticity in G-protein coupled receptors as demonstrated by the allosteric actions of homocysteine and computer-assisted analysis of disordered domains. Brain Res Rev 2008;58:459-74
  • Tovo-Rodrigues L, Roux A, Hutz MH, et al. Functional characterization of G protein-coupled receptors: a bioinformatics approach. Neuroscience 2014;277:764-79
  • Nemoto W, Toh H. Prediction of interfaces for oligomerization of G-protein coupled receptors. Proteins 2005;58:644-60
  • Wu B, Chien EY, Mol CD, et al. Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists. Science 2010;330:1066-71
  • Wu H, Wacker D, Mileni M, et al. Structure of the human k-opioid receptor in complex with JDTic. Nature 2012;485:327-32
  • Hebert TE, Moffett S, Morello JP, et al. A peptide derived from a beta2-adrenergic receptor transmembrane domain inhibits both receptor dimerization and activation. J Biol Chem 1996;271:16384-92
  • Guo W, Urizar E, Kralikova M, et al. Dopamine D2 receptors form higher order oligomers at physiological expression levels. EMBO J 2008;27:2293-304
  • Borroto-Escuela DO, Romero-Fernandez W, Tarakanov AO, et al. Characterization of the A2AR-D2R interface: focus on the role of C-terminal tail and the transmembrane helices. Biochem Biophys Res Commun 2010;402:801-7
  • Hu J, Thor D, Zhou Y, et al. Structural aspects of M3 muscarinic acetylcholine receptor dimer formation and activation. FASEB J 2012;26:604-16
  • Mancia F, Assur Z, Herman AG, et al. Ligand sensitivity in dimeric associations of the serotonin 5HT2c receptor. EMBO Rep 2008;9:363-9
  • Manglik A, Kruse AC, Kobilka TS, et al. Crystal structure of the μ-opioid receptor bound to a morphinan antagonist. Nature 2012;485:321-7
  • Portoghese PS, Larson DL, Yim CB, et al. Stereostructure-activity relationship of opioid agonist and antagonist bivalent ligands. Evidence for bridging between vicinal opioid receptors. J Med Chem 1985;28:1140-1
  • Wu H, Wang C, Gregory KJ, et al. Structure of a class C GPCR metabotropic glutamate receptor 1 bound to an allosteric modulator. Science 2014;344:58-64
  • Doré AS, Okrasa K, Patel JC, et al. Structure of class C GPCR metabotropic glutamate receptor 5 transmembrane domain. Nature 2014;511:557-62
  • Borroto-Escuela DO, Brito I, Romero-Fernandez W, et al. The G protein-coupled receptor heterodimer network (GPCR-HetNet) and its hub components. Int J Mol Sci 2014;15:8570-90
  • Huang J, Chen S, Zhang J, et al. Crystal structure of oligomeric beta1-adrenergic G protein-coupled receptors in ligand-free basal state. Nat Struct Mol Biol 2013;20:419-25
  • Kniazeff J, Prézeau L, Rondard P, et al. Dimers and beyond: the functional puzzles of class C GPCRs. Pharmacol Ther 2011;130:9-25
  • Ciruela F, Burgueno J, Casado V, et al. Combining mass spectrometry and pull-down techniques for the study of receptor heteromerization. Direct epitope-epitope electrostatic interactions between adenosine A2A and dopamine D2 receptors. Anal Chem 2004;76:5354-63
  • Woods AS, Ciruela F, Fuxe K, et al. Role of electrostatic interaction in receptor-receptor heteromerization. J Mol Neurosci 2005;26:125-32
  • Lohse MJ, Benovic JL, Codina J, et al. beta-Arrestin: a protein that regulates beta-adrenergic receptor function. Science 1990;248:1547-50
  • Lefkowitz RJ, Shenoy SK. Transduction of receptor signals by beta-arrestins. Science 2005;308:512-17
  • Reiter E, Ahn S, Shukla AK, et al. Molecular mechanism of b-arrestin-biased agonism at seven-transmembrane receptors. Annu Rev Pharmacol Toxicol 2012;52:179-97
  • Le Naour M, Lunzer MM, Powers MD, et al. Putative kappa opioid heteromers as targets for developing analgesics free of adverse effects. J Med Chem 2014;57:6383-92
  • Chakrabarti S, Liu NJ, Gintzler AR. Formation of mu-/kappa-opioid receptor heterodimer is sex-dependent and mediates female-specific opioid analgesia. Proc Natl Acad Sci USA 2010;107:20115-19
  • Jordan BA, Devi LA. G-protein-coupled receptor heterodimerization modulates receptor function. Nature 1999;399:697-700
  • Guidolin D, Fuxe K, Neri G, et al. On the role of receptor-receptor interactions and volume transmission in learning and memory. Brain Res Rev 2007;55:119-33
  • Vilardaga JP, Nikolaev VO, Lorenz K, et al. Conformational cross-talk between alpha2A-adrenergic and mu-opioid receptors controls cell signaling. Nat Chem Biol 2008;4:126-31
  • Alemany R, Perona JS, Sánchez-Dominguez JM, et al. G protein coupled receptor systems and their lipid environment in health disorders during aging. Biochim Biophys Acta 2007;1768:964-75
  • Agnati LF, Guidolin D, Leo G, et al. Role of cooperativity in protein folding and protein mosaic assemblage. Relevance for protein conformational disease. Curr Protein Pept Sci 2007;8:460-70
  • Frauenfelder H, Sligar SG, Wolynes PG. The energy landscapes and motions of proteins. Science 1991;254:1598-603
  • Fuxe K, Marcellino D, Borroto-Escuela DO, et al. The changing world of G protein-coupled receptors: from monomers to dimers and receptor mosaics with allosteric receptor-receptor interactions. J Recept Signal Transduct Res 2010;30:272-83
  • Khelashvili G, Dorff K, Shan J, et al. GPCR-OKB: the G Protein-Coupled Receptor Oligomer Knowledge Base. Bioinformatics 2010;26:1804-5
  • Kamiya T, Saitoh O, Yoshioka K, et al. Oligomerization of adenosine A2A and dopamine D2 receptors in living cells. Biochem Biophys Res Commun 2003;306:544-9
  • Fuxe K, Agnati LF, Jacobsen K, et al. Receptor heteromerization in adenosine A2A receptor signaling: relevance for striatal function and Parkinson’s disease. Neurology 2003;61:S19-23
  • Diaz-Cabiale Z, Hurd Y, Guidolin D, et al. Adenosine A2A agonist CGS 21680 decreases the affinity of dopamine D2 receptors for dopamine in human striatum. Neuroreport 2001;12:1831-4
  • Fuxe K, Marcellino D, Genedani S, et al. Adenosine A(2A) receptors, dopamine D(2) receptors and their interactions in Parkinson’s disease. Mov Disord 2007;22:1990-2017
  • Kull B, Ferré S, Arslan G, et al. Reciprocal interactions between adenosine A2A and dopamine D2 receptors in Chinese hamster ovary cells co-transfected with the two receptors. Biochem Pharmacol 1999;58:1035-45
  • Hillion J, Canals M, Torvinen M, et al. Coaggregation, cointernalization, and codesensitization of adenosine A2A receptors and dopamine D2 receptors. J Biol Chem 2002;277:18091-7
  • Genedani S, Guidolin D, Leo G, et al. Computer-assisted image analysis of caveolin-1 involvement in the internalization process of adenosine A2A-dopamine D2 receptor heterodimers. J Mol Neurosci 2005;26:177-84
  • Borroto-Escuela DO, Romero-Fernandez W, Tarakanov AO, et al. On the existence of a possible A2A-D2-beta-arrestin2 complex: A2A agonist modulation of D2 agonist-induced beta-arrestin2 recruitment. J Mol Biol 2011;406:687-99
  • Agnati LF, Ferré S, Genedani S, et al. Allosteric modulation of dopamine D2 receptors by homocysteine. J Proteome Res 2006;5:3077-83
  • Cabello N, Gandía J, Bertarelli DC, et al. Metabotropic glutamate type 5, dopamine D2 and adenosine A2a receptors form higher-order oligomers in living cells. J Neurochem 2009;109:1497-507
  • Popoli P, Pèzzola A, Torvinen M, et al. The selective mGlu(5) receptor agonist CHPG inhibits quinpirole-induced turning in 6-hydroxydopamine-lesioned rats and modulates the binding characteristics of dopamine D(2) receptors in the rat striatum: interactions with adenosine A(2a) receptors. Neuropsychopharmacology 2001;25:505-13
  • Lee SP, So CH, Rashid AJ, et al. Dopamine D1 and D2 receptor co-activation generates a novel phospholipase C-mediated calcium signal. J Biol Chem 2004;279:35671-8
  • Rashid AJ, So CH, Kong MM, et al. D1-D2 dopamine receptor heterooligomers with unique pharmacology are coupled to rapid activation of Gq/11 in the striatum. Proc Natl Acad Sci USA 2007;104:654-9
  • Urizar E, Yano H, Kolster R, et al. CODA-RET reveals functional selectivity as a result of GPCR heteromerization. Nat Chem Biol 2011;7:624-30
  • Borroto-Escuela DO, Romero-Fernandez W, Tarakanov AO, et al. Dopamine D2 and 5-hydroxytryptamine 5-HT((2)A) receptors assemble into functionally interacting heteromers. Biochem Biophys Res Commun 2010;401:605-10
  • Lukasiewicz S, Polit A, Kedracka-Krok S, et al. Hetero-dimerization of serotonin 5-HT(2A) and dopamine D(2) receptors. Biochim Biophys Acta 2010;1803:1347-58
  • Kern A, Albarran-Zeckler R, Walsh HE, et al. Apo-ghrelin receptor forms heteromers with DRD2 in hypothalamic neurons and is essential for anorexigenic effects of DRD2 agonism. Neuron 2012;73:317-32
  • Ramsay D, Kellett E, McVey M, et al. Homo- and hetero-oligomeric interactions between G-protein-coupled receptors in living cells monitored by two variants of bioluminescence resonance energy transfer (BRET): hetero-oligomers between receptor subtypes form more efficiently than between less closely related sequences. Biochem J 2002;365:429-40
  • Bhushan RG, Sharma SK, Xie Z, et al. A bivalent ligand (KDN-21) reveals spinal delta and kappa opioid receptors are organized as heterodimers that give rise to delta(1) and kappa(2) phenotypes. Selective targeting of delta-kappa heterodimers. J Med Chem 2004;47:2969-72
  • Rothman RB, Bowen WD, Herkenham M, et al. A quantitative study of [3H]D-Ala2-D-Leu5-enkephalin binding to rat brain membranes. Evidence that oxymorphone is a noncompetitive inhibitor of the lower affinity delta-binding site. Mol Pharmacol 1985;27:399-409
  • Abdelhamid EE, Sultana M, Portoghese PS, et al. Selective blockage of delta opioid receptors prevents the development of morphine tolerance and dependence in mice. J Pharmacol Exp Ther 1991;258:299-303
  • Kest B, Lee CE, McLemore GL, et al. An antisense oligodeoxynucleotide to the delta opioid receptor (DOR-1) inhibits morphine tolerance and acute dependence in mice. Brain Res Bull 1996;39:185-8
  • Zhu Y, King MA, Schuller AG, et al. Retention of supraspinal delta-like analgesia and loss of morphine tolerance in delta opioid receptor knockout mice. Neuron 1999;24:243-52
  • Yekkirala AS, Banks ML, Lunzer MM, et al. Clinically employed opioid analgesics produce antinociception via mu-delta opioid receptor heteromers in rhesus monkey. ACS Chem Neurosci 2012;3:720-7
  • Gomes I, Gupta A, Filipovska J, et al. A role for heterodimerization of mu and delta opiate receptors in enhancing morphine analgesia. Proc Natl Acad Sci USA 2004;101:5135-9
  • Kabli N, Martin N, Fan T, et al. Agonists at the delta-opioid receptor modify the binding of micro-receptor agonists to the micro-delta receptor hetero-oligomer. Br J Pharmacol 2010;161:1122-36
  • George SR, Fan T, Xie Z, et al. Oligomerization of mu- and delta-opioid receptors. Generation of novel functional properties. J Biol Chem 2000;275:26128-35
  • Daniels DJ, Lenard NR, Etienne CL, et al. Opioid-induced tolerance and dependence in mice is modulated by the distance between pharmacophores in a bivalent ligand series. Proc Natl Acad Sci USA 2005;102:19208-13
  • Gago B, Fuxe K, Agnati L, et al. Dopamine D(4) receptor activation decreases the expression of mu-opioid receptors in the rat striatum. J Comp Neurol 2007;502:358-66
  • Suarez-Boomgaard D, Gago B, Valderrama-Carvajal A, et al. Dopamine D4 receptor counteracts morphine-induced changes in mu opioid receptor signaling in the striosomes of the rat caudate putamen. Int J Mol Sci 2014;15:1481-98
  • Ferrada C, Moreno E, Casadò V, et al. Marked changes in signal transduction upon heteromerization of dopamine D1 and histamine H3 receptors. Br J Pharmacol 2009;157:64-75
  • Moreno E, Hoffmann H, Gonzalez-Sepùlveda M, et al. Dopamine D1-histamine H3 receptor heteromers provide a selective link to MAPK signaling in GABAergic neurons of the direct striatal pathway. J Biol Chem 2011;286:5846-54
  • Mallat A, Lotersztajn S. Endocannabinoids and liver disease. I. Endocannabinoids and their receptors in the liver. Am J Physiol Gastrointest Liver Physiol 2008;294:G9-G12
  • Rozenfeld R, Gupta A, Gagnidze K, et al. AT1R-CBR heteromerization reveals a new mechanism for the pathogenic properties of angiotensin II. EMBO J 2011;30:2350-63
  • Xu K, Bastia E, Schwarzschild M. Therapeutic potential of adenosine A2A receptor antagonists in Parkinson’s disease. Pharmacol Therap 2005;105:267-310
  • Fuxe K, Marcellino D, Rivera A, et al. Receptor–receptor interactions within receptor mosaics. Impact on neuropsychopharmacology. Brain Res Rev 2008;58:415-52
  • Seeman P, Schwarz J, Chen JF, et al. Psychosis pathways converge via D2high dopamine receptors. Synapse 2006;60:319-46
  • Borroto-Escuela DO, Corrales F, Narvaez M, et al. Hallucinogenic 5-HT2AR agonists LSD and DOI enhance dopamine D2R protomer recognition and signalling of D2-5-HT2A heteroreceptor complexes. Biochem Biophys Res Commun 2014;443:278-84
  • Fuxe K, Tarakanov A, Romero Fernandez W, et al. Diversity and bias through receptor–receptor interactions in GPCR heteroreceptor complexes. Focus on examples from dopamine D2 receptor heteromerization. Front Endocrinol (Lausanne) 2014;5:71
  • Gonzalez-Maeso J, Ang RL, Yuen T, et al. Identification of a serotonin/glutamate receptor complex implicated in psychosis. Nature 2008;452:93-7
  • Mallei A, Shi B, Mocchetti I. Antidepressant treatments induce the expression of basic fibroblast growth factor in cortical and hippocampal neurons. Mol Pharmacol 2002;61:1017-24
  • Kitayama IT, Otani M, Murase S. Contribution of the stress-induced degeneration of the locus coeruleus noradrenergic neurons to the pathophysiology of depression: a study on an animal model. Acta Neuropsychiatr 2004;16:190-9
  • Abul-Husn NS, Sutak M, Milne B, et al. Augmentation of spinal morphine analgesia and inhibition of tolerance by low doses of mu- and delta-opioid receptor antagonists. Br J Pharmacol 2007;151:877-87
  • Schröder H, Wu DF, Seifert A, et al. Allosteric modulation of metabotropic glutamate receptor 5 affects phosphorylation, internalization, and desensitization of the micro-opioid receptor. Neuropharmacology 2009;56:768-78
  • Yekkirala AS, Lunzer MM, McCurdy CR, et al. N-naphtoyl-beta-naltrexamine (NNTA), a highly selective and potent activator of µ/kappa-opioid heteromers. Proc Natl Acad Sci USA 2011;108:5098-103
  • Bushlin I, Gupta A, Stockton SDJr, et al. Dimerization with cannabinoid receptors allosterically modulates delta opioid receptor activity during neuropathic pain. PLoS One 2012;7:e49789
  • Brady LS, Herkenham M, Long JB, et al. Chronic morphine increases mu-opiate receptor binding in rat brain: a quantitative autoradiographic study. Brain Res 1989;477:382-6
  • Gago B, Suarez-Boomgaard D, Fuxe K, et al. Effect of acute and continuous morphine treatment on transcription factor expression in subregions of the rat caudate putamen. Marked modulation by D4 receptor activation. Brain Res 2011;1407:47-61
  • Moreno E, Andradas C, Medrano M, et al. Targeting CB2-GPR55 receptor heteromers modulates cancer cell signaling. J Biol Chem 2014;289:21960-72
  • Agnati LF, Guidolin D, Albertin G, et al. An integrated view on the role of receptor mosaics at perisynaptic level: focus on adenosine A2A, dopamine D2, cannabinoid CB1, and metabotropic glutamate mGlu5 receptors. J Recept Signal Transduct Res 2010;30:355-69
  • Navarro G, Ferré S, Cordomi A, et al. Interactions between intracellular domains as key determinants of the quaternary structure and function of receptor heteromers. J Biol Chem 2010;285:27346-59
  • Canals M, Marcellino D, Fanelli F, et al. Adenosine A2A-dopamine D2 receptor-receptor heteromerization: qualitative and quantitative assessment by fluorescence and bioluminescence energy transfer. J Biol Chem 2003;278:46741-9
  • Thévenin D, Lazarova T, Roberts MF, et al. Oligomerization of the fifth transmembrane domain from adenosine A2A receptor. Protein Sci 2005;14:2177-86
  • Borroto-Escuela DO, Marcellino D, Narvaez N, et al. A serine point mutation in the adenosine A2AR C-terminal tail reduces receptor heteromerization and allosteric modulation of the dopamine D2R. Biochem Biophys Res Commun 2010;393:767-72
  • Hernanz-Falcon P, Rodriguez-Frade JM, Serrano A, et al. Identification of amino acid residues crucial for chemokine receptor dimerization. Nat Immunol 2004;5:216-23
  • Guo W, Shi L, Javitch JA. The fourth transmembrane segment forms the interface of the dopamine D2 receptor homodimer. J Biol Chem 2003;278:4385-8
  • Filizola M, Olmea O, Weinstein H. Prediction of heteromerization interfaces of G-protein coupled receptors with a new subtractive correlated mutation method. Protein Eng 2002;15:881-5
  • Johnston JM, Aburi M, Provasi D, et al. Making structural sense of dimerization interfaces of delta opioid receptor homodimers. Biochemistry 2011;50:1682-90
  • Borroto-Escuela DO, Correia PA, Perez Alea M, et al. Impaired M(3) muscarinic acetylcholine receptor signal transduction through blockade of binding of multiple proteins to its third intracellular loop. Cell Physiol Biochem 2010;25:397-408
  • Liang Y, Fotiadis D, Filipek S, et al. Organization of the G protein-coupled receptors rhodopsin and opsin in native membranes. J Biol Chem 2003;278:21655-62
  • Mally J, Stone TW. The effect of theophylline on parkinsonian symptoms. J Pharm Pharmacol 1994;46:515-17
  • Kostic VS, Svetel M, Sternic N, et al. Theophylline increases “on” time in advanced parkinsonian patients. Neurology 1999;52:1916
  • Kulisevsky J, Barbanoj M, Gironell A, et al. A double-blind crossover, placebo-controlled study of the adenosine A2A antagonist theophylline in Parkinson’s disease. Clin Neuropharmacol 2002;25:25-31
  • Bara-Jimenez W, Sherzai A, Dimitrova T, et al. Adenosine A(2A) receptor antagonist treatment of Parkinson’s disease. Neurology 2003;61:293-6
  • Hauser RA, Hubble JP, Truong DD. Randomized trial of the adenosine A(2A) receptor antagonist istradefylline in advanced PD. Neurology 2003;61:297-303
  • Stacy MA; The 60002-US-005/US-006 Clinical Investigator Group. Istradefylline (KW-6002) as adjunctive therapy in patients with advanced Parkinson’s disease: a positive safety profile with supporting efficacy. Mov Disord 2004;19(S9):S215; P605
  • LeWitt PA, Guttman M, Tetrud JW, et al. Adenosine A2A receptor antagonist Istradefylline (KW-6002) reduces “off” time in Parkinson’s disease: a double-blind, randomized, multicenter clinical trial (6002-US-005). Ann Neurol 2008;63:295-302

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.