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Triplet Puzzle: Homologies of Receptor Heteromers

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Abstract

Based on a mathematical approach, we deduce a set of triplet homologies that may be responsible for receptor–receptor interactions. We show how such triplets of amino acid residues and their 'teams' may be utilized to construct a kind of code that determines (and/or predicts) which receptors should or should not form heterodimers. Based on the obtained results, we propose a 'guide-and-clasp' manner for receptor–receptor interactions where 'adhesive guides' might be the triplet homologies. We also demonstrate their relevance to protein–protein interactions and mention possible implications for novel pharmacological targets and strategies for treatment of diseases, e.g. neuroinflammatory diseases.

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References

  • AbdAlla S, Lother H, el Massiery A, Quitterer U (2001) Increased AT(1) receptor heterodimers in preeclampsia mediate enhanced angiotensin II responsiveness. Nat Med 7:1003–1009

    Article  CAS  PubMed  Google Scholar 

  • Adamian L, Jackups R, Binkowski A, Liang J (2003) Higher-order interhelical spatial interactions in membrane proteins. J Mol Bio 327:251–272

    Article  CAS  Google Scholar 

  • Agnati LF, Ferre S, Lluis C, Franco R, Fuxe K (2003) Molecular mechanisms and therapeutical implications of intramembrane receptor/receptor interactions among heptahelical receptors with examples from the striatopallidal GABA neurone. Pharmacol Rev 55:509–550

    Article  CAS  PubMed  Google Scholar 

  • Agnati LF, Tarakanov AO, Ferré S, Fuxe K, Guidolin D (2005) Receptor-receptor interactions, receptor mosaics, and basic principles of molecular network organization: possible implications for drug development. J Mol Neurosci 26(2–3):193–208

    Article  CAS  PubMed  Google Scholar 

  • Akira S, Uematsu S, Takeuchi O (2006) Pathogen recognition and innate immunity. Cell 124(4):783–801

    Article  CAS  PubMed  Google Scholar 

  • Ayoub MA, Levoye A, Delagrange P, Jockers R (2004) Preferential formation of MT1/MT2 melatonin receptor heterodimers with distinct ligand interaction properties compared with MT2 homodimers. Mol Pharmacol 66:312–321

    Article  CAS  PubMed  Google Scholar 

  • Baardsnes J, Jelokhani-Niaraki J, Kondejewski LH et al (2001) Antifreeze protein from shorthorn sculpin: identification of the ice-binding surface. Protein Sci 10(12):2566–2576

    Article  CAS  PubMed  Google Scholar 

  • Baker JG, Hill SJ (2007) Multiple GPCR conformations and signalling pathways: implications for antagonist affinity estimates. Trends Pharmacol Sci 28:374–381

    Article  CAS  PubMed  Google Scholar 

  • Bell JK, Botos I, Hall PR et al (2005) The molecular structure of the Toll-like receptor 3 ligand-binding domain. Proc Natl Acad Sci U S A 102(31):10976–10980

    Article  CAS  PubMed  Google Scholar 

  • Block M, Zecca L, Hong JS (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 8(1):57–69

    Article  CAS  PubMed  Google Scholar 

  • Canals M, Marcellino D, Fanelli F et al (2003) Adenosine A2A-dopamine D2 receptor-receptor heteromerization: qualitative and quantitative assessment by fluorescence and bioluminescence energy transfer. J Biol Chem 278(47):46741–46749

    Article  CAS  PubMed  Google Scholar 

  • Carriba P, Ortiz O, Patkar K et al (2007) Striatal adenosine A2A and cannabinoid CB1 receptors form functional heteromeric complexes that mediate the motor effects of cannabinoids. Neuropsychopharmacol 32(11):2249–2259

    Article  CAS  Google Scholar 

  • Ciruela F, Burqueño J, Casadó V et al (2004) 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 76(18):5354–5363

    Article  CAS  PubMed  Google Scholar 

  • Ciruela F, Casadó V, Rodrigues RJ et al (2006) Presynaptic control of striatal glutamatergic neurotransmission by adenosine A1–A2A receptor heteromers. J Neurosci 26(7):2080–2087

    Article  CAS  PubMed  Google Scholar 

  • Dasgupta S, Li XM, Jansson A et al (1996) Regulation of dopamine D2 receptor affinity by cholecystokinin octapeptide in fibroblast cells cotransfected with human CCKB and D2L receptor cDNAs. Mol Brain Res 36(2):292–299

    Article  CAS  PubMed  Google Scholar 

  • Díaz-Cabiale Z, Fuxe K, Narváez JA et al (2002) Neurotensin-induced modulation of dopamine D2 receptors and their function in rat striatum: counteraction by a NTR1-like receptor antagonist. NeuroReport 13(6):763–766

    Article  PubMed  Google Scholar 

  • Doyle CA, Strominger JL (1987) Interaction between CD4 and class II MHC molecules mediates cell adhesion. Nature 330:256–259

    Article  CAS  PubMed  Google Scholar 

  • El-Asmar L, Springael JY, Ballet S, Andrieu EU, Vassart G, Parmentier M (2005) Evidence for negative binding cooperativity within CCR5-CCR2b heterodimers. Mol Pharmacol 67:460–469

    Article  CAS  PubMed  Google Scholar 

  • Ellis J, Pediani JD, Canals M, Milasta S, Milligan G (2006) Orexin-1 receptor-cannabinoid CB1 receptor heterodimerization results in both ligand-dependent and -independent coordinated alterations of receptor localization and function. J Biol Chem 281(50):38812–38824

    Article  CAS  PubMed  Google Scholar 

  • Fanelli F (2007) Dimerization of the lutropin receptor: insights from computational modeling. Mol Cell Endocrinol 260–262:59–64

    Article  PubMed  CAS  Google Scholar 

  • Fereiro DU, Walczak AM, Komives EA, Wolynes PG (2008) The energy landscapes of repeat-containing proteins: topology, cooperativity, and the folding funnels of one-domensional architectures. PLoS Compt Biol 4(5):e1000070

    Article  CAS  Google Scholar 

  • Ferré S, Karcz-Kubicha M, Hope BT et al (2002) Synergistic interaction between adenosine A2A and glutamate mGlu5 receptors: implications for striatal neuronal function. Proc Natl Acad Sci U S A 99(18):11940–11945

    Article  PubMed  CAS  Google Scholar 

  • Franco R, Casadó V, Cortéz A et al (2008) Novel pharmacological targets based on receptor heteromers. Brain Res Rev 58(2):475–482

    Article  CAS  PubMed  Google Scholar 

  • Fuxe K, Ferré S, Zoli M, Agnati LF (1998) 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 Rev 26:258–273

    Article  CAS  PubMed  Google Scholar 

  • Fuxe K, Canals M, Torvinen M et al (2007) Intramembrane receptor-receptor interactions: a novel principle in molecular medicine. J Neural Transm 114(1):49–75

    Article  CAS  PubMed  Google Scholar 

  • Fuxe K, Marcellino D, Rivera A et al (2008a) Receptor-receptor interactions within receptor mosaics. Impact on neuropsychopharmacology. Brain Res Rev 58(2):415–452

    Article  CAS  PubMed  Google Scholar 

  • Fuxe KG, Tarakanov AO, Goncharova LB, Agnati LF (2008b) A new road to neuroinflammation in Parkinson's disease? Brain Res Rev 58(2):453–458

    Article  CAS  PubMed  Google Scholar 

  • Gandia J, Galino J, Amaral OB et al (2008) Detection of higher-order G protein-coupled receptor oligomers by a combined BRET-BiFC technique. FEBS Lett 582(20):2979–2984

    Article  CAS  PubMed  Google Scholar 

  • Gao GF, Tormo J, Gerth UC et al (1997) Crystal structure of the complex between human CD8alpha and HLA-A2. Nature 387(6633):630–634

    Article  CAS  PubMed  Google Scholar 

  • Gay NJ, Gangloff M, Weber AN (2006) Toll-like receptors as molecular switches. Nat Rev Immunol 6(9):693–698

    Article  CAS  PubMed  Google Scholar 

  • Gilchrist A (2007) Modulating G-protein-coupled receptors: from traditional pharmacology to allosterics. Trends Pharmacol Sci 28:431–437

    Article  CAS  PubMed  Google Scholar 

  • Ginés S, Hillion J, Torvinen M et al (2000) Dopamine D1 and adenosine A1 receptors form functionally interacting heteromeric complexes. Proc Natl Acad Sci U S A 97(15):8606–8611

    Article  PubMed  Google Scholar 

  • Gomes I, Jordan BA, Gupta A, Trapaidze N, Nagy V, Devi LA (2000) Heterodimerization of mu and delta opioid receptors: a role in opiate synergy. J Neurosci 20:RC110

    CAS  PubMed  Google Scholar 

  • Goncharova LB, Tarakanov AO (2008a) Nanotubes at neural and immune synapses. Curr Med Chem 15(3):210–218

    Article  CAS  PubMed  Google Scholar 

  • Goncharova LB, Tarakanov AO (2008b) Why chemokines are cytokines while their receptors are not cytokine ones? Curr Med Chem 15(13):1297–1304

    Article  CAS  PubMed  Google Scholar 

  • Gonzalez-Maeso J, Ang RL, Yuen T et al (2008) Identification of a serotonin/glutamate receptor complex implicated in psychosis. Nature 452:93–97

    Article  CAS  PubMed  Google Scholar 

  • Goodey NM, Benkovic SJ (2008) Allosteric regulation and catalysis emerge via a common route. Nat Chem Biol 4:474–482

    Article  CAS  PubMed  Google Scholar 

  • Guo W, Shi L, Filizola M, Weinstein H, Javitch JA (2005) From the cover: crosstalk in G protein-coupled receptors: changes at the transmembrane homodimer interface determine activation. Proc Natl Acad Sci U S A 102(48):17495–17500

    Article  CAS  PubMed  Google Scholar 

  • Guo W, Urizar E, Kravilkova M et al (2008) Dopamine D2 receptors form higher order oligomers at physiological expression levels. EMBO J 27(17):2293–2304

    Article  CAS  PubMed  Google Scholar 

  • Gurevich VV, Gurevich EV (2008) How and why do GPCRs dimerize? Trends Pharmacol Sci 29:234–240

    Article  CAS  PubMed  Google Scholar 

  • Guyon A, Nahon JL (2007) Multiple actions of the chemokine stromal cell-derived factor-1a on neuronal activity. J Mol Endocrinol 38:365–376

    Article  CAS  PubMed  Google Scholar 

  • Hague C, Lee SE, Chen Z, Prinster SC, Hall RA, Minneman KP (2006) Heterodimers of alpha1B- and alpha1D-adrenergic receptors form a single functional entity. Mol Pharmacol 69(1):45–55

    CAS  PubMed  Google Scholar 

  • Hillion J, Canals M, Torvinen M et al (2002) Coaggregation, cointernalization, and codesensitization of adenosine A2A receptors and dopamine D2 receptors. J Biol Chem 277:18091–18097

    Article  CAS  PubMed  Google Scholar 

  • Hilton DJ, Zhang JG, Metcalf D, Alexander WS, Nicola NA, Wilson TA (1996) Cloning and characterization of a binding subunit of the interleukin 13 receptor that is also a component of the interleukin 4 receptor. Proc Natl Acad Sci U S A 96:497–501

    Article  Google Scholar 

  • Hirono M, Yoshioka T, Konishi S (2001) GABA(B) receptor activation enhances mGluR-mediated responses at cerebellar excitatory synapses. Nat Neurosci 4:1207–1216

    Article  CAS  PubMed  Google Scholar 

  • Jin MS, Kim SE, Heo JY et al (2007) Crystal structure of the TL1-TLR2 heterodimer induced by binding of a tri-acylated lipopeptide. Cell 130:1071–1082

    Article  CAS  PubMed  Google Scholar 

  • Jordan BA, Devi LA (1999) G-protein-coupled receptor heterodimerization modulates receptor function. Nature 399:697–700

    Article  CAS  PubMed  Google Scholar 

  • Kamiya T, Saitoh O, Yoshioka K, Nakata H (2003) Oligomerization of adenosine A2A and dopamine D2 receptors in living cells. Biochem Biophys Res Commun 306(2):544–549

    Article  CAS  PubMed  Google Scholar 

  • Kearn CS, Blake-Palmer K, Daniel E, Mackie K, Glass M (2005) Concurrent stimulation of cannabinoid CB1 and dopamine D2 receptors enhances heterodimer formation: a mechanism for receptor cross-talk? Mol Pharmacol 67(5):1697–1704

    Article  CAS  PubMed  Google Scholar 

  • Kenakin T (2007) Collateral efficacy in drug discovery: taking advantage of the good (allosteric) nature of 7TM receptors. Trends Pharmacol Sci 28:407–415

    Article  CAS  PubMed  Google Scholar 

  • Kohl A, Binz HK, Forrer P, Stumpp MT, Plückthun A, Grütter MG (2003) Designed to be stable: crystal structure of a consensus ankyrin repeat protein. Proc Natl Acad Sci U S A 100(4):1700–1705

    Article  CAS  PubMed  Google Scholar 

  • König R, Zhou Y, Elleder D et al (2008) Global analysis of host-pathogen interactions that regulate early-stage HIV-1 replication. Cell 135:49–60

    Article  PubMed  CAS  Google Scholar 

  • Kuner R, Köhr G, Grünewald S, Eisenhardt G, Bach A, Kornau HC (1999) Role of heteromer formation in GABAB receptor function. Science 283:74–77

    Article  CAS  PubMed  Google Scholar 

  • Lee SP, So CH, Rashid AJ et al (2004) Dopamine D1 and D2 receptor co-activation generanks a novel phospholipase C-mediated calcium signal. J Biol Chem 279(34):35671–35678

    Article  CAS  PubMed  Google Scholar 

  • Liu F, Wan Q, Pristupa ZB, Yu XM, Wang YT, Niznik HB (2000) Direct protein-protein coupling enables cross-talk between dopamine D5 and g-aminobutyric acid A receptors. Nature 403:274–280

    Article  CAS  PubMed  Google Scholar 

  • Lopez-Gimenez JF, Canals M, Pediani JD, Milligan G (2007) The alpha1b-adrenoceptor exists as a higher-order oligomer: effective oligomerization is required for receptor maturation, surface delivery, and function. Mol Pharmacol 71(4):1015–1029

    Article  CAS  PubMed  Google Scholar 

  • Marcellino D, Ferré S, Casadó V et al (2008a) Identification of dopamine D1–D3 receptor heteromers. Indications for a role of synergistic D1–D3 receptor interactions in the striatum. J Biol Chem 283:26016–26025

    Article  CAS  PubMed  Google Scholar 

  • Marcellino D, Carriba P, Filip M et al (2008b) Antagonistic cannabinoid CB1/dopamine D2 receptor interactions in striatal CB1/D2 heteromers. A combined neurochemical and behavioral analysis. Neuropharmac 54(5):815–823

    Article  CAS  Google Scholar 

  • Marshall FH, Jones KA, Kaupmann K, Bettler B (2001) GABAB receptors—the first 7TM heterodimers. Trends Pharmacol Sci 20(10):396–399

    Article  Google Scholar 

  • Matsushima N, Tanaka T, Enkhbayar P et al (2007) Comparative sequence analysis of leucine-rich repeats (LRRs) within vertebrate toll-like receptors. BMC Genomics 8:124–145

    Article  PubMed  CAS  Google Scholar 

  • Milligan G (2008) A day in the life of a G protein-coupled receptor: the contribution to function of G protein-coupled receptor dimerization. Br J Pharmacol 153:S216–S229

    Article  CAS  PubMed  Google Scholar 

  • Mizuno T, Zhang G, Takeuchi H et al (2008) Interferon-γ directly induces neurotoxicity through a neuron specific, calcium-permeable complex of IFN-γ receptor and AMPA GluR1 receptor. FASEB J 22:1797–1806

    Article  CAS  PubMed  Google Scholar 

  • Moran MF, Koch CA, Sadowski I, Pawson T (1988) Mutational analysis of a phosphotransfer motif essential for v-fps tyrosine kinase activity. Oncogene 3(6):665–672

    CAS  PubMed  Google Scholar 

  • NCBI (2009) National center for biotechnology information (http://www.ncbi.nlm.nih.gov).

  • Percherancier Y, Berchiche A, Slight I et al (2005) Bioluminescence resonance energy transfer reveals ligand-induced conformational changes in CXCR4 homo- and heterodimers. J Biol Chem 280(11):9895–9903

    Article  CAS  PubMed  Google Scholar 

  • Pfeiffer M, Kirscht S, Stumm R et al (2003) Heterodimerization of substance P and mu-opioid receptors regulates receptor trafficking and resensitization. J Biol Chem 278(51):51630–51637

    Article  CAS  PubMed  Google Scholar 

  • Pin JP, Neubig R, Bouvier M et al (2007) International Union of Basic and Clinical Pharmacology. LXVII. Recommendations for the recognition and Nomenclature of G protein-coupled receptor heteromultimers. Pharmacol Rev 59:5–13

    Article  CAS  PubMed  Google Scholar 

  • Popoli P, Pèzzola A, Torvinen M et al (2001) 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. Neuropsychopharmacol 25(4):505–513

    Article  CAS  Google Scholar 

  • Rashid AJ, So CH, Kong MM et al (2007) D1–D2 dopamine receptor heterooligomers with unique pharmacology are coupled to rapid activation of Gq/11 in the striatum. Proc Natl Acad Sci U S A 104(2):654–659

    Article  CAS  PubMed  Google Scholar 

  • Rios C, Gomes I, Devi LA (2006) Mu opioid and CB1 cannabinoid receptor interactions: reciprocal inhibition of receptor signaling and neuritogenesis. Br J Pharmacol 148(4):387–395

    Article  CAS  PubMed  Google Scholar 

  • Rocheville M, Lange DC, Kumar U, Patel SC, Patel YC (2000a) Receptors for dopamine and somatostatin: formation of hetero-oligomers with enhanced functional activity. Science 288:154–157

    Article  CAS  PubMed  Google Scholar 

  • Rocheville M, Lange DC, Kumar U, Sasi R, Patel SC, Patel YC (2000b) Subtypes of the somatostatin receptor assemble as functional homo- and heterodimers. J Biol Chem 275:7862–7869

    Article  CAS  PubMed  Google Scholar 

  • Scarselli M, Novi F, Schallmach E et al (2001) D2/D3 dopamine receptor heterodimers exhibit unique functional properties. J Biol Chem 276(32):30308–303014

    Article  CAS  PubMed  Google Scholar 

  • Suzuki S, Chuang LF, Yau P, Doi RH, Chuang RY (2002) Interactions of opioid and chemokine receptors: oligomerization of mu, kappa, and delta with CCR5 on immune cells. Exp Cell Res 280(2):192–200

    Article  CAS  PubMed  Google Scholar 

  • Szidonya L, Cserzo M, Hunyady L (2008) Dimerization and oligomerization of G-protein-coupled receptors: debated structures with established and emerging functions. J Endocrinol 196:435–453

    Article  CAS  PubMed  Google Scholar 

  • Tarakanov A, Prokaev A (2007) Identification of cellular automata by immunocomputing. J Cell Autom 2(1):39–45

    Google Scholar 

  • Tarakanov AO, Goncharova LB (2009) Cell-cell nanotubes: Tunneling through several types of synapses. Commun Integr Biol 2(4):359–361

    Article  CAS  PubMed  Google Scholar 

  • Tarakanov AO, Fuxe KG, Agnati LF, Goncharova LB (2009) Possible role of receptor heteromers in multiple sclerosis. J Neural Transmis 116:989–994

    Article  CAS  Google Scholar 

  • Tobin AB, Butcher AJ, Kong KC (2008) Location, location, location... site-specific GPCR phosphorylation offers a mechanism for cell-type-specific signalling. Trends Pharmacol Sci 29(8):413–420

    Article  CAS  PubMed  Google Scholar 

  • Torvinen M, Marcellino D, Canals M et al (2005) Adenosine A2A receptor and dopamine D3 receptor interactions: evidence of functional A2A/D3 heteromeric complexes. Mol Pharmacol 67(2):400–407

    Article  CAS  PubMed  Google Scholar 

  • von Euler G (1991) Biochemical characterization of the intramembrane interaction between neurotensin and dopamine D2 receptors in the rat brain. Brain Res 561:93–98

    Article  Google Scholar 

  • Wang JH, Meijers R, Xiong Y et al (2001) Crystal structure of the human CD4 N-terminal two-domain fragments complexed to a class II MHC molecule. Proc Natl Acad Sci U S A 98(19):10799–10804

    Article  CAS  PubMed  Google Scholar 

  • Woods AS, Ferré S (2005) Amazing stability of the arginine-phosphate electrostatic interaction. Proteome Res 4:1397–1402

    Article  CAS  Google Scholar 

  • Woods AS, Marcellino D, Jackson SN et al (2008) How calmodulin interacts with the adenosine A2A and the dopamine D2 receptotrs. J Proteome Res 7(8):3428–3434

    Article  CAS  PubMed  Google Scholar 

  • Xie Z, Lee SP, O’Dowd BF, George SR (1999) Serotonin 5-HT1B and 5-HT1D receptors from homodimers when expressed alone and heterodimers when coexpressed. FEBS Lett 456:63–67

    Article  CAS  PubMed  Google Scholar 

  • Yoshioka K, Saitoh O, Nakata H (2001) Heteromeric association creates a P2Y-like adenosine receptor. Proc Natl Acad Sci U S A 98:7617–7622

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Russian Academy of Sciences, St. Petersburg Institute for Informatics and Automation, Saint Petersburg, Russia

    Alexander O. Tarakanov

  2. Department of Neuroscience, Karolinska Institute, Stockholm, Sweden

    Kjell G. Fuxe

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  1. Alexander O. Tarakanov
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  2. Kjell G. Fuxe
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Correspondence to Alexander O. Tarakanov.

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Tarakanov, A.O., Fuxe, K.G. Triplet Puzzle: Homologies of Receptor Heteromers. J Mol Neurosci 41, 294–303 (2010). https://doi.org/10.1007/s12031-009-9313-5

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