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Searching the GPCR Heterodimer Network (GPCR-hetnet) Database for Information to Deduce the Receptor–Receptor Interface and Its Role in the Integration of Receptor Heterodimer Functions

  • Ismel Brito
  • Manuel Narvaez
  • David Savelli
  • Kirill Shumilov
  • Michael Di Palma
  • Stefano Sartini
  • Kamila Skieterska
  • Kathleen Van Craenenbroeck
  • Ismael Valladolid-Acebes
  • Rauner Zaldivar-Oro
  • Malgorzata Filip
  • Riccardo Cuppini
  • Alicia Rivera
  • Fang Liu
  • Patrizia Ambrogini
  • Miguel Pérez de la Mora
  • Kjell Fuxe
  • Dasiel O. Borroto-Escuela
Protocol
Part of the Neuromethods book series (NM, volume 140)

Abstract

The G protein-coupled receptor heterocomplex network database (GPCR-hetnet) is a database designed to store information on GPCR heteroreceptor complexes and their allosteric receptor–receptor interactions. It is an expert-authored and peer-reviewed, curated collection of well-documented GPCR–GPCR interactions that span the gamut from classical GPCR–GPCR interactions to more complex receptor–receptor interactions (GPCR-Receptor Tyrosine Kinase and GPCR-ionotropic receptor/ligand gated ion channel). Although GPCR-hetnet contains interactions among GPCR from several different species, the curators have initially focused on receptor–receptor interactions in humans. Currently (August 2017) GPCR-hetnet contains information on 250 receptors (192 GPCR, 52 RTK, and 6 ionotropic receptors) and >1023 interactions. The GPCR-hetnet provides four searchable datasets: the hetnet, the non-hetnet, the rtknet, and the ionnet. Other supporting datasets include information about receptors that are present in GPCR-hetnet such as literature citations. This chapter describes in a basic protocol how to use, navigate, and browse through the GPCR-hetnet database to identify the clusters in which a receptor protomer of interest is involved, while further applicability are also described and introduced.

Key words

G protein-coupled receptors Ionotropic receptor/ligand gated ion channel Receptor tyrosine kinase Network Heterodimerization Heteromers Dimerization Oligomerization Hubs Receptor–receptor interactions Clusters Architecture 

Notes

Acknowledgments

The work was supported by the Swedish Medical Research Council (62X-00715-50-3) to K.F., by ParkinsonFonden 2015, AFA Försäkring (130328) to K.F., and by Hjärnfonden (FO2016-0302) and Karolinska Institutet Forskningsstiftelser (2016–2017) to D.O.B-E. D.O.B-E. belongs to the “Academia de Biólogos Cubanos” group.

References

  1. 1.
    Fuxe K, Ferre 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 Brain Res Rev 26(2-3):258–273CrossRefPubMedGoogle Scholar
  2. 2.
    Fuxe K, Borroto-Escuela DO (2016) Heteroreceptor complexes and their allosteric receptor-receptor interactions as a novel biological principle for integration of communication in the CNS: targets for drug development. Neuropsychopharmacology 41(1):380–382. https://doi.org/10.1038/npp.2015.244 CrossRefPubMedGoogle Scholar
  3. 3.
    Fuxe K, Agnati LF, Borroto-Escuela DO (2014) The impact of receptor-receptor interactions in heteroreceptor complexes on brain plasticity. Expert Rev Neurother 14(7):719–721. https://doi.org/10.1586/14737175.2014.922878 CrossRefPubMedGoogle Scholar
  4. 4.
    Fuxe K, Borroto-Escuela D, Fisone G, Agnati LF, Tanganelli S (2014) Understanding the role of heteroreceptor complexes in the central nervous system. Curr Protein Pept Sci 15(7):647CrossRefPubMedGoogle Scholar
  5. 5.
    Fuxe K, Borroto-Escuela DO, Ciruela F, Guidolin D, Agnati LF (2014) Receptor-receptor interactions in heteroreceptor complexes: a new principle in biology. Focus on their role in learning and memory. Neurosci Discov 2(1):6. https://doi.org/10.7243/2052-6946-2-6 CrossRefGoogle Scholar
  6. 6.
    Borroto-Escuela DO, Li X, Tarakanov AO, Savelli D, Narvaez M, Shumilov K, Andrade-Talavera Y, Jimenez-Beristain A, Pomierny B, Diaz-Cabiale Z, Cuppini R, Ambrogini P, Lindskog M, Fuxe K (2017) Existence of brain 5-HT1A-5-HT2A isoreceptor complexes with antagonistic allosteric receptor-receptor interactions regulating 5-HT1A receptor recognition. ACS Omega 2(8):4779–4789. https://doi.org/10.1021/acsomega.7b00629 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Borroto-Escuela DO, DuPont CM, Li X, Savelli D, Lattanzi D, Srivastava I, Narvaez M, Di Palma M, Barbieri E, Andrade-Talavera Y, Cuppini R, Odagaki Y, Palkovits M, Ambrogini P, Lindskog M, Fuxe K (2017) Disturbances in the FGFR1-5-HT1A heteroreceptor complexes in the Raphe-hippocampal 5-HT system develop in a genetic rat model of depression. Front Cell Neurosci 11:309. https://doi.org/10.3389/fncel.2017.00309 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Borroto-Escuela DO, Wydra K, Pintsuk J, Narvaez M, Corrales F, Zaniewska M, Agnati LF, Franco R, Tanganelli S, Ferraro L, Filip M, Fuxe K (2016) Understanding the functional plasticity in neural networks of the basal ganglia in cocaine use disorder: a role for allosteric receptor-receptor interactions in A2A-D2 heteroreceptor complexes. Neural Plast 2016:4827268. https://doi.org/10.1155/2016/4827268 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Borroto-Escuela DO, Romero-Fernandez W, Mudo G, Perez-Alea M, Ciruela F, Tarakanov AO, Narvaez M, Di Liberto V, Agnati LF, Belluardo N, Fuxe K (2012) Fibroblast growth factor receptor 1- 5-hydroxytryptamine 1A heteroreceptor complexes and their enhancement of hippocampal plasticity. Biol Psychiatry 71(1):84–91. https://doi.org/10.1016/j.biopsych.2011.09.012 CrossRefPubMedGoogle Scholar
  10. 10.
    Borroto-Escuela DO, Tarakanov AO, Guidolin D, Ciruela F, Agnati LF, Fuxe K (2011) Moonlighting characteristics of G protein-coupled receptors: focus on receptor heteromers and relevance for neurodegeneration. IUBMB Life 63(7):463–472. https://doi.org/10.1002/iub.473 CrossRefPubMedGoogle Scholar
  11. 11.
    Franco R, Ferre S, Agnati L, Torvinen M, Gines S, Hillion J, Casado V, Lledo P, Zoli M, Lluis C, Fuxe K (2000) Evidence for adenosine/dopamine receptor interactions: indications for heteromerization. Neuropsychopharmacology 23(4 Suppl):S50–S59. https://doi.org/10.1016/S0893-133X(00)00144-5 CrossRefPubMedGoogle Scholar
  12. 12.
    Gines S, Hillion J, Torvinen M, Le Crom S, Casado V, Canela EI, Rondin S, Lew JY, Watson S, Zoli M, Agnati LF, Verniera P, Lluis C, Ferre S, Fuxe K, Franco R (2000) Dopamine D1 and adenosine A1 receptors form functionally interacting heteromeric complexes. Proc Natl Acad Sci U S A 97(15):8606–8611. https://doi.org/10.1073/pnas.150241097 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Navarro G, Borroto-Escuela D, Angelats E, Etayo I, Reyes-Resina I, Pulido-Salgado M, Rodriguez-Perez AI, Canela EI, Saura J, Lanciego JL, Labandeira-Garcia JL, Saura CA, Fuxe K, Franco R (2018) Receptor-heteromer mediated regulation of endocannabinoid signaling in activated microglia. Role of CB1 and CB2 receptors and relevance for Alzheimer’s disease and levodopa-induced dyskinesia. Brain Behav Immun 67:139–151. https://doi.org/10.1016/j.bbi.2017.08.015 CrossRefPubMedGoogle Scholar
  14. 14.
    Angers S, Salahpour A, Bouvier M (2001) Biochemical and biophysical demonstration of GPCR oligomerization in mammalian cells. Life Sci 68(19-20):2243–2250CrossRefPubMedGoogle Scholar
  15. 15.
    Angers S, Salahpour A, Joly E, Hilairet S, Chelsky D, Dennis M, Bouvier M (2000) Detection of beta 2-adrenergic receptor dimerization in living cells using bioluminescence resonance energy transfer (BRET). Proc Natl Acad Sci U S A 97(7):3684–3689. https://doi.org/10.1073/pnas.060590697 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Hebert TE, Loisel TP, Adam L, Ethier N, Onge SS, Bouvier M (1998) Functional rescue of a constitutively desensitized beta2AR through receptor dimerization. Biochem J 330(Pt 1):287–293CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Han Y, Moreira IS, Urizar E, Weinstein H, Javitch JA (2009) Allosteric communication between protomers of dopamine class A GPCR dimers modulates activation. Nat Chem Biol 5(9):688–695. https://doi.org/10.1038/nchembio.199 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Guo W, Urizar E, Kralikova M, Mobarec JC, Shi L, Filizola M, Javitch JA (2008) Dopamine D2 receptors form higher order oligomers at physiological expression levels. EMBO J 27(17):2293–2304. https://doi.org/10.1038/emboj.2008.153 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Goupil E, Laporte SA, Hebert TE (2013) A simple method to detect allostery in GPCR dimers. Methods Cell Biol 117:165–179. https://doi.org/10.1016/B978-0-12-408143-7.00009-8 CrossRefPubMedGoogle Scholar
  20. 20.
    Dean MK, Higgs C, Smith RE, Bywater RP, Snell CR, Scott PD, Upton GJ, Howe TJ, Reynolds CA (2001) Dimerization of G-protein-coupled receptors. J Med Chem 44(26):4595–4614CrossRefPubMedGoogle Scholar
  21. 21.
    Gouldson PR, Higgs C, Smith RE, Dean MK, Gkoutos GV, Reynolds CA (2000) Dimerization and domain swapping in G-protein-coupled receptors: a computational study. Neuropsychopharmacology 23(4 Suppl):S60–S77. https://doi.org/10.1016/S0893-133X(00)00153-6 CrossRefPubMedGoogle Scholar
  22. 22.
    Gouldson PR, Snell CR, Bywater RP, Higgs C, Reynolds CA (1998) Domain swapping in G-protein coupled receptor dimers. Protein Eng 11(12):1181–1193CrossRefPubMedGoogle Scholar
  23. 23.
    Devi LA (2001) Heterodimerization of G-protein-coupled receptors: pharmacology, signaling and trafficking. Trends Pharmacol Sci 22(10):532–537CrossRefPubMedGoogle Scholar
  24. 24.
    Kenakin T (2002) Drug efficacy at G protein-coupled receptors. Annu Rev Pharmacol Toxicol 42:349–379. https://doi.org/10.1146/annurev.pharmtox.42.091401.113012 CrossRefPubMedGoogle Scholar
  25. 25.
    Lee SP, Xie Z, Varghese G, Nguyen T, O'Dowd BF, George SR (2000) Oligomerization of dopamine and serotonin receptors. Neuropsychopharmacology 23(4 Suppl):S32–S40. https://doi.org/10.1016/S0893-133X(00)00155-X CrossRefPubMedGoogle Scholar
  26. 26.
    Xie Z, Lee SP, O'Dowd BF, George SR (1999) Serotonin 5-HT1B and 5-HT1D receptors form homodimers when expressed alone and heterodimers when co-expressed. FEBS Lett 456(1):63–67CrossRefPubMedGoogle Scholar
  27. 27.
    Zeng F, Wess J (2000) Molecular aspects of muscarinic receptor dimerization. Neuropsychopharmacology 23(4 Suppl):S19–S31. https://doi.org/10.1016/S0893-133X(00)00146-9 CrossRefPubMedGoogle Scholar
  28. 28.
    Overton MC, Blumer KJ (2000) G-protein-coupled receptors function as oligomers in vivo. Curr Biol 10(6):341–344CrossRefPubMedGoogle Scholar
  29. 29.
    Bockaert J, Pin JP (1999) Molecular tinkering of G protein-coupled receptors: an evolutionary success. EMBO J 18(7):1723–1729. https://doi.org/10.1093/emboj/18.7.1723 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Portoghese PS (2001) From models to molecules: opioid receptor dimers, bivalent ligands, and selective opioid receptor probes. J Med Chem 44(14):2259–2269CrossRefPubMedGoogle Scholar
  31. 31.
    Waldhoer M, Fong J, Jones RM, Lunzer MM, Sharma SK, Kostenis E, Portoghese PS, Whistler JL (2005) A heterodimer-selective agonist shows in vivo relevance of G protein-coupled receptor dimers. Proc Natl Acad Sci U S A 102(25):9050–9055. https://doi.org/10.1073/pnas.0501112102 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    van Rijn RM, Whistler JL, Waldhoer M (2010) Opioid-receptor-heteromer-specific trafficking and pharmacology. Curr Opin Pharmacol 10(1):73–79. https://doi.org/10.1016/j.coph.2009.09.007 CrossRefPubMedGoogle Scholar
  33. 33.
    van Rijn RM, Chazot PL, Shenton FC, Sansuk K, Bakker RA, Leurs R (2006) Oligomerization of recombinant and endogenously expressed human histamine H(4) receptors. Mol Pharmacol 70(2):604–615. https://doi.org/10.1124/mol.105.020818 CrossRefPubMedGoogle Scholar
  34. 34.
    Schellekens H, De Francesco PN, Kandil D, Theeuwes WF, McCarthy T, van Oeffelen WE, Perello M, Giblin L, Dinan TG, Cryan JF (2015) Ghrelin’s orexigenic effect is modulated via a serotonin 2C receptor interaction. ACS Chem Neurosci 6(7):1186–1197. https://doi.org/10.1021/cn500318q CrossRefPubMedGoogle Scholar
  35. 35.
    Schellekens H, Dinan TG, Cryan JF (2013) Taking two to tango: a role for ghrelin receptor heterodimerization in stress and reward. Front Neurosci 7:148. https://doi.org/10.3389/fnins.2013.00148 CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Borroto-Escuela DO, Romero-Fernandez W, Garriga P, Ciruela F, Narvaez M, Tarakanov AO, Palkovits M, Agnati LF, Fuxe K (2013) G protein-coupled receptor heterodimerization in the brain. Methods Enzymol 521:281–294. https://doi.org/10.1016/B978-0-12-391862-8.00015-6 CrossRefPubMedGoogle Scholar
  37. 37.
    Borroto-Escuela DO, Flajolet M, Agnati LF, Greengard P, Fuxe K (2013) Bioluminescence resonance energy transfer methods to study G protein-coupled receptor-receptor tyrosine kinase heteroreceptor complexes. Methods Cell Biol 117:141–164. https://doi.org/10.1016/B978-0-12-408143-7.00008-6 CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Fernandez-Duenas V, Llorente J, Gandia J, Borroto-Escuela DO, Agnati LF, Tasca CI, Fuxe K, Ciruela F (2012) Fluorescence resonance energy transfer-based technologies in the study of protein-protein interactions at the cell surface. Methods 57(4):467–472. https://doi.org/10.1016/j.ymeth.2012.05.007 CrossRefPubMedGoogle Scholar
  39. 39.
    Skieterska K, Duchou J, Lintermans B, Van Craenenbroeck K (2013) Detection of G protein-coupled receptor (GPCR) dimerization by coimmunoprecipitation. Methods Cell Biol 117:323–340. https://doi.org/10.1016/B978-0-12-408143-7.00017-7 CrossRefPubMedGoogle Scholar
  40. 40.
    Achour L, Kamal M, Jockers R, Marullo S (2011) Using quantitative BRET to assess G protein-coupled receptor homo- and heterodimerization. Methods Mol Biol 756:183–200. https://doi.org/10.1007/978-1-61779-160-4_9 CrossRefPubMedGoogle Scholar
  41. 41.
    Lohse MJ, Nuber S, Hoffmann C (2012) Fluorescence/bioluminescence resonance energy transfer techniques to study G-protein-coupled receptor activation and signaling. Pharmacol Rev 64(2):299–336. https://doi.org/10.1124/pr.110.004309 CrossRefPubMedGoogle Scholar
  42. 42.
    Hink MA, Postma M (2013) Monitoring receptor oligomerization by line-scan fluorescence cross-correlation spectroscopy. Methods Cell Biol 117:197–212. https://doi.org/10.1016/B978-0-12-408143-7.00011-6 CrossRefPubMedGoogle Scholar
  43. 43.
    Herrick-Davis K, Grinde E, Cowan A, Mazurkiewicz JE (2013) Fluorescence correlation spectroscopy analysis of serotonin, adrenergic, muscarinic, and dopamine receptor dimerization: the oligomer number puzzle. Mol Pharmacol 84(4):630–642. https://doi.org/10.1124/mol.113.087072 CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Kuhn C, Bufe B, Batram C, Meyerhof W (2010) Oligomerization of TAS2R bitter taste receptors. Chem Senses 35(5):395–406. https://doi.org/10.1093/chemse/bjq027 CrossRefPubMedGoogle Scholar
  45. 45.
    Xia Y, Yu H, Jansen R, Seringhaus M, Baxter S, Greenbaum D, Zhao H, Gerstein M (2004) Analyzing cellular biochemistry in terms of molecular networks. Annu Rev Biochem 73:1051–1087. https://doi.org/10.1146/annurev.biochem.73.011303.073950 CrossRefPubMedGoogle Scholar
  46. 46.
    Borroto-Escuela DO, Agnati LF, Fuxe K, Ciruela F (2012) Muscarinic acetylcholine receptor-interacting proteins (mAChRIPs): targeting the receptorsome. Curr Drug Targets 13(1):53–71CrossRefPubMedGoogle Scholar
  47. 47.
    Borroto-Escuela DO, Correia PA, Romero-Fernandez W, Narvaez M, Fuxe K, Ciruela F, Garriga P (2011) Muscarinic receptor family interacting proteins: role in receptor function. J Neurosci Methods 195(2):161–169. https://doi.org/10.1016/j.jneumeth.2010.11.025 CrossRefPubMedGoogle Scholar
  48. 48.
    Choura M, Rebai A (2010) Application of computational approaches to study signalling networks of nuclear and Tyrosine kinase receptors. Biol Direct 5:58. https://doi.org/10.1186/1745-6150-5-58 CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Borroto-Escuela DO, Brito I, Romero-Fernandez W, Di Palma M, Oflijan J, Skieterska K, Duchou J, Van Craenenbroeck K, Suarez-Boomgaard D, Rivera A, Guidolin D, Agnati LF, Fuxe K (2014) The G protein-coupled receptor heterodimer network (GPCR-HetNet) and its hub components. Int J Mol Sci 15(5):8570–8590. https://doi.org/10.3390/ijms15058570 CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Barabasi AL, Oltvai ZN (2004) Network biology: understanding the cell's functional organization. Nat Rev Genet 5(2):101–113. https://doi.org/10.1038/nrg1272 CrossRefPubMedGoogle Scholar
  51. 51.
    Yook SH, Oltvai ZN, Barabasi AL (2004) Functional and topological characterization of protein interaction networks. Proteomics 4(4):928–942. https://doi.org/10.1002/pmic.200300636 CrossRefPubMedGoogle Scholar
  52. 52.
    Zhu X, Gerstein M, Snyder M (2007) Getting connected: analysis and principles of biological networks. Genes Dev 21(9):1010–1024. https://doi.org/10.1101/gad.1528707 CrossRefPubMedGoogle Scholar
  53. 53.
    Albert R, Jeong H, Barabasi AL (2000) Error and attack tolerance of complex networks. Nature 406(6794):378–382. https://doi.org/10.1038/35019019 CrossRefPubMedGoogle Scholar
  54. 54.
    Han JD, Bertin N, Hao T, Goldberg DS, Berriz GF, Zhang LV, Dupuy D, Walhout AJ, Cusick ME, Roth FP, Vidal M (2004) Evidence for dynamically organized modularity in the yeast protein-protein interaction network. Nature 430(6995):88–93. https://doi.org/10.1038/nature02555 CrossRefPubMedGoogle Scholar
  55. 55.
    Wuchty S, Almaas E (2005) Peeling the yeast protein network. Proteomics 5(2):444–449. https://doi.org/10.1002/pmic.200400962 CrossRefPubMedGoogle Scholar
  56. 56.
    Batada NN, Reguly T, Breitkreutz A, Boucher L, Breitkreutz BJ, Hurst LD, Tyers M (2006) Stratus not altocumulus: a new view of the yeast protein interaction network. PLoS Biol 4(10):e317. https://doi.org/10.1371/journal.pbio.0040317 CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Ekman D, Light S, Bjorklund AK, Elofsson A (2006) What properties characterize the hub proteins of the protein-protein interaction network of Saccharomyces cerevisiae? Genome Biol 7(6):R45. https://doi.org/10.1186/gb-2006-7-6-r45 CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Vallabhajosyula RR, Chakravarti D, Lutfeali S, Ray A, Raval A (2009) Identifying hubs in protein interaction networks. PLoS One 4(4):e5344. https://doi.org/10.1371/journal.pone.0005344 CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Delprato A (2012) Topological and functional properties of the small GTPases protein interaction network. PLoS One 7(9):e44882. https://doi.org/10.1371/journal.pone.0044882 CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Borroto-Escuela DO, Romero-Fernandez W, Tarakanov AO, Gomez-Soler M, Corrales F, Marcellino D, Narvaez M, Frankowska M, Flajolet M, Heintz N, Agnati LF, Ciruela F, Fuxe K (2010) Characterization of the A2AR-D2R interface: focus on the role of the C-terminal tail and the transmembrane helices. Biochem Biophys Res Commun 402(4):801–807. https://doi.org/10.1016/j.bbrc.2010.10.122 CrossRefPubMedGoogle Scholar
  61. 61.
    Maggio R, Barbier P, Colelli A, Salvadori F, Demontis G, Corsini GU (1999) G protein-linked receptors: pharmacological evidence for the formation of heterodimers. J Pharmacol Exp Ther 291(1):251–257PubMedGoogle Scholar
  62. 62.
    Harikumar KG, Wootten D, Pinon DI, Koole C, Ball AM, Furness SG, Graham B, Dong M, Christopoulos A, Miller LJ, Sexton PM (2012) Glucagon-like peptide-1 receptor dimerization differentially regulates agonist signaling but does not affect small molecule allostery. Proc Natl Acad Sci U S A 109(45):18607–18612. https://doi.org/10.1073/pnas.1205227109 CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Yanagawa M, Yamashita T, Shichida Y (2011) Comparative fluorescence resonance energy transfer analysis of metabotropic glutamate receptors: implications about the dimeric arrangement and rearrangement upon ligand bindings. J Biol Chem 286(26):22971–22981. https://doi.org/10.1074/jbc.M110.206870 CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Elsner A, Tarnow P, Schaefer M, Ambrugger P, Krude H, Gruters A, Biebermann H (2006) MC4R oligomerizes independently of extracellular cysteine residues. Peptides 27(2):372–379. https://doi.org/10.1016/j.peptides.2005.02.027 CrossRefPubMedGoogle Scholar
  65. 65.
    Arachiche A, Mumaw MM, de la Fuente M, Nieman MT (2013) Protease-activated receptor 1 (PAR1) and PAR4 heterodimers are required for PAR1-enhanced cleavage of PAR4 by alpha-thrombin. J Biol Chem 288(45):32553–32562. https://doi.org/10.1074/jbc.M113.472373 CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Leger AJ, Jacques SL, Badar J, Kaneider NC, Derian CK, Andrade-Gordon P, Covic L, Kuliopulos A (2006) Blocking the protease-activated receptor 1-4 heterodimer in platelet-mediated thrombosis. Circulation 113(9):1244–1254. https://doi.org/10.1161/CIRCULATIONAHA.105.587758 CrossRefPubMedGoogle Scholar
  67. 67.
    Laroche G, Lepine MC, Theriault C, Giguere P, Giguere V, Gallant MA, de Brum-Fernandes A, Parent JL (2005) Oligomerization of the alpha and beta isoforms of the thromboxane A2 receptor: relevance to receptor signaling and endocytosis. Cell Signal 17(11):1373–1383. https://doi.org/10.1016/j.cellsig.2005.02.008 CrossRefPubMedGoogle Scholar
  68. 68.
    Gao F, Harikumar KG, Dong M, Lam PC, Sexton PM, Christopoulos A, Bordner A, Abagyan R, Miller LJ (2009) Functional importance of a structurally distinct homodimeric complex of the family B G protein-coupled secretin receptor. Mol Pharmacol 76(2):264–274. https://doi.org/10.1124/mol.109.055756 CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Schulz A, Grosse R, Schultz G, Gudermann T, Schoneberg T (2000) Structural implication for receptor oligomerization from functional reconstitution studies of mutant V2 vasopressin receptors. J Biol Chem 275(4):2381–2389CrossRefPubMedGoogle Scholar
  70. 70.
    Li E, Wimley WC, Hristova K (2012) Transmembrane helix dimerization: beyond the search for sequence motifs. Biochim Biophys Acta 1818(2):183–193. https://doi.org/10.1016/j.bbamem.2011.08.031 CrossRefPubMedGoogle Scholar
  71. 71.
    Lemmon MA, Treutlein HR, Adams PD, Brunger AT, Engelman DM (1994) A dimerization motif for transmembrane alpha-helices. Nat Struct Biol 1(3):157–163CrossRefPubMedGoogle Scholar
  72. 72.
    Kay BK, Williamson MP, Sudol M (2000) The importance of being proline: the interaction of proline-rich motifs in signaling proteins with their cognate domains. FASEB J 14(2):231–241CrossRefPubMedGoogle Scholar
  73. 73.
    Sal-Man N, Gerber D, Bloch I, Shai Y (2007) Specificity in transmembrane helix-helix interactions mediated by aromatic residues. J Biol Chem 282(27):19753–19761. https://doi.org/10.1074/jbc.M610368200 CrossRefPubMedGoogle Scholar

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Authors and Affiliations

  • Ismel Brito
    • 1
    • 2
  • Manuel Narvaez
    • 3
  • David Savelli
    • 4
  • Kirill Shumilov
    • 5
  • Michael Di Palma
    • 4
  • Stefano Sartini
    • 4
  • Kamila Skieterska
    • 6
  • Kathleen Van Craenenbroeck
    • 6
  • Ismael Valladolid-Acebes
    • 7
  • Rauner Zaldivar-Oro
    • 8
  • Malgorzata Filip
    • 9
  • Riccardo Cuppini
    • 4
  • Alicia Rivera
    • 5
  • Fang Liu
    • 10
  • Patrizia Ambrogini
    • 4
  • Miguel Pérez de la Mora
    • 11
  • Kjell Fuxe
    • 12
  • Dasiel O. Borroto-Escuela
    • 1
    • 2
    • 4
  1. 1.Department of NeuroscienceKarolinska InstitutetStockholmSweden
  2. 2.Observatorio Cubano de NeurocienciasGrupo Bohío-EstudioYaguajayCuba
  3. 3.Facultad de Medicina, Instituto de Investigación Biomédica de MálagaUniversidad de MálagaMálagaSpain
  4. 4.Department of Biomolecular Science, Section of PhysiologyUniversity of UrbinoUrbinoItaly
  5. 5.Departamento de Biología CelularUniversidad de MálagaMálagaSpain
  6. 6.Laboratory of Eukaryotic Gene Expression and Signal Transduction (LEGEST)Ghent UniversityGhentBelgium
  7. 7.The Rolf Luft Research Center for Diabetes and EndocrinologyKarolinska Institutet, Karolinska University Hospital L1StockholmSweden
  8. 8.Departamento de Bioquímica, Facultat de BiologíaUniversidad de la HabanaLa HabanaCuba
  9. 9.Laboratory of Drug Addiction Pharmacology, Institute of PharmacologyPolish Academy of SciencesKrakówPoland
  10. 10.Campbell Research Institute, Centre for Addiction and Mental HealthUniversity of TorontoTorontoCanada
  11. 11.Instituto de Fisiología CelularUniversidad Nacional Autónoma de MéxicoMexico CityMexico
  12. 12.Department of NeuroscienceKarolinska InstitutetStockholmSweden

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