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.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
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):258–273
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
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
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):647
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
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
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
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
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
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
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
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
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
Angers S, Salahpour A, Bouvier M (2001) Biochemical and biophysical demonstration of GPCR oligomerization in mammalian cells. Life Sci 68(19-20):2243–2250
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
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):287–293
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
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
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
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):4595–4614
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
Gouldson PR, Snell CR, Bywater RP, Higgs C, Reynolds CA (1998) Domain swapping in G-protein coupled receptor dimers. Protein Eng 11(12):1181–1193
Devi LA (2001) Heterodimerization of G-protein-coupled receptors: pharmacology, signaling and trafficking. Trends Pharmacol Sci 22(10):532–537
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
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
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):63–67
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
Overton MC, Blumer KJ (2000) G-protein-coupled receptors function as oligomers in vivo. Curr Biol 10(6):341–344
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
Portoghese PS (2001) From models to molecules: opioid receptor dimers, bivalent ligands, and selective opioid receptor probes. J Med Chem 44(14):2259–2269
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Borroto-Escuela DO, Agnati LF, Fuxe K, Ciruela F (2012) Muscarinic acetylcholine receptor-interacting proteins (mAChRIPs): targeting the receptorsome. Curr Drug Targets 13(1):53–71
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
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
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
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
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
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
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
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
Wuchty S, Almaas E (2005) Peeling the yeast protein network. Proteomics 5(2):444–449. https://doi.org/10.1002/pmic.200400962
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
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
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
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
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
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):251–257
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
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
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
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
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
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
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
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):2381–2389
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
Lemmon MA, Treutlein HR, Adams PD, Brunger AT, Engelman DM (1994) A dimerization motif for transmembrane alpha-helices. Nat Struct Biol 1(3):157–163
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):231–241
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
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.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2018 Springer Science+Business Media, LLC, part of Springer Nature
About this protocol
Cite this protocol
Brito, I. et al. (2018). 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. In: FUXE, K., Borroto-Escuela, D. (eds) Receptor-Receptor Interactions in the Central Nervous System. Neuromethods, vol 140. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-8576-0_18
Download citation
DOI: https://doi.org/10.1007/978-1-4939-8576-0_18
Published:
Publisher Name: Humana Press, New York, NY
Print ISBN: 978-1-4939-8575-3
Online ISBN: 978-1-4939-8576-0
eBook Packages: Springer Protocols