{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,29]],"date-time":"2026-03-29T01:15:24Z","timestamp":1774746924565,"version":"3.50.1"},"reference-count":93,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2019,4,4]],"date-time":"2019-04-04T00:00:00Z","timestamp":1554336000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003132","name":"Agentschap voor Innovatie door Wetenschap en Technologie","doi-asserted-by":"publisher","award":["140028"],"award-info":[{"award-number":["140028"]}],"id":[{"id":"10.13039\/501100003132","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014440","name":"Ministerio de Ciencia, Innovaci\u00f3n y Universidades","doi-asserted-by":"publisher","award":["SAF2017-87199-R"],"award-info":[{"award-number":["SAF2017-87199-R"]}],"id":[{"id":"10.13039\/100014440","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Dopamine D2 receptors (D2R) are known to form transient homodimer complexes, of which the increased formation has already been associated with development of schizophrenia. Pharmacological targeting and modulation of the equilibrium of these receptor homodimers might lead to a better understanding of the critical role played by these complexes in physiological and pathological conditions. Whereas agonist addition has shown to prolong the D2R dimer lifetime and increase the level of dimer formation, the possible influence of D2R antagonists on dimerization has remained rather unexplored. Here, using a live-cell reporter assay based on the functional complementation of a split Nanoluciferase, a panel of six D2R antagonists were screened for their ability to modulate the level of D2LR dimer formation. Incubation with the D2R antagonist spiperone decreased the level of D2LR dimer formation significantly by 40\u201360% in real-time and after long-term (\u226516 h) incubations. The fact that dimer formation of the well-studied A2a\u2013D2LR dimer was not altered following incubation with spiperone supports the specificity of this observation. Other D2R antagonists, such as clozapine, risperidone, and droperidol did not significantly evoke this dissociation event. Furthermore, molecular modeling reveals that spiperone presents specific Tyr1995.48 and Phe3906.52 conformations, compared to clozapine, which may determine D2R homodimerization.<\/jats:p>","DOI":"10.3390\/ijms20071686","type":"journal-article","created":{"date-parts":[[2019,4,4]],"date-time":"2019-04-04T11:31:57Z","timestamp":1554377517000},"page":"1686","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Distinct Dopamine D2 Receptor Antagonists Differentially Impact D2 Receptor Oligomerization"],"prefix":"10.3390","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9117-4759","authenticated-orcid":false,"given":"Elise","family":"Wouters","sequence":"first","affiliation":[{"name":"Laboratory of Toxicology, Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adri\u00e1n Ricarte","family":"Mar\u00edn","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Neuropharmacology and Bioinformatics, Unitat de Bioestad\u00edstica, Institut de Neuroci\u00e8ncies, Universitat Aut\u00f2noma de Barcelona, 08193 Bellaterra, Spain"},{"name":"Instituto de Salud Carlos III, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Salud Mental, CIBERSAM, Universitat Aut\u00f2noma de Barcelona, 08193 Bellaterra, Spain"},{"name":"Unitat de Neuroci\u00e8ncia Traslacional, Parc Taul\u00ed Hospital Universitari, Institut d\u2019Investigaci\u00f3 i Innovaci\u00f3 Parc Taul\u00ed (I3PT), Institut de Neuroci\u00e8ncies, Universitat Aut\u00f2noma de Barcelona, 08193 Bellaterra, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James Andrew Rupert","family":"Dalton","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Neuropharmacology and Bioinformatics, Unitat de Bioestad\u00edstica, Institut de Neuroci\u00e8ncies, Universitat Aut\u00f2noma de Barcelona, 08193 Bellaterra, Spain"},{"name":"Instituto de Salud Carlos III, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Salud Mental, CIBERSAM, Universitat Aut\u00f2noma de Barcelona, 08193 Bellaterra, Spain"},{"name":"Unitat de Neuroci\u00e8ncia Traslacional, Parc Taul\u00ed Hospital Universitari, Institut d\u2019Investigaci\u00f3 i Innovaci\u00f3 Parc Taul\u00ed (I3PT), Institut de Neuroci\u00e8ncies, Universitat Aut\u00f2noma de Barcelona, 08193 Bellaterra, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7082-4695","authenticated-orcid":false,"given":"Jes\u00fas","family":"Giraldo","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Neuropharmacology and Bioinformatics, Unitat de Bioestad\u00edstica, Institut de Neuroci\u00e8ncies, Universitat Aut\u00f2noma de Barcelona, 08193 Bellaterra, Spain"},{"name":"Instituto de Salud Carlos III, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Salud Mental, CIBERSAM, Universitat Aut\u00f2noma de Barcelona, 08193 Bellaterra, Spain"},{"name":"Unitat de Neuroci\u00e8ncia Traslacional, Parc Taul\u00ed Hospital Universitari, Institut d\u2019Investigaci\u00f3 i Innovaci\u00f3 Parc Taul\u00ed (I3PT), Institut de Neuroci\u00e8ncies, Universitat Aut\u00f2noma de Barcelona, 08193 Bellaterra, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7126-348X","authenticated-orcid":false,"given":"Christophe","family":"Stove","sequence":"additional","affiliation":[{"name":"Laboratory of Toxicology, Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,4,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1124\/pr.110.002642","article-title":"The physiology, signaling, and pharmacology of dopamine receptors","volume":"63","author":"Beaulieu","year":"2011","journal-title":"Pharm. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"349","DOI":"10.14336\/AD.2015.0330","article-title":"Dopamine Receptors and Neurodegeneration","volume":"6","author":"Coronel","year":"2015","journal-title":"Aging Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1152\/physrev.1998.78.1.189","article-title":"Dopamine receptors: From structure to function","volume":"78","author":"Missale","year":"1998","journal-title":"Physiol. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.phrs.2017.01.008","article-title":"An update on the physiological and therapeutic relevance of GPCR oligomers","volume":"117","author":"Farran","year":"2017","journal-title":"Pharmacol. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1124\/pr.113.008052","article-title":"G protein-coupled receptor oligomerization revisited: Functional and pharmacological perspectives","volume":"66","author":"Ferre","year":"2014","journal-title":"Pharm. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.coph.2009.09.008","article-title":"Dimerization of dopamine D1 and D3 receptors in the regulation of striatal function","volume":"10","author":"Fiorentini","year":"2010","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.pharep.2016.10.016","article-title":"Genetic variants of dopamine D2 receptor impact heterodimerization with dopamine D1 receptor","volume":"69","author":"Blasiak","year":"2017","journal-title":"Pharmacol. Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1016\/j.bbrc.2012.12.139","article-title":"D5 dopamine receptor carboxyl tail involved in D5-D2 heteromer formation","volume":"431","author":"Nguyen","year":"2013","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"659","DOI":"10.2174\/1389203715666140901110256","article-title":"Role of dimerization in dopamine D(4) receptor biogenesis","volume":"15","author":"Skieterska","year":"2014","journal-title":"Curr. Protein Pept. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1007\/s00540-008-0661-z","article-title":"Dopamine D2 receptor Taq IA polymorphism is associated with postoperative nausea and vomiting","volume":"22","author":"Nakagawa","year":"2008","journal-title":"J. Anesth."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.neulet.2015.01.076","article-title":"Association between ANKK1 (rs1800497) polymorphism of DRD2 gene and attention deficit hyperactivity disorder: A meta-analysis","volume":"590","author":"Pan","year":"2015","journal-title":"Neurosci. Lett."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1016\/j.biopsych.2014.03.013","article-title":"Presynaptic D2 dopamine receptors control long-term depression expression and memory processes in the temporal hippocampus","volume":"77","author":"Rocchetti","year":"2015","journal-title":"Biol. Psychiatry"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1038\/s41419-017-0221-2","article-title":"Dopamine D2 receptor-mediated neuroprotection in a G2019S Lrrk2 genetic model of Parkinson\u2019s disease","volume":"9","author":"Tozzi","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.biopsych.2016.10.011","article-title":"New Concepts in Dopamine D2 Receptor Biased Signaling and Implications for Schizophrenia Therapy","volume":"81","author":"Urs","year":"2017","journal-title":"Biol. Psychiatry"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1833","DOI":"10.1111\/ejn.14019","article-title":"Enhanced dopamine D2 autoreceptor function in the adult prefrontal cortex contributes to dopamine hypoactivity following adolescent social stress","volume":"48","author":"Weber","year":"2018","journal-title":"Eur. J. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1506","DOI":"10.1038\/mp.2017.107","article-title":"PET imaging of dopamine-D2 receptor internalization in schizophrenia","volume":"23","author":"Weinstein","year":"2018","journal-title":"Mol. Psychiatry"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/0197-0186(92)90071-X","article-title":"Structure and expression of human and rat D2 dopamine receptor genes","volume":"21","author":"Araki","year":"1992","journal-title":"Neurochem. Int."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4025","DOI":"10.1002\/j.1460-2075.1989.tb08585.x","article-title":"The dopamine D2 receptor: Two molecular forms generated by alternative splicing","volume":"8","author":"Sommer","year":"1989","journal-title":"EMBO J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"829","DOI":"10.3389\/fphar.2018.00829","article-title":"Mapping the Interface of a GPCR Dimer: A Structural Model of the A2A Adenosine and D2 Dopamine Receptor Heteromer","volume":"9","author":"Rodriguez","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"46741","DOI":"10.1074\/jbc.M306451200","article-title":"Adenosine A2A-dopamine D2 receptor-receptor heteromerization: Qualitative and quantitative assessment by fluorescence and bioluminescence energy transfer","volume":"278","author":"Canals","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1855","DOI":"10.1016\/j.bbamcr.2017.07.012","article-title":"Bradykinin B2 and dopamine D2 receptors form a functional dimer","volume":"1864","author":"Polit","year":"2017","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1697","DOI":"10.1124\/mol.104.006882","article-title":"Concurrent stimulation of cannabinoid CB1 and dopamine D2 receptors enhances heterodimer formation: A mechanism for receptor cross-talk?","volume":"67","author":"Kearn","year":"2005","journal-title":"Mol. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.expneurol.2013.12.021","article-title":"L-DOPA disrupts adenosine A(2A)-cannabinoid CB(1)-dopamine D(2) receptor heteromer cross-talk in the striatum of hemiparkinsonian rats: Biochemical and behavioral studies","volume":"253","author":"Pinna","year":"2014","journal-title":"Exp. Neurol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1006\/bbrc.1996.1489","article-title":"Dopamine D2 receptor dimers and receptor-blocking peptides","volume":"227","author":"Ng","year":"1996","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"22621","DOI":"10.1074\/jbc.M006936200","article-title":"Dopamine D2 receptor dimer formation: Evidence from ligand binding","volume":"276","author":"Armstrong","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/S0014-5793(01)02969-6","article-title":"Agonist-independent and -dependent oligomerization of dopamine D(2) receptors by fusion to fluorescent proteins","volume":"507","author":"Wurch","year":"2001","journal-title":"FEBS Lett."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4774","DOI":"10.1128\/MCB.00283-07","article-title":"Ubiquitination-induced conformational change within the deiodinase dimer is a switch regulating enzyme activity","volume":"27","author":"Sagar","year":"2007","journal-title":"Mol. Cell Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1007\/s12013-017-0829-y","article-title":"The Class-A GPCR Dopamine D2 Receptor Forms Transient Dimers Stabilized by Agonists: Detection by Single-Molecule Tracking","volume":"76","author":"Kasai","year":"2018","journal-title":"Cell Biochem. Biophys."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1007\/s00894-016-3065-2","article-title":"The dopamine D2 receptor dimer and its interaction with homobivalent antagonists: Homology modeling, docking and molecular dynamics","volume":"22","author":"Kaczor","year":"2016","journal-title":"J. Mol. Model."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/bs.mcb.2015.11.002","article-title":"Computational methods for studying G protein-coupled receptors (GPCRs)","volume":"132","author":"Kaczor","year":"2016","journal-title":"Methods Cell Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"33233","DOI":"10.1038\/srep33233","article-title":"Visualization and ligand-induced modulation of dopamine receptor dimerization at the single molecule level","volume":"6","author":"Tabor","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"9335","DOI":"10.1021\/acs.jmedchem.8b01249","article-title":"Design of a True Bivalent Ligand with Picomolar Binding Affinity for a G Protein-Coupled Receptor Homodimer","volume":"61","author":"Pulido","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"11023","DOI":"10.1021\/bi0345539","article-title":"D2 dopamine receptor homodimerization is mediated by multiple sites of interaction, including an intermolecular interaction involving transmembrane domain 4","volume":"42","author":"Lee","year":"2003","journal-title":"Biochemistry"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4385","DOI":"10.1074\/jbc.C200679200","article-title":"The fourth transmembrane segment forms the interface of the dopamine D2 receptor homodimer","volume":"278","author":"Guo","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"E3609","DOI":"10.1073\/pnas.1507704112","article-title":"Allosteric interactions between agonists and antagonists within the adenosine A2A receptor-dopamine D2 receptor heterotetramer","volume":"112","author":"Bonaventura","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"243","DOI":"10.3389\/fphar.2018.00243","article-title":"Essential Control of the Function of the Striatopallidal Neuron by Pre-coupled Complexes of Adenosine A2A-Dopamine D2 Receptor Heterotetramers and Adenylyl Cyclase","volume":"9","author":"Ferre","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.bcp.2015.05.006","article-title":"Dopamine D2 and angiotensin II type 1 receptors form functional heteromers in rat striatum","volume":"96","author":"Navarro","year":"2015","journal-title":"Biochem. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1242","DOI":"10.1038\/s41467-018-03522-3","article-title":"Evidence for functional pre-coupled complexes of receptor heteromers and adenylyl cyclase","volume":"9","author":"Navarro","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1857","DOI":"10.1038\/s41598-017-02037-z","article-title":"Angiotensin II type 1\/adenosine A 2A receptor oligomers: A novel target for tardive dyskinesia","volume":"7","author":"Oliveira","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"8212","DOI":"10.1021\/acs.jmedchem.8b00671","article-title":"Synthesis toward Bivalent Ligands for the Dopamine D2 and Metabotropic Glutamate 5 Receptors","volume":"61","author":"Qian","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1124\/mol.114.093096","article-title":"Functional selectivity of allosteric interactions within G protein-coupled receptor oligomers: The dopamine D1-D3 receptor heterotetramer","volume":"86","author":"Guitart","year":"2014","journal-title":"Mol. Pharmacol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.ceb.2013.11.008","article-title":"Single-molecule imaging revealed dynamic GPCR dimerization","volume":"27","author":"Kasai","year":"2014","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2293","DOI":"10.1038\/emboj.2008.153","article-title":"Dopamine D2 receptors form higher order oligomers at physiological expression levels","volume":"27","author":"Guo","year":"2008","journal-title":"EMBO J."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1385\/JMN:26:2-3:155","article-title":"Oligomers of D2 dopamine receptors: Evidence from ligand binding","volume":"26","author":"Strange","year":"2005","journal-title":"J. Mol. Neurosci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2693","DOI":"10.1073\/pnas.0907915107","article-title":"Formation and dissociation of M1 muscarinic receptor dimers seen by total internal reflection fluorescence imaging of single molecules","volume":"107","author":"Hern","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1083\/jcb.201009128","article-title":"Full characterization of GPCR monomer-dimer dynamic equilibrium by single molecule imaging","volume":"192","author":"Kasai","year":"2011","journal-title":"J. Cell Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1073\/pnas.1205798110","article-title":"Single-molecule analysis of fluorescently labeled G-protein-coupled receptors reveals complexes with distinct dynamics and organization","volume":"110","author":"Calebiro","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/1756-6606-3-25","article-title":"Schizophrenia, amphetamine-induced sensitized state and acute amphetamine exposure all show a common alteration: Increased dopamine D2 receptor dimerization","volume":"3","author":"Wang","year":"2010","journal-title":"Mol. Brain"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"4079","DOI":"10.1074\/jbc.RA118.006231","article-title":"A dynamic and screening-compatible nanoluciferase-based complementation assay enables profiling of individual GPCR-G protein interactions","volume":"294","author":"Laschet","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Atwood, B.K., Lopez, J., Wager-Miller, J., Mackie, K., and Straiker, A. (2011). Expression of G protein-coupled receptors and related proteins in HEK293, AtT20, BV2, and N18 cell lines as revealed by microarray analysis. BMC Genomics, 12.","DOI":"10.1186\/1471-2164-12-14"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1124\/jpet.109.162701","article-title":"Ligand-induced regulation and localization of cannabinoid CB1 and dopamine D2L receptor heterodimers","volume":"332","author":"Przybyla","year":"2010","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"11476","DOI":"10.1021\/acs.analchem.6b02600","article-title":"Detection and Activity Profiling of Synthetic Cannabinoids and Their Metabolites with a Newly Developed Bioassay","volume":"88","author":"Cannaert","year":"2016","journal-title":"Anal. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1016\/S0006-291X(02)02259-3","article-title":"Glycosylation of beta(1)-adrenergic receptors regulates receptor surface expression and dimerization","volume":"297","author":"He","year":"2002","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.neuropharm.2015.05.028","article-title":"Allosteric mechanisms within the adenosine A2A-dopamine D2 receptor heterotetramer","volume":"104","author":"Ferre","year":"2016","journal-title":"Neuropharmacology"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1038\/nature25758","article-title":"Structure of the D2 dopamine receptor bound to the atypical antipsychotic drug risperidone","volume":"555","author":"Wang","year":"2018","journal-title":"Nature"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/S1043-9471(05)80049-7","article-title":"Integrated methods for the construction of three-dimensional models and computational probing of structure-function relations in G protein-coupled receptors","volume":"25","author":"Ballesteros","year":"1995","journal-title":"Methods Neurosci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1920","DOI":"10.1002\/pro.2814","article-title":"Implications of aromatic-aromatic interactions: From protein structures to peptide models","volume":"24","author":"Mahalakshmi","year":"2015","journal-title":"Protein Sci. A Publ. Protein Soc."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Lyskov, S., Chou, F.C., Conchuir, S.O., Der, B.S., Drew, K., Kuroda, D., Xu, J., Weitzner, B.D., Renfrew, P.D., and Sripakdeevong, P. (2013). Serverification of molecular modeling applications: The Rosetta Online Server that Includes Everyone (ROSIE). PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0063906"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Herrick-Davis, K., Milligan, G., and Di Giovanni, G. (2017). Historical Perspectives: From Monomers to Dimers and Beyond, an Exciting Journey in the World of G Protein-Coupled Receptors. G-Protein-Coupled Receptor Dimers, Springer International Publishing.","DOI":"10.1007\/978-3-319-60174-8"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"19533","DOI":"10.1074\/jbc.M109.017145","article-title":"Pirenzepine promotes the dimerization of muscarinic M1 receptors through a three-step binding process","volume":"284","author":"Ilien","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1124\/mol.104.000497","article-title":"G protein-coupled receptor dimerization: Function and ligand pharmacology","volume":"66","author":"Milligan","year":"2004","journal-title":"Mol. Pharmacol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1517\/17460441003720467","article-title":"Heterodimerisation of G protein-coupled receptors: Implications for drug design and ligand screening","volume":"5","author":"Milligan","year":"2010","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1021\/acschembio.5b00753","article-title":"NanoLuc Complementation Reporter Optimized for Accurate Measurement of Protein Interactions in Cells","volume":"11","author":"Dixon","year":"2016","journal-title":"ACS Chem. Biol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2039","DOI":"10.1016\/j.bcp.2004.02.017","article-title":"Inverse agonist properties of atypical antipsychotic drugs","volume":"67","author":"Akam","year":"2004","journal-title":"Biochem. Pharmacol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"18522","DOI":"10.1021\/jacs.7b07659","article-title":"Optical Control of Dopamine Receptors Using a Photoswitchable Tethered Inverse Agonist","volume":"139","author":"Donthamsetti","year":"2017","journal-title":"J. Am. Chem. Soc."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Newton, C.L., Wood, M.D., and Strange, P.G. (2016). Examining the Effects of Sodium Ions on the Binding of Antagonists to Dopamine D2 and D3 Receptors. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0158808"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1038\/sj.bjp.0706073","article-title":"Mechanisms of inverse agonist action at D2 dopamine receptors","volume":"145","author":"Roberts","year":"2005","journal-title":"Br. J. Pharm."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2134","DOI":"10.1038\/s41598-017-02249-3","article-title":"A Molecular Basis for Selective Antagonist Destabilization of Dopamine D3 Receptor Quaternary Organization","volume":"7","author":"Marsango","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1100\/tsw.2008.136","article-title":"Detection of heteromers formed by cannabinoid CB1, dopamine D2, and adenosine A2A G-protein-coupled receptors by combining bimolecular fluorescence complementation and bioluminescence energy transfer","volume":"8","author":"Navarro","year":"2008","journal-title":"Sci. World J."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2979","DOI":"10.1016\/j.febslet.2008.07.045","article-title":"Detection of higher-order G protein-coupled receptor oligomers by a combined BRET-BiFC technique","volume":"582","author":"Gandia","year":"2008","journal-title":"FEBS Lett."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1016\/j.jmb.2011.01.022","article-title":"On the existence of a possible A2A-D2-beta-Arrestin2 complex: A2A agonist modulation of D2 agonist-induced beta-arrestin2 recruitment","volume":"406","author":"Tarakanov","year":"2011","journal-title":"J. Mol. Biol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"4952","DOI":"10.1007\/s12035-017-0696-y","article-title":"Antipsychotic-Like Efficacy of Dopamine D2 Receptor-Biased Ligands is Dependent on Adenosine A2A Receptor Expression","volume":"55","author":"Sahlholm","year":"2018","journal-title":"Mol. Neurobiol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/j.bbrc.2010.02.168","article-title":"A serine point mutation in the adenosine A2AR C-terminal tail reduces receptor heteromerization and allosteric modulation of the dopamine D2R","volume":"394","author":"Marcellino","year":"2010","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.jns.2006.05.019","article-title":"Experimental studies and theoretical aspects on A2A\/D2 receptor interactions in a model of Parkinson\u2019s disease. Relevance for L-dopa induced dyskinesias","volume":"248","author":"Antonelli","year":"2006","journal-title":"J. Neurol. Sci."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"S19","DOI":"10.1212\/01.WNL.0000095206.44418.5C","article-title":"Receptor heteromerization in adenosine A2A receptor signaling: Relevance for striatal function and Parkinson\u2019s disease","volume":"61","author":"Fuxe","year":"2003","journal-title":"Neurology"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1990","DOI":"10.1002\/mds.21440","article-title":"Adenosine A(2A) receptors, dopamine D(2) receptors and their interactions in Parkinson\u2019s disease","volume":"22","author":"Fuxe","year":"2007","journal-title":"Mov. Disord."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"5590","DOI":"10.1021\/jm900298c","article-title":"Adenosine A2A receptor-antagonist\/dopamine D2 receptor-agonist bivalent ligands as pharmacological tools to detect A2A-D2 receptor heteromers","volume":"52","author":"Soriano","year":"2009","journal-title":"J. Med. Chem."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1124\/mol.58.1.120","article-title":"Inhibition of cell surface expression by mutant receptors demonstrates that D2 dopamine receptors exist as oligomers in the cell","volume":"58","author":"Lee","year":"2000","journal-title":"Mol. Pharmacol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1124\/mol.105.021246","article-title":"Agonist-induced cell surface trafficking of an intracellularly sequestered D1 dopamine receptor homo-oligomer","volume":"70","author":"Kong","year":"2006","journal-title":"Mol. Pharmacol."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Platania, C.B., Salomone, S., Leggio, G.M., Drago, F., and Bucolo, C. (2012). Homology modeling of dopamine D2 and D3 receptors: Molecular dynamics refinement and docking evaluation. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0044316"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/B978-0-12-408143-7.00017-7","article-title":"Detection of G protein-coupled receptor (GPCR) dimerization by coimmunoprecipitation","volume":"117","author":"Skieterska","year":"2013","journal-title":"Methods Cell Biol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/jcc.20084","article-title":"UCSF Chimera\u2014A visualization system for exploratory research and analysis","volume":"25","author":"Pettersen","year":"2004","journal-title":"J. Comput. Chem."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"D1202","DOI":"10.1093\/nar\/gkv951","article-title":"PubChem Substance and Compound databases","volume":"44","author":"Kim","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"2785","DOI":"10.1002\/jcc.21256","article-title":"AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility","volume":"30","author":"Morris","year":"2009","journal-title":"J. Comput. Chem."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1038\/nature10954","article-title":"Crystal structure of the micro-opioid receptor bound to a morphinan antagonist","volume":"485","author":"Manglik","year":"2012","journal-title":"Nature"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1668","DOI":"10.1002\/jcc.20290","article-title":"The Amber biomolecular simulation programs","volume":"26","author":"Case","year":"2005","journal-title":"J. Comput. Chem."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1002\/jcc.20945","article-title":"CHARMM-GUI: A web-based graphical user interface for CHARMM","volume":"29","author":"Jo","year":"2008","journal-title":"J. Comput. Chem."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1093\/bioinformatics\/btk023","article-title":"OPM: Orientations of proteins in membranes database","volume":"22","author":"Lomize","year":"2006","journal-title":"Bioinformatics"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"2135","DOI":"10.1002\/jcc.23354","article-title":"CHARMM36 all-atom additive protein force field: Validation based on comparison to NMR data","volume":"34","author":"Huang","year":"2013","journal-title":"J. Comput. Chem."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1002\/jcc.21367","article-title":"CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields","volume":"31","author":"Vanommeslaeghe","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1632","DOI":"10.1021\/ct9000685","article-title":"ACEMD: Accelerating Biomolecular Dynamics in the Microsecond Time Scale","volume":"5","author":"Harvey","year":"2009","journal-title":"J. Chem. Theory Comput."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/0263-7855(96)00018-5","article-title":"VMD: Visual molecular dynamics","volume":"14","author":"Humphrey","year":"1996","journal-title":"J. Mol. Graph."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"W382","DOI":"10.1093\/nar\/gki387","article-title":"The FoldX web server: An online force field","volume":"33","author":"Schymkowitz","year":"2005","journal-title":"Nucleic Acids Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/7\/1686\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:42:56Z","timestamp":1760186576000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/7\/1686"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,4,4]]},"references-count":93,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2019,4]]}},"alternative-id":["ijms20071686"],"URL":"https:\/\/doi.org\/10.3390\/ijms20071686","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,4,4]]}}}