Visualization and ligand-induced modulation of dopamine receptor dimerization at the single molecule level
G protein–coupled receptors (GPCRs), including dopamine receptors, represent a group of important pharmacological targets. An increased formation of dopamine receptor D 2 homodimers has been suggested to be associated with the pathophysiology of schizophrenia. Selective labeling and ligand-induced m...
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creator | Tabor, Alina Weisenburger, Siegfried Banerjee, Ashutosh Purkayastha, Nirupam Kaindl, Jonas M. Hübner, Harald Wei, Luxi Grömer, Teja W. Kornhuber, Johannes Tschammer, Nuska Birdsall, Nigel J. M. Mashanov, Gregory I. Sandoghdar, Vahid Gmeiner, Peter |
description | G protein–coupled receptors (GPCRs), including dopamine receptors, represent a group of important pharmacological targets. An increased formation of dopamine receptor D
2
homodimers has been suggested to be associated with the pathophysiology of schizophrenia. Selective labeling and ligand-induced modulation of dimerization may therefore allow the investigation of the pathophysiological role of these dimers. Using TIRF microscopy at the single molecule level, transient formation of homodimers of dopamine receptors in the membrane of stably transfected CHO cells has been observed. The equilibrium between dimers and monomers was modulated by the binding of ligands; whereas antagonists showed a ratio that was identical to that of unliganded receptors, agonist-bound D
2
receptor-ligand complexes resulted in an increase in dimerization. Addition of bivalent D
2
receptor ligands also resulted in a large increase in D
2
receptor dimers. A physical interaction between the protomers was confirmed using high resolution cryogenic localization microscopy, with ca. 9 nm between the centers of mass. |
doi_str_mv | 10.1038/srep33233 |
format | Article |
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2
homodimers has been suggested to be associated with the pathophysiology of schizophrenia. Selective labeling and ligand-induced modulation of dimerization may therefore allow the investigation of the pathophysiological role of these dimers. Using TIRF microscopy at the single molecule level, transient formation of homodimers of dopamine receptors in the membrane of stably transfected CHO cells has been observed. The equilibrium between dimers and monomers was modulated by the binding of ligands; whereas antagonists showed a ratio that was identical to that of unliganded receptors, agonist-bound D
2
receptor-ligand complexes resulted in an increase in dimerization. Addition of bivalent D
2
receptor ligands also resulted in a large increase in D
2
receptor dimers. A physical interaction between the protomers was confirmed using high resolution cryogenic localization microscopy, with ca. 9 nm between the centers of mass.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/srep33233</identifier><identifier>PMID: 27615810</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/154 ; 631/57 ; Animals ; Antagonists ; CHO Cells ; Cricetulus ; Dimerization ; Dopamine ; Dopamine Antagonists - metabolism ; Dopamine D2 receptors ; G protein-coupled receptors ; Humanities and Social Sciences ; Humans ; Kinetics ; Ligands ; Localization ; Mental disorders ; Microscopy ; Microscopy, Fluorescence ; Monomers ; multidisciplinary ; Protein Binding ; Protein Multimerization ; Protein Transport ; Receptors, Dopamine D2 - metabolism ; Schizophrenia ; Science ; Single-Cell Analysis ; Spiperone - metabolism</subject><ispartof>Scientific reports, 2016-09, Vol.6 (1), p.33233-33233, Article 33233</ispartof><rights>The Author(s) 2016</rights><rights>Copyright Nature Publishing Group Sep 2016</rights><rights>Copyright © 2016, The Author(s) 2016 The Author(s)</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c504t-f5d734e4650c360fe6b7c0c09be1015b1cd63e2f74b5a07617c74e46cfcacb33</citedby><cites>FETCH-LOGICAL-c504t-f5d734e4650c360fe6b7c0c09be1015b1cd63e2f74b5a07617c74e46cfcacb33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5018964/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5018964/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,27924,27925,41120,42189,51576,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27615810$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tabor, Alina</creatorcontrib><creatorcontrib>Weisenburger, Siegfried</creatorcontrib><creatorcontrib>Banerjee, Ashutosh</creatorcontrib><creatorcontrib>Purkayastha, Nirupam</creatorcontrib><creatorcontrib>Kaindl, Jonas M.</creatorcontrib><creatorcontrib>Hübner, Harald</creatorcontrib><creatorcontrib>Wei, Luxi</creatorcontrib><creatorcontrib>Grömer, Teja W.</creatorcontrib><creatorcontrib>Kornhuber, Johannes</creatorcontrib><creatorcontrib>Tschammer, Nuska</creatorcontrib><creatorcontrib>Birdsall, Nigel J. M.</creatorcontrib><creatorcontrib>Mashanov, Gregory I.</creatorcontrib><creatorcontrib>Sandoghdar, Vahid</creatorcontrib><creatorcontrib>Gmeiner, Peter</creatorcontrib><title>Visualization and ligand-induced modulation of dopamine receptor dimerization at the single molecule level</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>G protein–coupled receptors (GPCRs), including dopamine receptors, represent a group of important pharmacological targets. An increased formation of dopamine receptor D
2
homodimers has been suggested to be associated with the pathophysiology of schizophrenia. Selective labeling and ligand-induced modulation of dimerization may therefore allow the investigation of the pathophysiological role of these dimers. Using TIRF microscopy at the single molecule level, transient formation of homodimers of dopamine receptors in the membrane of stably transfected CHO cells has been observed. The equilibrium between dimers and monomers was modulated by the binding of ligands; whereas antagonists showed a ratio that was identical to that of unliganded receptors, agonist-bound D
2
receptor-ligand complexes resulted in an increase in dimerization. Addition of bivalent D
2
receptor ligands also resulted in a large increase in D
2
receptor dimers. A physical interaction between the protomers was confirmed using high resolution cryogenic localization microscopy, with ca. 9 nm between the centers of mass.</description><subject>631/154</subject><subject>631/57</subject><subject>Animals</subject><subject>Antagonists</subject><subject>CHO Cells</subject><subject>Cricetulus</subject><subject>Dimerization</subject><subject>Dopamine</subject><subject>Dopamine Antagonists - metabolism</subject><subject>Dopamine D2 receptors</subject><subject>G protein-coupled receptors</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Kinetics</subject><subject>Ligands</subject><subject>Localization</subject><subject>Mental disorders</subject><subject>Microscopy</subject><subject>Microscopy, Fluorescence</subject><subject>Monomers</subject><subject>multidisciplinary</subject><subject>Protein Binding</subject><subject>Protein Multimerization</subject><subject>Protein Transport</subject><subject>Receptors, Dopamine D2 - metabolism</subject><subject>Schizophrenia</subject><subject>Science</subject><subject>Single-Cell Analysis</subject><subject>Spiperone - metabolism</subject><issn>2045-2322</issn><issn>2045-2322</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNplkV1LHTEQhoO0qKgX_QNloTe1sDpJNvtxUyhiVRB6I96GbDJ7zCGbbJNdof56czj2cGznZgbmmXdmeAn5ROGCAm8vU8SJc8b5ATlmUImSccY-7NVH5CylNeQQrKtod0iOWFNT0VI4JutHmxbl7IuabfCF8qZwdpVTab1ZNJpiDGZx224YChMmNVqPRUSN0xxiYeyIcTc_F_MTFsn6lcM86lAvuXD4jO6UfByUS3j2lk_Iw8_rh6vb8v7Xzd3Vj_tSC6jmchCm4RVWtQDNaxiw7hsNGroeKVDRU21qjmxoql4oyI80utngetBK95yfkO9b2WnpRzQa_RyVk1O0o4p_ZFBWvu94-yRX4VkKoG1XV1ng65tADL8XTLMcbdLonPIYliRpSzvKKLSbXV_-QddhiT5_l6mug0Z0DDJ1vqV0DCnbNeyOoSA3Hsqdh5n9vH_9jvzrWAa-bYGUW36FcW_lf2qvgKmoOw</recordid><startdate>20160912</startdate><enddate>20160912</enddate><creator>Tabor, Alina</creator><creator>Weisenburger, Siegfried</creator><creator>Banerjee, Ashutosh</creator><creator>Purkayastha, Nirupam</creator><creator>Kaindl, Jonas M.</creator><creator>Hübner, Harald</creator><creator>Wei, Luxi</creator><creator>Grömer, Teja W.</creator><creator>Kornhuber, Johannes</creator><creator>Tschammer, Nuska</creator><creator>Birdsall, Nigel J. M.</creator><creator>Mashanov, Gregory I.</creator><creator>Sandoghdar, Vahid</creator><creator>Gmeiner, Peter</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88I</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20160912</creationdate><title>Visualization and ligand-induced modulation of dopamine receptor dimerization at the single molecule level</title><author>Tabor, Alina ; Weisenburger, Siegfried ; Banerjee, Ashutosh ; Purkayastha, Nirupam ; Kaindl, Jonas M. ; Hübner, Harald ; Wei, Luxi ; Grömer, Teja W. ; Kornhuber, Johannes ; Tschammer, Nuska ; Birdsall, Nigel J. M. ; Mashanov, Gregory I. ; Sandoghdar, Vahid ; Gmeiner, Peter</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c504t-f5d734e4650c360fe6b7c0c09be1015b1cd63e2f74b5a07617c74e46cfcacb33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>631/154</topic><topic>631/57</topic><topic>Animals</topic><topic>Antagonists</topic><topic>CHO Cells</topic><topic>Cricetulus</topic><topic>Dimerization</topic><topic>Dopamine</topic><topic>Dopamine Antagonists - metabolism</topic><topic>Dopamine D2 receptors</topic><topic>G protein-coupled receptors</topic><topic>Humanities and Social Sciences</topic><topic>Humans</topic><topic>Kinetics</topic><topic>Ligands</topic><topic>Localization</topic><topic>Mental disorders</topic><topic>Microscopy</topic><topic>Microscopy, Fluorescence</topic><topic>Monomers</topic><topic>multidisciplinary</topic><topic>Protein Binding</topic><topic>Protein Multimerization</topic><topic>Protein Transport</topic><topic>Receptors, Dopamine D2 - metabolism</topic><topic>Schizophrenia</topic><topic>Science</topic><topic>Single-Cell Analysis</topic><topic>Spiperone - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tabor, Alina</creatorcontrib><creatorcontrib>Weisenburger, Siegfried</creatorcontrib><creatorcontrib>Banerjee, Ashutosh</creatorcontrib><creatorcontrib>Purkayastha, Nirupam</creatorcontrib><creatorcontrib>Kaindl, Jonas M.</creatorcontrib><creatorcontrib>Hübner, Harald</creatorcontrib><creatorcontrib>Wei, Luxi</creatorcontrib><creatorcontrib>Grömer, Teja W.</creatorcontrib><creatorcontrib>Kornhuber, Johannes</creatorcontrib><creatorcontrib>Tschammer, Nuska</creatorcontrib><creatorcontrib>Birdsall, Nigel J. M.</creatorcontrib><creatorcontrib>Mashanov, Gregory I.</creatorcontrib><creatorcontrib>Sandoghdar, Vahid</creatorcontrib><creatorcontrib>Gmeiner, Peter</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>Access via ProQuest (Open Access)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Scientific reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tabor, Alina</au><au>Weisenburger, Siegfried</au><au>Banerjee, Ashutosh</au><au>Purkayastha, Nirupam</au><au>Kaindl, Jonas M.</au><au>Hübner, Harald</au><au>Wei, Luxi</au><au>Grömer, Teja W.</au><au>Kornhuber, Johannes</au><au>Tschammer, Nuska</au><au>Birdsall, Nigel J. M.</au><au>Mashanov, Gregory I.</au><au>Sandoghdar, Vahid</au><au>Gmeiner, Peter</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Visualization and ligand-induced modulation of dopamine receptor dimerization at the single molecule level</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2016-09-12</date><risdate>2016</risdate><volume>6</volume><issue>1</issue><spage>33233</spage><epage>33233</epage><pages>33233-33233</pages><artnum>33233</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><abstract>G protein–coupled receptors (GPCRs), including dopamine receptors, represent a group of important pharmacological targets. An increased formation of dopamine receptor D
2
homodimers has been suggested to be associated with the pathophysiology of schizophrenia. Selective labeling and ligand-induced modulation of dimerization may therefore allow the investigation of the pathophysiological role of these dimers. Using TIRF microscopy at the single molecule level, transient formation of homodimers of dopamine receptors in the membrane of stably transfected CHO cells has been observed. The equilibrium between dimers and monomers was modulated by the binding of ligands; whereas antagonists showed a ratio that was identical to that of unliganded receptors, agonist-bound D
2
receptor-ligand complexes resulted in an increase in dimerization. Addition of bivalent D
2
receptor ligands also resulted in a large increase in D
2
receptor dimers. A physical interaction between the protomers was confirmed using high resolution cryogenic localization microscopy, with ca. 9 nm between the centers of mass.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>27615810</pmid><doi>10.1038/srep33233</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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subjects | 631/154 631/57 Animals Antagonists CHO Cells Cricetulus Dimerization Dopamine Dopamine Antagonists - metabolism Dopamine D2 receptors G protein-coupled receptors Humanities and Social Sciences Humans Kinetics Ligands Localization Mental disorders Microscopy Microscopy, Fluorescence Monomers multidisciplinary Protein Binding Protein Multimerization Protein Transport Receptors, Dopamine D2 - metabolism Schizophrenia Science Single-Cell Analysis Spiperone - metabolism |
title | Visualization and ligand-induced modulation of dopamine receptor dimerization at the single molecule level |
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