Plasticity of seven-transmembrane-helix receptor heteromers in human vascular smooth muscle cells

Recently, we reported that the chemokine (C-X-C motif) receptor 4 (CXCR4) and atypical chemokine receptor 3 (ACKR3) heteromerize with [alpha].sub.1A/B/D -adrenoceptors (ARs) and arginine vasopressin receptor 1A (AVPR1A) in recombinant systems and in rodent and human vascular smooth muscle cells (hVS...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:PloS one 2021-06, Vol.16 (6), p.e0253821-e0253821
Hauptverfasser: Albee, Lauren J, Gao, Xianlong, Majetschak, Matthias
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page e0253821
container_issue 6
container_start_page e0253821
container_title PloS one
container_volume 16
creator Albee, Lauren J
Gao, Xianlong
Majetschak, Matthias
description Recently, we reported that the chemokine (C-X-C motif) receptor 4 (CXCR4) and atypical chemokine receptor 3 (ACKR3) heteromerize with [alpha].sub.1A/B/D -adrenoceptors (ARs) and arginine vasopressin receptor 1A (AVPR1A) in recombinant systems and in rodent and human vascular smooth muscle cells (hVSMCs). In these studies, we observed that heteromerization between two receptor partners may depend on the presence and the expression levels of other partnering receptors. To test this hypothesis and to gain initial insight into the formation of these receptor heteromers in native cells, we utilized proximity ligation assays in hVSMCs to visualize receptor-receptor proximity and systematically studied how manipulation of the expression levels of individual protomers affect heteromerization patterns among other interacting receptor partners. We confirmed subtype-specific heteromerization between endogenously expressed [alpha].sub.1A/B/D -ARs and detected that AVPR1A also heteromerizes with [alpha].sub.1A/B/D -ARs. siRNA knockdown of CXCR4 and of ACKR3 resulted in a significant re-arrangement of the heteromerization patterns among [alpha].sub.1 -AR subtypes. Similarly, siRNA knockdown of AVPR1A significantly increased heteromerization signals for seven of the ten receptor pairs between CXCR4, ACKR3, and [alpha].sub.1A/B/D -ARs. Our findings suggest plasticity of seven transmembrane helix (7TM) receptor heteromerization in native cells and could be explained by a supramolecular organization of these receptors within dynamic clusters in the plasma membrane. Because we previously observed that recombinant CXCR4, ACKR3, [alpha].sub.1a -AR and AVPR1A form hetero-oligomeric complexes composed of 2-4 different protomers, which show signaling properties distinct from individual protomers, re-arrangements of receptor heteromerization patterns in native cells may contribute to the phenomenon of context-dependent GPCR signaling. Furthermore, these findings advise caution in the interpretation of functional consequences after 7TM receptor knockdown in experimental models. Alterations of the heteromerization patterns among other receptor partners may alter physiological and pathological responses, in particular in more complex systems, such as studies on the function of isolated organs or in in vivo experiments.
doi_str_mv 10.1371/journal.pone.0253821
format Article
fullrecord <record><control><sourceid>gale_plos_</sourceid><recordid>TN_cdi_plos_journals_2544865167</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A666328466</galeid><doaj_id>oai_doaj_org_article_a737bd5cbffa44ffa105dd066ea4bfa9</doaj_id><sourcerecordid>A666328466</sourcerecordid><originalsourceid>FETCH-LOGICAL-c669t-206968dd15fa3a5e655e881951dbc3e3237a68dc617a85a599676c21989c4a323</originalsourceid><addsrcrecordid>eNqNk12L1DAUhoso7jr6DwQLguhFx6b5aHsjLIsfAwsrft2GM-npNEPazCbpsPvvzcxU2cpeSCAJOU_ec_KSkyQvSb4ktCTvt3Z0A5jlzg64zAtOq4I8Ss5JTYtMFDl9fG9_ljzzfpvnERLiaXJGGRGCleI8ga8GfNBKh7vUtqnHPQ5ZcDD4Hvt1XDHr0Ojb1KHCXbAu7TCgsz06n-oh7cYehnQPXo0GXOp7a0OX9qNXBlOFxvjnyZMWjMcX07pIfn76-OPyS3Z1_Xl1eXGVKSHqkBW5qEXVNIS3QIGj4ByritScNGtFkRa0hBhXgpRQceB1LUqhClJXtWIQw4vk1Ul3Z6yXkzteFpyxSnAiykisTkRjYSt3Tvfg7qQFLY8H1m0kuOiFQQklLdcNV-u2BcbiRHLeNLkQCGzdQh21PkzZxnWPjcIhmmZmovPIoDu5sXtZFQWrKY0CbycBZ29G9EH22h8Mi5bb8Vg3Fzmjx7pf_4M-_LqJ2kB8gB5aG_Oqg6i8EELQomJxXiTLB6g4Guy1il-p1fF8duHd7EJkAt6GDYzey9X3b__PXv-as2_usR2CCZ23ZgzaDn4OshOonPXeYfvXZJLLQyf8cUMeOkFOnUB_A6yr-w0</addsrcrecordid><sourcetype>Open Website</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2544865167</pqid></control><display><type>article</type><title>Plasticity of seven-transmembrane-helix receptor heteromers in human vascular smooth muscle cells</title><source>Public Library of Science (PLoS) Journals Open Access</source><source>PubMed Central Free</source><source>DOAJ Directory of Open Access Journals</source><source>EZB-FREE-00999 freely available EZB journals</source><source>Free Full-Text Journals in Chemistry</source><creator>Albee, Lauren J ; Gao, Xianlong ; Majetschak, Matthias</creator><contributor>Raju, Raghavan</contributor><creatorcontrib>Albee, Lauren J ; Gao, Xianlong ; Majetschak, Matthias ; Raju, Raghavan</creatorcontrib><description>Recently, we reported that the chemokine (C-X-C motif) receptor 4 (CXCR4) and atypical chemokine receptor 3 (ACKR3) heteromerize with [alpha].sub.1A/B/D -adrenoceptors (ARs) and arginine vasopressin receptor 1A (AVPR1A) in recombinant systems and in rodent and human vascular smooth muscle cells (hVSMCs). In these studies, we observed that heteromerization between two receptor partners may depend on the presence and the expression levels of other partnering receptors. To test this hypothesis and to gain initial insight into the formation of these receptor heteromers in native cells, we utilized proximity ligation assays in hVSMCs to visualize receptor-receptor proximity and systematically studied how manipulation of the expression levels of individual protomers affect heteromerization patterns among other interacting receptor partners. We confirmed subtype-specific heteromerization between endogenously expressed [alpha].sub.1A/B/D -ARs and detected that AVPR1A also heteromerizes with [alpha].sub.1A/B/D -ARs. siRNA knockdown of CXCR4 and of ACKR3 resulted in a significant re-arrangement of the heteromerization patterns among [alpha].sub.1 -AR subtypes. Similarly, siRNA knockdown of AVPR1A significantly increased heteromerization signals for seven of the ten receptor pairs between CXCR4, ACKR3, and [alpha].sub.1A/B/D -ARs. Our findings suggest plasticity of seven transmembrane helix (7TM) receptor heteromerization in native cells and could be explained by a supramolecular organization of these receptors within dynamic clusters in the plasma membrane. Because we previously observed that recombinant CXCR4, ACKR3, [alpha].sub.1a -AR and AVPR1A form hetero-oligomeric complexes composed of 2-4 different protomers, which show signaling properties distinct from individual protomers, re-arrangements of receptor heteromerization patterns in native cells may contribute to the phenomenon of context-dependent GPCR signaling. Furthermore, these findings advise caution in the interpretation of functional consequences after 7TM receptor knockdown in experimental models. Alterations of the heteromerization patterns among other receptor partners may alter physiological and pathological responses, in particular in more complex systems, such as studies on the function of isolated organs or in in vivo experiments.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0253821</identifier><identifier>PMID: 34166476</identifier><language>eng</language><publisher>San Francisco: Public Library of Science</publisher><subject>Antibodies ; Argipressin ; Argipressin receptors ; Biology and life sciences ; Chemokine receptors ; Chemokines ; Complex systems ; CXCR4 protein ; Experiments ; G protein-coupled receptors ; Genetic aspects ; In vivo methods and tests ; Medical research ; Medicine ; Medicine and Health Sciences ; Muscles ; Organs ; Physiology ; Plastic properties ; Plasticity ; Proteins ; Receptors ; Receptors (physiology) ; Signaling ; siRNA ; Smooth muscle ; Surgery ; Vasopressin</subject><ispartof>PloS one, 2021-06, Vol.16 (6), p.e0253821-e0253821</ispartof><rights>COPYRIGHT 2021 Public Library of Science</rights><rights>2021 Albee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2021 Albee et al 2021 Albee et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c669t-206968dd15fa3a5e655e881951dbc3e3237a68dc617a85a599676c21989c4a323</citedby><cites>FETCH-LOGICAL-c669t-206968dd15fa3a5e655e881951dbc3e3237a68dc617a85a599676c21989c4a323</cites><orcidid>0000-0002-4086-0887</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8224933/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8224933/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids></links><search><contributor>Raju, Raghavan</contributor><creatorcontrib>Albee, Lauren J</creatorcontrib><creatorcontrib>Gao, Xianlong</creatorcontrib><creatorcontrib>Majetschak, Matthias</creatorcontrib><title>Plasticity of seven-transmembrane-helix receptor heteromers in human vascular smooth muscle cells</title><title>PloS one</title><description>Recently, we reported that the chemokine (C-X-C motif) receptor 4 (CXCR4) and atypical chemokine receptor 3 (ACKR3) heteromerize with [alpha].sub.1A/B/D -adrenoceptors (ARs) and arginine vasopressin receptor 1A (AVPR1A) in recombinant systems and in rodent and human vascular smooth muscle cells (hVSMCs). In these studies, we observed that heteromerization between two receptor partners may depend on the presence and the expression levels of other partnering receptors. To test this hypothesis and to gain initial insight into the formation of these receptor heteromers in native cells, we utilized proximity ligation assays in hVSMCs to visualize receptor-receptor proximity and systematically studied how manipulation of the expression levels of individual protomers affect heteromerization patterns among other interacting receptor partners. We confirmed subtype-specific heteromerization between endogenously expressed [alpha].sub.1A/B/D -ARs and detected that AVPR1A also heteromerizes with [alpha].sub.1A/B/D -ARs. siRNA knockdown of CXCR4 and of ACKR3 resulted in a significant re-arrangement of the heteromerization patterns among [alpha].sub.1 -AR subtypes. Similarly, siRNA knockdown of AVPR1A significantly increased heteromerization signals for seven of the ten receptor pairs between CXCR4, ACKR3, and [alpha].sub.1A/B/D -ARs. Our findings suggest plasticity of seven transmembrane helix (7TM) receptor heteromerization in native cells and could be explained by a supramolecular organization of these receptors within dynamic clusters in the plasma membrane. Because we previously observed that recombinant CXCR4, ACKR3, [alpha].sub.1a -AR and AVPR1A form hetero-oligomeric complexes composed of 2-4 different protomers, which show signaling properties distinct from individual protomers, re-arrangements of receptor heteromerization patterns in native cells may contribute to the phenomenon of context-dependent GPCR signaling. Furthermore, these findings advise caution in the interpretation of functional consequences after 7TM receptor knockdown in experimental models. Alterations of the heteromerization patterns among other receptor partners may alter physiological and pathological responses, in particular in more complex systems, such as studies on the function of isolated organs or in in vivo experiments.</description><subject>Antibodies</subject><subject>Argipressin</subject><subject>Argipressin receptors</subject><subject>Biology and life sciences</subject><subject>Chemokine receptors</subject><subject>Chemokines</subject><subject>Complex systems</subject><subject>CXCR4 protein</subject><subject>Experiments</subject><subject>G protein-coupled receptors</subject><subject>Genetic aspects</subject><subject>In vivo methods and tests</subject><subject>Medical research</subject><subject>Medicine</subject><subject>Medicine and Health Sciences</subject><subject>Muscles</subject><subject>Organs</subject><subject>Physiology</subject><subject>Plastic properties</subject><subject>Plasticity</subject><subject>Proteins</subject><subject>Receptors</subject><subject>Receptors (physiology)</subject><subject>Signaling</subject><subject>siRNA</subject><subject>Smooth muscle</subject><subject>Surgery</subject><subject>Vasopressin</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNk12L1DAUhoso7jr6DwQLguhFx6b5aHsjLIsfAwsrft2GM-npNEPazCbpsPvvzcxU2cpeSCAJOU_ec_KSkyQvSb4ktCTvt3Z0A5jlzg64zAtOq4I8Ss5JTYtMFDl9fG9_ljzzfpvnERLiaXJGGRGCleI8ga8GfNBKh7vUtqnHPQ5ZcDD4Hvt1XDHr0Ojb1KHCXbAu7TCgsz06n-oh7cYehnQPXo0GXOp7a0OX9qNXBlOFxvjnyZMWjMcX07pIfn76-OPyS3Z1_Xl1eXGVKSHqkBW5qEXVNIS3QIGj4ByritScNGtFkRa0hBhXgpRQceB1LUqhClJXtWIQw4vk1Ul3Z6yXkzteFpyxSnAiykisTkRjYSt3Tvfg7qQFLY8H1m0kuOiFQQklLdcNV-u2BcbiRHLeNLkQCGzdQh21PkzZxnWPjcIhmmZmovPIoDu5sXtZFQWrKY0CbycBZ29G9EH22h8Mi5bb8Vg3Fzmjx7pf_4M-_LqJ2kB8gB5aG_Oqg6i8EELQomJxXiTLB6g4Guy1il-p1fF8duHd7EJkAt6GDYzey9X3b__PXv-as2_usR2CCZ23ZgzaDn4OshOonPXeYfvXZJLLQyf8cUMeOkFOnUB_A6yr-w0</recordid><startdate>20210624</startdate><enddate>20210624</enddate><creator>Albee, Lauren J</creator><creator>Gao, Xianlong</creator><creator>Majetschak, Matthias</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-4086-0887</orcidid></search><sort><creationdate>20210624</creationdate><title>Plasticity of seven-transmembrane-helix receptor heteromers in human vascular smooth muscle cells</title><author>Albee, Lauren J ; Gao, Xianlong ; Majetschak, Matthias</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c669t-206968dd15fa3a5e655e881951dbc3e3237a68dc617a85a599676c21989c4a323</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Antibodies</topic><topic>Argipressin</topic><topic>Argipressin receptors</topic><topic>Biology and life sciences</topic><topic>Chemokine receptors</topic><topic>Chemokines</topic><topic>Complex systems</topic><topic>CXCR4 protein</topic><topic>Experiments</topic><topic>G protein-coupled receptors</topic><topic>Genetic aspects</topic><topic>In vivo methods and tests</topic><topic>Medical research</topic><topic>Medicine</topic><topic>Medicine and Health Sciences</topic><topic>Muscles</topic><topic>Organs</topic><topic>Physiology</topic><topic>Plastic properties</topic><topic>Plasticity</topic><topic>Proteins</topic><topic>Receptors</topic><topic>Receptors (physiology)</topic><topic>Signaling</topic><topic>siRNA</topic><topic>Smooth muscle</topic><topic>Surgery</topic><topic>Vasopressin</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Albee, Lauren J</creatorcontrib><creatorcontrib>Gao, Xianlong</creatorcontrib><creatorcontrib>Majetschak, Matthias</creatorcontrib><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing &amp; Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological &amp; Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health &amp; Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology 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>Materials Science &amp; Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies &amp; Aerospace Collection</collection><collection>Agricultural &amp; Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing &amp; Allied Health Database (Alumni Edition)</collection><collection>Meteorological &amp; Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health &amp; Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing &amp; Allied Health Premium</collection><collection>Advanced Technologies &amp; Aerospace Database</collection><collection>ProQuest Advanced Technologies &amp; Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Albee, Lauren J</au><au>Gao, Xianlong</au><au>Majetschak, Matthias</au><au>Raju, Raghavan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Plasticity of seven-transmembrane-helix receptor heteromers in human vascular smooth muscle cells</atitle><jtitle>PloS one</jtitle><date>2021-06-24</date><risdate>2021</risdate><volume>16</volume><issue>6</issue><spage>e0253821</spage><epage>e0253821</epage><pages>e0253821-e0253821</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Recently, we reported that the chemokine (C-X-C motif) receptor 4 (CXCR4) and atypical chemokine receptor 3 (ACKR3) heteromerize with [alpha].sub.1A/B/D -adrenoceptors (ARs) and arginine vasopressin receptor 1A (AVPR1A) in recombinant systems and in rodent and human vascular smooth muscle cells (hVSMCs). In these studies, we observed that heteromerization between two receptor partners may depend on the presence and the expression levels of other partnering receptors. To test this hypothesis and to gain initial insight into the formation of these receptor heteromers in native cells, we utilized proximity ligation assays in hVSMCs to visualize receptor-receptor proximity and systematically studied how manipulation of the expression levels of individual protomers affect heteromerization patterns among other interacting receptor partners. We confirmed subtype-specific heteromerization between endogenously expressed [alpha].sub.1A/B/D -ARs and detected that AVPR1A also heteromerizes with [alpha].sub.1A/B/D -ARs. siRNA knockdown of CXCR4 and of ACKR3 resulted in a significant re-arrangement of the heteromerization patterns among [alpha].sub.1 -AR subtypes. Similarly, siRNA knockdown of AVPR1A significantly increased heteromerization signals for seven of the ten receptor pairs between CXCR4, ACKR3, and [alpha].sub.1A/B/D -ARs. Our findings suggest plasticity of seven transmembrane helix (7TM) receptor heteromerization in native cells and could be explained by a supramolecular organization of these receptors within dynamic clusters in the plasma membrane. Because we previously observed that recombinant CXCR4, ACKR3, [alpha].sub.1a -AR and AVPR1A form hetero-oligomeric complexes composed of 2-4 different protomers, which show signaling properties distinct from individual protomers, re-arrangements of receptor heteromerization patterns in native cells may contribute to the phenomenon of context-dependent GPCR signaling. Furthermore, these findings advise caution in the interpretation of functional consequences after 7TM receptor knockdown in experimental models. Alterations of the heteromerization patterns among other receptor partners may alter physiological and pathological responses, in particular in more complex systems, such as studies on the function of isolated organs or in in vivo experiments.</abstract><cop>San Francisco</cop><pub>Public Library of Science</pub><pmid>34166476</pmid><doi>10.1371/journal.pone.0253821</doi><tpages>e0253821</tpages><orcidid>https://orcid.org/0000-0002-4086-0887</orcidid><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 1932-6203
ispartof PloS one, 2021-06, Vol.16 (6), p.e0253821-e0253821
issn 1932-6203
1932-6203
language eng
recordid cdi_plos_journals_2544865167
source Public Library of Science (PLoS) Journals Open Access; PubMed Central Free; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; Free Full-Text Journals in Chemistry
subjects Antibodies
Argipressin
Argipressin receptors
Biology and life sciences
Chemokine receptors
Chemokines
Complex systems
CXCR4 protein
Experiments
G protein-coupled receptors
Genetic aspects
In vivo methods and tests
Medical research
Medicine
Medicine and Health Sciences
Muscles
Organs
Physiology
Plastic properties
Plasticity
Proteins
Receptors
Receptors (physiology)
Signaling
siRNA
Smooth muscle
Surgery
Vasopressin
title Plasticity of seven-transmembrane-helix receptor heteromers in human vascular smooth muscle cells
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-25T04%3A20%3A16IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Plasticity%20of%20seven-transmembrane-helix%20receptor%20heteromers%20in%20human%20vascular%20smooth%20muscle%20cells&rft.jtitle=PloS%20one&rft.au=Albee,%20Lauren%20J&rft.date=2021-06-24&rft.volume=16&rft.issue=6&rft.spage=e0253821&rft.epage=e0253821&rft.pages=e0253821-e0253821&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0253821&rft_dat=%3Cgale_plos_%3EA666328466%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2544865167&rft_id=info:pmid/34166476&rft_galeid=A666328466&rft_doaj_id=oai_doaj_org_article_a737bd5cbffa44ffa105dd066ea4bfa9&rfr_iscdi=true