Loss of biased signaling at a G protein-coupled receptor in overexpressed systems
G protein-coupled receptors (GPCRs) regulate cellular signaling pathways by coupling to two classes of transducers: heterotrimeric G proteins and β-arrestins. [Sarcosine1Ile4Ile8]-angiotensin II (SII), an analog of the endogenous ligand angiotensin II (AngII) for the angiotensin II type 1 receptor (...
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| creator | Li, Angus Liu, Samuel Huang, Rennica Ahn, Seungkirl Lefkowitz, Robert J |
| description | G protein-coupled receptors (GPCRs) regulate cellular signaling pathways by coupling to two classes of transducers: heterotrimeric G proteins and β-arrestins. [Sarcosine1Ile4Ile8]-angiotensin II (SII), an analog of the endogenous ligand angiotensin II (AngII) for the angiotensin II type 1 receptor (AT1R), fails to activate G protein in physiologically relevant models. Despite this, SII and several derivatives induce cellular signaling outcomes through β-arrestin-2-dependent mechanisms. However, studies reliant on exogenous AT1R overexpression indicate that SII is a partial agonist for G protein signaling and lacks β-arrestin-exclusive functional specificity. We investigated this apparent discrepancy by profiling changes in functional specificity at increasing expression levels of AT1R using a stably integrated tetracycline-titratable expression system stimulated with AngII, SII, and four other AngII analogs displaying different signaling biases. Unbiased and G protein-biased ligands activated dose-dependent calcium responses at all tested receptor concentrations. In contrast, β-arrestin-biased ligands induced dose-dependent calcium signaling only at higher AT1R overexpression levels. Using inhibitors of G proteins, we demonstrated that both Gi and Gq/11 mediated overexpression-dependent calcium signaling by β-arrestin-biased ligands. Regarding β-arrestin-mediated cellular events, the β-arrestin-biased ligand TRV026 induced receptor internalization at low physiological receptor levels insufficient for it to initiate calcium signaling. In contrast, unbiased AngII exhibited no relative preference between these outcomes under such low receptor conditions. However, with high receptor overexpression, TRV026 lost its functional selectivity. These results suggest receptor overexpression misleadingly distorts the bias of AT1R ligands and highlight the risks of using overexpressed systems to infer the signaling bias of GPCR ligands in physiologically relevant contexts. |
| doi_str_mv | 10.1371/journal.pone.0283477 |
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[Sarcosine1Ile4Ile8]-angiotensin II (SII), an analog of the endogenous ligand angiotensin II (AngII) for the angiotensin II type 1 receptor (AT1R), fails to activate G protein in physiologically relevant models. Despite this, SII and several derivatives induce cellular signaling outcomes through β-arrestin-2-dependent mechanisms. However, studies reliant on exogenous AT1R overexpression indicate that SII is a partial agonist for G protein signaling and lacks β-arrestin-exclusive functional specificity. We investigated this apparent discrepancy by profiling changes in functional specificity at increasing expression levels of AT1R using a stably integrated tetracycline-titratable expression system stimulated with AngII, SII, and four other AngII analogs displaying different signaling biases. Unbiased and G protein-biased ligands activated dose-dependent calcium responses at all tested receptor concentrations. In contrast, β-arrestin-biased ligands induced dose-dependent calcium signaling only at higher AT1R overexpression levels. Using inhibitors of G proteins, we demonstrated that both Gi and Gq/11 mediated overexpression-dependent calcium signaling by β-arrestin-biased ligands. Regarding β-arrestin-mediated cellular events, the β-arrestin-biased ligand TRV026 induced receptor internalization at low physiological receptor levels insufficient for it to initiate calcium signaling. In contrast, unbiased AngII exhibited no relative preference between these outcomes under such low receptor conditions. However, with high receptor overexpression, TRV026 lost its functional selectivity. These results suggest receptor overexpression misleadingly distorts the bias of AT1R ligands and highlight the risks of using overexpressed systems to infer the signaling bias of GPCR ligands in physiologically relevant contexts.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0283477</identifier><identifier>PMID: 36961836</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Analogs ; Analysis ; Angiotensin ; Angiotensin II ; Angiotensin II - metabolism ; Angiotensin II - pharmacology ; Antibiotics ; Arrestin ; beta-Arrestin 1 - metabolism ; beta-Arrestins - metabolism ; Bias ; Biology and Life Sciences ; Calcium ; Calcium signalling ; Cell receptors ; Engineering and Technology ; G protein-coupled receptors ; G proteins ; GTP-Binding Proteins - metabolism ; Health aspects ; HEK293 Cells ; Humans ; Internalization ; Kinases ; Ligands ; Medicine and Health Sciences ; Physiology ; Proteins ; Receptor, Angiotensin, Type 1 - metabolism ; Receptors ; Receptors, G-Protein-Coupled - metabolism ; Research and Analysis Methods ; Selectivity ; Signal Transduction ; Signaling ; Smooth muscle ; Transducers</subject><ispartof>PloS one, 2023-03, Vol.18 (3), p.e0283477-e0283477</ispartof><rights>Copyright: © 2023 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</rights><rights>COPYRIGHT 2023 Public Library of Science</rights><rights>2023 Li 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>2023 Li et al 2023 Li et al</rights><rights>2023 Li 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><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c623t-ff0c627b154c6dbf638b83224cec77882a1235abf5cf0b80567e9f0929da6d753</citedby><cites>FETCH-LOGICAL-c623t-ff0c627b154c6dbf638b83224cec77882a1235abf5cf0b80567e9f0929da6d753</cites><orcidid>0000-0001-5681-3789 ; 0000-0003-1472-7545</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/PMC10038289/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10038289/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36961836$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Shukla, Arun</contributor><creatorcontrib>Li, Angus</creatorcontrib><creatorcontrib>Liu, Samuel</creatorcontrib><creatorcontrib>Huang, Rennica</creatorcontrib><creatorcontrib>Ahn, Seungkirl</creatorcontrib><creatorcontrib>Lefkowitz, Robert J</creatorcontrib><title>Loss of biased signaling at a G protein-coupled receptor in overexpressed systems</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>G protein-coupled receptors (GPCRs) regulate cellular signaling pathways by coupling to two classes of transducers: heterotrimeric G proteins and β-arrestins. [Sarcosine1Ile4Ile8]-angiotensin II (SII), an analog of the endogenous ligand angiotensin II (AngII) for the angiotensin II type 1 receptor (AT1R), fails to activate G protein in physiologically relevant models. Despite this, SII and several derivatives induce cellular signaling outcomes through β-arrestin-2-dependent mechanisms. However, studies reliant on exogenous AT1R overexpression indicate that SII is a partial agonist for G protein signaling and lacks β-arrestin-exclusive functional specificity. We investigated this apparent discrepancy by profiling changes in functional specificity at increasing expression levels of AT1R using a stably integrated tetracycline-titratable expression system stimulated with AngII, SII, and four other AngII analogs displaying different signaling biases. Unbiased and G protein-biased ligands activated dose-dependent calcium responses at all tested receptor concentrations. In contrast, β-arrestin-biased ligands induced dose-dependent calcium signaling only at higher AT1R overexpression levels. Using inhibitors of G proteins, we demonstrated that both Gi and Gq/11 mediated overexpression-dependent calcium signaling by β-arrestin-biased ligands. Regarding β-arrestin-mediated cellular events, the β-arrestin-biased ligand TRV026 induced receptor internalization at low physiological receptor levels insufficient for it to initiate calcium signaling. In contrast, unbiased AngII exhibited no relative preference between these outcomes under such low receptor conditions. However, with high receptor overexpression, TRV026 lost its functional selectivity. These results suggest receptor overexpression misleadingly distorts the bias of AT1R ligands and highlight the risks of using overexpressed systems to infer the signaling bias of GPCR ligands in physiologically relevant contexts.</description><subject>Analogs</subject><subject>Analysis</subject><subject>Angiotensin</subject><subject>Angiotensin II</subject><subject>Angiotensin II - metabolism</subject><subject>Angiotensin II - pharmacology</subject><subject>Antibiotics</subject><subject>Arrestin</subject><subject>beta-Arrestin 1 - metabolism</subject><subject>beta-Arrestins - metabolism</subject><subject>Bias</subject><subject>Biology and Life Sciences</subject><subject>Calcium</subject><subject>Calcium signalling</subject><subject>Cell receptors</subject><subject>Engineering and Technology</subject><subject>G protein-coupled receptors</subject><subject>G proteins</subject><subject>GTP-Binding Proteins - metabolism</subject><subject>Health aspects</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Internalization</subject><subject>Kinases</subject><subject>Ligands</subject><subject>Medicine and Health Sciences</subject><subject>Physiology</subject><subject>Proteins</subject><subject>Receptor, Angiotensin, Type 1 - metabolism</subject><subject>Receptors</subject><subject>Receptors, G-Protein-Coupled - metabolism</subject><subject>Research and Analysis Methods</subject><subject>Selectivity</subject><subject>Signal Transduction</subject><subject>Signaling</subject><subject>Smooth muscle</subject><subject>Transducers</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNkl1r2zAUhs3YWLtu_2BshsHYLpLJkq2Pq1HK1gUCZZ-3QpaPEgXHciW5tP9-SuKWePRi6EJCet73SEdvlr0u0LwgrPi0cYPvVDvvXQdzhDkpGXuSnRaC4BnFiDw9Wp9kL0LYIFQRTunz7IRQQQtO6Gn2felCyJ3Ja6sCNHmwq2Rqu1WuYq7yy7z3LoLtZtoNfZsADxr66Hxuu9zdgIfb3kPYS-9ChG14mT0zqg3wapzPst9fv_y6-DZbXl0uLs6XM00xiTNjUFqwuqhKTZvaUMJrTjAuNWjGOMeqwKRStam0QTVHFWUgDBJYNIo2rCJn2duDb9-6IMduBImZQASVVUkSsTgQjVMb2Xu7Vf5OOmXlfsP5lVQ-Wt2CLCimNYemKJUqmdC8VFpQqlltoKhEnbw-j9WGeguNhi561U5MpyedXcuVu5EFQoRjLpLDh9HBu-sBQpRbGzS0rerADfuLp3-tKooS-u4f9PHnjdRKpRfYzrhUWO9M5TkrMWeCCp6o-SNUGg1srU7ZMTbtTwQfJ4LERLiNKzWEIBc_f_w_e_Vnyr4_Yteg2rgOrh2idV2YguUB1D5l04N56HKB5C76992Qu-jLMfpJ9ub4hx5E91knfwFcAP5W</recordid><startdate>20230324</startdate><enddate>20230324</enddate><creator>Li, Angus</creator><creator>Liu, Samuel</creator><creator>Huang, Rennica</creator><creator>Ahn, Seungkirl</creator><creator>Lefkowitz, Robert J</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><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>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>AEUYN</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>COVID</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>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0001-5681-3789</orcidid><orcidid>https://orcid.org/0000-0003-1472-7545</orcidid></search><sort><creationdate>20230324</creationdate><title>Loss of biased signaling at a G protein-coupled receptor in overexpressed systems</title><author>Li, Angus ; Liu, Samuel ; Huang, Rennica ; Ahn, Seungkirl ; Lefkowitz, Robert J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c623t-ff0c627b154c6dbf638b83224cec77882a1235abf5cf0b80567e9f0929da6d753</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Analogs</topic><topic>Analysis</topic><topic>Angiotensin</topic><topic>Angiotensin II</topic><topic>Angiotensin II - metabolism</topic><topic>Angiotensin II - pharmacology</topic><topic>Antibiotics</topic><topic>Arrestin</topic><topic>beta-Arrestin 1 - metabolism</topic><topic>beta-Arrestins - metabolism</topic><topic>Bias</topic><topic>Biology and Life Sciences</topic><topic>Calcium</topic><topic>Calcium signalling</topic><topic>Cell receptors</topic><topic>Engineering and Technology</topic><topic>G protein-coupled receptors</topic><topic>G proteins</topic><topic>GTP-Binding Proteins - metabolism</topic><topic>Health aspects</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Internalization</topic><topic>Kinases</topic><topic>Ligands</topic><topic>Medicine and Health Sciences</topic><topic>Physiology</topic><topic>Proteins</topic><topic>Receptor, Angiotensin, Type 1 - metabolism</topic><topic>Receptors</topic><topic>Receptors, G-Protein-Coupled - metabolism</topic><topic>Research and Analysis Methods</topic><topic>Selectivity</topic><topic>Signal Transduction</topic><topic>Signaling</topic><topic>Smooth muscle</topic><topic>Transducers</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Li, Angus</creatorcontrib><creatorcontrib>Liu, Samuel</creatorcontrib><creatorcontrib>Huang, Rennica</creatorcontrib><creatorcontrib>Ahn, Seungkirl</creatorcontrib><creatorcontrib>Lefkowitz, Robert J</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><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>Proquest Nursing & Allied Health Source</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>ProQuest 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 & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & 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>Coronavirus Research Database</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 & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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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>Li, Angus</au><au>Liu, Samuel</au><au>Huang, Rennica</au><au>Ahn, Seungkirl</au><au>Lefkowitz, Robert J</au><au>Shukla, Arun</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Loss of biased signaling at a G protein-coupled receptor in overexpressed systems</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2023-03-24</date><risdate>2023</risdate><volume>18</volume><issue>3</issue><spage>e0283477</spage><epage>e0283477</epage><pages>e0283477-e0283477</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>G protein-coupled receptors (GPCRs) regulate cellular signaling pathways by coupling to two classes of transducers: heterotrimeric G proteins and β-arrestins. [Sarcosine1Ile4Ile8]-angiotensin II (SII), an analog of the endogenous ligand angiotensin II (AngII) for the angiotensin II type 1 receptor (AT1R), fails to activate G protein in physiologically relevant models. Despite this, SII and several derivatives induce cellular signaling outcomes through β-arrestin-2-dependent mechanisms. However, studies reliant on exogenous AT1R overexpression indicate that SII is a partial agonist for G protein signaling and lacks β-arrestin-exclusive functional specificity. We investigated this apparent discrepancy by profiling changes in functional specificity at increasing expression levels of AT1R using a stably integrated tetracycline-titratable expression system stimulated with AngII, SII, and four other AngII analogs displaying different signaling biases. Unbiased and G protein-biased ligands activated dose-dependent calcium responses at all tested receptor concentrations. In contrast, β-arrestin-biased ligands induced dose-dependent calcium signaling only at higher AT1R overexpression levels. Using inhibitors of G proteins, we demonstrated that both Gi and Gq/11 mediated overexpression-dependent calcium signaling by β-arrestin-biased ligands. Regarding β-arrestin-mediated cellular events, the β-arrestin-biased ligand TRV026 induced receptor internalization at low physiological receptor levels insufficient for it to initiate calcium signaling. In contrast, unbiased AngII exhibited no relative preference between these outcomes under such low receptor conditions. However, with high receptor overexpression, TRV026 lost its functional selectivity. These results suggest receptor overexpression misleadingly distorts the bias of AT1R ligands and highlight the risks of using overexpressed systems to infer the signaling bias of GPCR ligands in physiologically relevant contexts.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>36961836</pmid><doi>10.1371/journal.pone.0283477</doi><tpages>e0283477</tpages><orcidid>https://orcid.org/0000-0001-5681-3789</orcidid><orcidid>https://orcid.org/0000-0003-1472-7545</orcidid><oa>free_for_read</oa></addata></record> |
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| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Analogs Analysis Angiotensin Angiotensin II Angiotensin II - metabolism Angiotensin II - pharmacology Antibiotics Arrestin beta-Arrestin 1 - metabolism beta-Arrestins - metabolism Bias Biology and Life Sciences Calcium Calcium signalling Cell receptors Engineering and Technology G protein-coupled receptors G proteins GTP-Binding Proteins - metabolism Health aspects HEK293 Cells Humans Internalization Kinases Ligands Medicine and Health Sciences Physiology Proteins Receptor, Angiotensin, Type 1 - metabolism Receptors Receptors, G-Protein-Coupled - metabolism Research and Analysis Methods Selectivity Signal Transduction Signaling Smooth muscle Transducers |
| title | Loss of biased signaling at a G protein-coupled receptor in overexpressed systems |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-29T00%3A40%3A45IST&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=Loss%20of%20biased%20signaling%20at%20a%20G%20protein-coupled%20receptor%20in%20overexpressed%20systems&rft.jtitle=PloS%20one&rft.au=Li,%20Angus&rft.date=2023-03-24&rft.volume=18&rft.issue=3&rft.spage=e0283477&rft.epage=e0283477&rft.pages=e0283477-e0283477&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0283477&rft_dat=%3Cgale_plos_%3EA742879698%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=2790304543&rft_id=info:pmid/36961836&rft_galeid=A742879698&rft_doaj_id=oai_doaj_org_article_1626b8ed14aa479c84ac966c7bfe159b&rfr_iscdi=true |