Spinophilin Blocks Arrestin Actions In vitro and In vivo at G Protein-Coupled Receptors
Arrestin regulates almost all G protein-coupled receptor (GPCR)-mediated signaling and trafficking. We report that the multidomain protein, spinophilin, antagonizes these multiple arrestin functions. Through blocking G protein receptor kinase 2 (GRK2) association with$receptor-G\beta \gamma$complexe...
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| Veröffentlicht in: | Science (American Association for the Advancement of Science) 2004-06, Vol.304 (5679), p.1940-1944 |
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| container_issue | 5679 |
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| container_title | Science (American Association for the Advancement of Science) |
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| creator | Wang, Qin Zhao, Jiali Brady, Ashley E. Feng, Jian Allen, Patrick B. Lefkowitz, Robert J. Greengard, Paul Limbird, Lee E. |
| description | Arrestin regulates almost all G protein-coupled receptor (GPCR)-mediated signaling and trafficking. We report that the multidomain protein, spinophilin, antagonizes these multiple arrestin functions. Through blocking G protein receptor kinase 2 (GRK2) association with$receptor-G\beta \gamma$complexes, spinophilin reduces arrestin-stabilized receptor phosphorylation, receptor endocytosis, and the acceleration of mitogen-activated protein kinase (MAPK) activity following endocytosis. Spinophilin knockout mice were more sensitive than wild-type mice to sedation elicited by stimulation of α2adrenergic receptors, whereas arrestin 3 knockout mice were more resistant, indicating that the signal-promoting, rather than the signal-terminating, roles of arrestin are more important for certain response pathways. The reciprocal interactions of GPCRs with spinophilin and arrestin represent a regulatory mechanism for fine-tuning complex receptor-orchestrated cell signaling and responses. |
| doi_str_mv | 10.1126/science.1098274 |
| format | Article |
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We report that the multidomain protein, spinophilin, antagonizes these multiple arrestin functions. Through blocking G protein receptor kinase 2 (GRK2) association with$receptor-G\beta \gamma$complexes, spinophilin reduces arrestin-stabilized receptor phosphorylation, receptor endocytosis, and the acceleration of mitogen-activated protein kinase (MAPK) activity following endocytosis. Spinophilin knockout mice were more sensitive than wild-type mice to sedation elicited by stimulation of α2adrenergic receptors, whereas arrestin 3 knockout mice were more resistant, indicating that the signal-promoting, rather than the signal-terminating, roles of arrestin are more important for certain response pathways. The reciprocal interactions of GPCRs with spinophilin and arrestin represent a regulatory mechanism for fine-tuning complex receptor-orchestrated cell signaling and responses.</description><identifier>ISSN: 0036-8075</identifier><identifier>EISSN: 1095-9203</identifier><identifier>DOI: 10.1126/science.1098274</identifier><identifier>PMID: 15218143</identifier><identifier>CODEN: SCIEAS</identifier><language>eng</language><publisher>Washington, DC: American Association for the Advancement of Science</publisher><subject>Adenosine - analogs & derivatives ; Adenosine - pharmacology ; Adrenergic alpha-Agonists - pharmacology ; Agonists ; Animals ; Arrestin - antagonists & inhibitors ; Arrestin - metabolism ; Arrestins - genetics ; Arrestins - metabolism ; beta-Adrenergic Receptor Kinases ; Biological and medical sciences ; Cell Line ; Cell physiology ; Cell receptors ; Cell structures and functions ; Cells ; Cellular signal transduction ; Cyclic AMP-Dependent Protein Kinases - metabolism ; Desensitization ; Drug interactions ; Endocytosis ; Enzyme Activation ; Epinephrine - pharmacology ; Fundamental and applied biological sciences. Psychology ; G proteins ; G-Protein-Coupled Receptor Kinase 3 ; Gene expression regulation ; Genotypes ; Graphs ; GTP-Binding Proteins - metabolism ; Humans ; MAP Kinase Signaling System ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Microfilament Proteins - genetics ; Microfilament Proteins - metabolism ; Miscellaneous ; Mitogen-Activated Protein Kinases - metabolism ; Molecular and cellular biology ; Motor Activity ; Nerve Tissue Proteins - genetics ; Nerve Tissue Proteins - metabolism ; Phosphorylation ; Physiological aspects ; Physiological regulation ; Proteins ; Receptors ; Receptors, Adrenergic, alpha-2 - metabolism ; Research Article ; Research universities ; Rodents ; Rotarod Performance Test ; Signal Transduction ; Transfection</subject><ispartof>Science (American Association for the Advancement of Science), 2004-06, Vol.304 (5679), p.1940-1944</ispartof><rights>Copyright 2004 American Association for the Advancement of Science</rights><rights>2004 INIST-CNRS</rights><rights>COPYRIGHT 2004 American Association for the Advancement of Science</rights><rights>Copyright American Association for the Advancement of Science Jun 25, 2004</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c779t-a97a3b8aeb9ae1c8f3a4a3366654aa3c58334ae450e370022857c79bcc0bce7a3</citedby><cites>FETCH-LOGICAL-c779t-a97a3b8aeb9ae1c8f3a4a3366654aa3c58334ae450e370022857c79bcc0bce7a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/3837197$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/3837197$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>314,780,784,803,2884,2885,27924,27925,58017,58250</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=15927211$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15218143$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Qin</creatorcontrib><creatorcontrib>Zhao, Jiali</creatorcontrib><creatorcontrib>Brady, Ashley E.</creatorcontrib><creatorcontrib>Feng, Jian</creatorcontrib><creatorcontrib>Allen, Patrick B.</creatorcontrib><creatorcontrib>Lefkowitz, Robert J.</creatorcontrib><creatorcontrib>Greengard, Paul</creatorcontrib><creatorcontrib>Limbird, Lee E.</creatorcontrib><title>Spinophilin Blocks Arrestin Actions In vitro and In vivo at G Protein-Coupled Receptors</title><title>Science (American Association for the Advancement of Science)</title><addtitle>Science</addtitle><description>Arrestin regulates almost all G protein-coupled receptor (GPCR)-mediated signaling and trafficking. We report that the multidomain protein, spinophilin, antagonizes these multiple arrestin functions. Through blocking G protein receptor kinase 2 (GRK2) association with$receptor-G\beta \gamma$complexes, spinophilin reduces arrestin-stabilized receptor phosphorylation, receptor endocytosis, and the acceleration of mitogen-activated protein kinase (MAPK) activity following endocytosis. Spinophilin knockout mice were more sensitive than wild-type mice to sedation elicited by stimulation of α2adrenergic receptors, whereas arrestin 3 knockout mice were more resistant, indicating that the signal-promoting, rather than the signal-terminating, roles of arrestin are more important for certain response pathways. The reciprocal interactions of GPCRs with spinophilin and arrestin represent a regulatory mechanism for fine-tuning complex receptor-orchestrated cell signaling and responses.</description><subject>Adenosine - analogs & derivatives</subject><subject>Adenosine - pharmacology</subject><subject>Adrenergic alpha-Agonists - pharmacology</subject><subject>Agonists</subject><subject>Animals</subject><subject>Arrestin - antagonists & inhibitors</subject><subject>Arrestin - metabolism</subject><subject>Arrestins - genetics</subject><subject>Arrestins - metabolism</subject><subject>beta-Adrenergic Receptor Kinases</subject><subject>Biological and medical sciences</subject><subject>Cell Line</subject><subject>Cell physiology</subject><subject>Cell receptors</subject><subject>Cell structures and functions</subject><subject>Cells</subject><subject>Cellular signal transduction</subject><subject>Cyclic AMP-Dependent Protein Kinases - metabolism</subject><subject>Desensitization</subject><subject>Drug interactions</subject><subject>Endocytosis</subject><subject>Enzyme Activation</subject><subject>Epinephrine - pharmacology</subject><subject>Fundamental and applied biological sciences. 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Science)</jtitle><addtitle>Science</addtitle><date>2004-06-25</date><risdate>2004</risdate><volume>304</volume><issue>5679</issue><spage>1940</spage><epage>1944</epage><pages>1940-1944</pages><issn>0036-8075</issn><eissn>1095-9203</eissn><coden>SCIEAS</coden><abstract>Arrestin regulates almost all G protein-coupled receptor (GPCR)-mediated signaling and trafficking. We report that the multidomain protein, spinophilin, antagonizes these multiple arrestin functions. Through blocking G protein receptor kinase 2 (GRK2) association with$receptor-G\beta \gamma$complexes, spinophilin reduces arrestin-stabilized receptor phosphorylation, receptor endocytosis, and the acceleration of mitogen-activated protein kinase (MAPK) activity following endocytosis. Spinophilin knockout mice were more sensitive than wild-type mice to sedation elicited by stimulation of α2adrenergic receptors, whereas arrestin 3 knockout mice were more resistant, indicating that the signal-promoting, rather than the signal-terminating, roles of arrestin are more important for certain response pathways. The reciprocal interactions of GPCRs with spinophilin and arrestin represent a regulatory mechanism for fine-tuning complex receptor-orchestrated cell signaling and responses.</abstract><cop>Washington, DC</cop><pub>American Association for the Advancement of Science</pub><pmid>15218143</pmid><doi>10.1126/science.1098274</doi><tpages>5</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0036-8075 |
| ispartof | Science (American Association for the Advancement of Science), 2004-06, Vol.304 (5679), p.1940-1944 |
| issn | 0036-8075 1095-9203 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_743466059 |
| source | MEDLINE; JSTOR Archive Collection A-Z Listing; American Association for the Advancement of Science |
| subjects | Adenosine - analogs & derivatives Adenosine - pharmacology Adrenergic alpha-Agonists - pharmacology Agonists Animals Arrestin - antagonists & inhibitors Arrestin - metabolism Arrestins - genetics Arrestins - metabolism beta-Adrenergic Receptor Kinases Biological and medical sciences Cell Line Cell physiology Cell receptors Cell structures and functions Cells Cellular signal transduction Cyclic AMP-Dependent Protein Kinases - metabolism Desensitization Drug interactions Endocytosis Enzyme Activation Epinephrine - pharmacology Fundamental and applied biological sciences. Psychology G proteins G-Protein-Coupled Receptor Kinase 3 Gene expression regulation Genotypes Graphs GTP-Binding Proteins - metabolism Humans MAP Kinase Signaling System Mice Mice, Inbred C57BL Mice, Knockout Microfilament Proteins - genetics Microfilament Proteins - metabolism Miscellaneous Mitogen-Activated Protein Kinases - metabolism Molecular and cellular biology Motor Activity Nerve Tissue Proteins - genetics Nerve Tissue Proteins - metabolism Phosphorylation Physiological aspects Physiological regulation Proteins Receptors Receptors, Adrenergic, alpha-2 - metabolism Research Article Research universities Rodents Rotarod Performance Test Signal Transduction Transfection |
| title | Spinophilin Blocks Arrestin Actions In vitro and In vivo at G Protein-Coupled Receptors |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-05T21%3A26%3A29IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Spinophilin%20Blocks%20Arrestin%20Actions%20In%20vitro%20and%20In%20vivo%20at%20G%20Protein-Coupled%20Receptors&rft.jtitle=Science%20(American%20Association%20for%20the%20Advancement%20of%20Science)&rft.au=Wang,%20Qin&rft.date=2004-06-25&rft.volume=304&rft.issue=5679&rft.spage=1940&rft.epage=1944&rft.pages=1940-1944&rft.issn=0036-8075&rft.eissn=1095-9203&rft.coden=SCIEAS&rft_id=info:doi/10.1126/science.1098274&rft_dat=%3Cgale_proqu%3EA119268985%3C/gale_proqu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=213578101&rft_id=info:pmid/15218143&rft_galeid=A119268985&rft_jstor_id=3837197&rfr_iscdi=true |