P‐glycoprotein in blood–brain barrier endothelial cells: interaction and oligomerization with caveolins
P‐glycoprotein (P‐gp), an adenosine triphosphate (ATP)‐binding cassette transporter which acts as a drug efflux pump, is highly expressed at the blood–brain barrier (BBB) where it plays an important role in brain protection. Recently, P‐gp has been reported to be located in the caveolae of multidrug...
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| Veröffentlicht in: | Journal of neurochemistry 2003-11, Vol.87 (4), p.1010-1023 |
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| creator | Jodoin, Julie Demeule, Michel Fenart, Laurence Cecchelli, Roméo Farmer, Sarah Linton, Kenneth J. Higgins, Christopher F. Béliveau, Richard |
| description | P‐glycoprotein (P‐gp), an adenosine triphosphate (ATP)‐binding cassette transporter which acts as a drug efflux pump, is highly expressed at the blood–brain barrier (BBB) where it plays an important role in brain protection. Recently, P‐gp has been reported to be located in the caveolae of multidrug‐resistant cells. In this study, we investigated the localization and the activity of P‐gp in the caveolae of endothelial cells of the BBB. We used an in vitro model of the BBB which is formed by co‐culture of bovine brain capillary endothelial cells (BBCEC) with astrocytes. Caveolar microdomains isolated from BBCEC are enriched in P‐gp, cholesterol, caveolin‐1, and caveolin‐2. Moreover, P‐gp interacts with caveolin‐1 and caveolin‐2; together, they form a high molecular mass complex. P‐gp in isolated caveolae is able to bind its substrates, and the caveolae‐disrupting agents filipin III and nystatin decrease P‐gp transport activity. In addition, mutations in the caveolin‐binding motif present in P‐gp reduced the interaction of P‐gp with caveolin‐1 and increased the transport activity of P‐gp. Thus, P‐gp expressed at the BBB is mainly localized in caveolae and its activity may be modulated by interaction with caveolin‐1. |
| doi_str_mv | 10.1046/j.1471-4159.2003.02081.x |
| format | Article |
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Recently, P‐gp has been reported to be located in the caveolae of multidrug‐resistant cells. In this study, we investigated the localization and the activity of P‐gp in the caveolae of endothelial cells of the BBB. We used an in vitro model of the BBB which is formed by co‐culture of bovine brain capillary endothelial cells (BBCEC) with astrocytes. Caveolar microdomains isolated from BBCEC are enriched in P‐gp, cholesterol, caveolin‐1, and caveolin‐2. Moreover, P‐gp interacts with caveolin‐1 and caveolin‐2; together, they form a high molecular mass complex. P‐gp in isolated caveolae is able to bind its substrates, and the caveolae‐disrupting agents filipin III and nystatin decrease P‐gp transport activity. In addition, mutations in the caveolin‐binding motif present in P‐gp reduced the interaction of P‐gp with caveolin‐1 and increased the transport activity of P‐gp. Thus, P‐gp expressed at the BBB is mainly localized in caveolae and its activity may be modulated by interaction with caveolin‐1.</description><identifier>ISSN: 0022-3042</identifier><identifier>EISSN: 1471-4159</identifier><identifier>DOI: 10.1046/j.1471-4159.2003.02081.x</identifier><identifier>PMID: 14622130</identifier><identifier>CODEN: JONRA9</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Science Ltd</publisher><subject>Animals ; Astrocytes - cytology ; Astrocytes - metabolism ; ATP Binding Cassette Transporter, Subfamily B, Member 1 - genetics ; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism ; Binding Sites - genetics ; Binding Sites - physiology ; Biochemistry, Molecular Biology ; Biological and medical sciences ; Blood-Brain Barrier - metabolism ; blood–brain barrier ; brain ; Brain - blood supply ; Capillaries - cytology ; Cattle ; caveolae ; Caveolae - chemistry ; Caveolae - metabolism ; caveolin ; Caveolin 1 ; Caveolin 2 ; Caveolins - metabolism ; Cells, Cultured ; Cerebral circulation. Blood-brain barrier. Choroid plexus. Cerebrospinal fluid. Circumventricular organ. Meninges ; Coculture Techniques ; Dogs ; endothelial cell ; Endothelium, Vascular - cytology ; Endothelium, Vascular - metabolism ; Fundamental and applied biological sciences. Psychology ; Kidney - cytology ; Kidney - metabolism ; Life Sciences ; Macromolecular Substances ; Models, Biological ; Mutagenesis, Site-Directed ; Protein Binding - physiology ; Protein Transport - physiology ; P‐glycoprotein ; Rats ; Vertebrates: nervous system and sense organs</subject><ispartof>Journal of neurochemistry, 2003-11, Vol.87 (4), p.1010-1023</ispartof><rights>2004 INIST-CNRS</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5101-f597ed5922a508b312513a0b9fcf33995e7794addacf2f6416e22dd6974e3dba3</citedby><cites>FETCH-LOGICAL-c5101-f597ed5922a508b312513a0b9fcf33995e7794addacf2f6416e22dd6974e3dba3</cites><orcidid>0000-0001-9285-0579</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1046%2Fj.1471-4159.2003.02081.x$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1046%2Fj.1471-4159.2003.02081.x$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,314,780,784,885,1417,1433,27924,27925,45574,45575,46409,46833</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=15274890$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/14622130$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://univ-artois.hal.science/hal-00527174$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Jodoin, Julie</creatorcontrib><creatorcontrib>Demeule, Michel</creatorcontrib><creatorcontrib>Fenart, Laurence</creatorcontrib><creatorcontrib>Cecchelli, Roméo</creatorcontrib><creatorcontrib>Farmer, Sarah</creatorcontrib><creatorcontrib>Linton, Kenneth J.</creatorcontrib><creatorcontrib>Higgins, Christopher F.</creatorcontrib><creatorcontrib>Béliveau, Richard</creatorcontrib><title>P‐glycoprotein in blood–brain barrier endothelial cells: interaction and oligomerization with caveolins</title><title>Journal of neurochemistry</title><addtitle>J Neurochem</addtitle><description>P‐glycoprotein (P‐gp), an adenosine triphosphate (ATP)‐binding cassette transporter which acts as a drug efflux pump, is highly expressed at the blood–brain barrier (BBB) where it plays an important role in brain protection. Recently, P‐gp has been reported to be located in the caveolae of multidrug‐resistant cells. In this study, we investigated the localization and the activity of P‐gp in the caveolae of endothelial cells of the BBB. We used an in vitro model of the BBB which is formed by co‐culture of bovine brain capillary endothelial cells (BBCEC) with astrocytes. Caveolar microdomains isolated from BBCEC are enriched in P‐gp, cholesterol, caveolin‐1, and caveolin‐2. Moreover, P‐gp interacts with caveolin‐1 and caveolin‐2; together, they form a high molecular mass complex. P‐gp in isolated caveolae is able to bind its substrates, and the caveolae‐disrupting agents filipin III and nystatin decrease P‐gp transport activity. In addition, mutations in the caveolin‐binding motif present in P‐gp reduced the interaction of P‐gp with caveolin‐1 and increased the transport activity of P‐gp. Thus, P‐gp expressed at the BBB is mainly localized in caveolae and its activity may be modulated by interaction with caveolin‐1.</description><subject>Animals</subject><subject>Astrocytes - cytology</subject><subject>Astrocytes - metabolism</subject><subject>ATP Binding Cassette Transporter, Subfamily B, Member 1 - genetics</subject><subject>ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism</subject><subject>Binding Sites - genetics</subject><subject>Binding Sites - physiology</subject><subject>Biochemistry, Molecular Biology</subject><subject>Biological and medical sciences</subject><subject>Blood-Brain Barrier - metabolism</subject><subject>blood–brain barrier</subject><subject>brain</subject><subject>Brain - blood supply</subject><subject>Capillaries - cytology</subject><subject>Cattle</subject><subject>caveolae</subject><subject>Caveolae - chemistry</subject><subject>Caveolae - metabolism</subject><subject>caveolin</subject><subject>Caveolin 1</subject><subject>Caveolin 2</subject><subject>Caveolins - metabolism</subject><subject>Cells, Cultured</subject><subject>Cerebral circulation. Blood-brain barrier. Choroid plexus. Cerebrospinal fluid. Circumventricular organ. Meninges</subject><subject>Coculture Techniques</subject><subject>Dogs</subject><subject>endothelial cell</subject><subject>Endothelium, Vascular - cytology</subject><subject>Endothelium, Vascular - metabolism</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Kidney - cytology</subject><subject>Kidney - metabolism</subject><subject>Life Sciences</subject><subject>Macromolecular Substances</subject><subject>Models, Biological</subject><subject>Mutagenesis, Site-Directed</subject><subject>Protein Binding - physiology</subject><subject>Protein Transport - physiology</subject><subject>P‐glycoprotein</subject><subject>Rats</subject><subject>Vertebrates: nervous system and sense organs</subject><issn>0022-3042</issn><issn>1471-4159</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkc1uFDEMxyMEokvLK6C5gNTDDHGS-QgSh2oFFLSCHtpz5Eky3SzZSUlm2y6nPgISb9gnYaa7aq9IkRLbPzu2_4RkQAugonq_KkDUkAsoZcEo5QVltIHi9hmZPQaekxmljOWcCnZAXqW0ohQqUcFLcgCiYgw4nZGfZ_d3fy79VoerGAbr-mw8rQ_B3N_9bSNOFsbobMxsb8KwtN6hz7T1Pn0Y2cFG1IMLfYa9yYJ3l2Fto_uND74bNywzjdd2DPTpiLzo0Cf7en8fkovPn87np_nix5ev85NFrkugkHelrK0pJWNY0qblwErgSFvZ6Y5zKUtb11KgMag71lUCKsuYMZWsheWmRX5Ijnd1l-jVVXRrjFsV0KnTk4WafJSWrIZaXMPIvtux4_i_NjYNau3SNB32NmySAslEJRs-gs0O1DGkFG33WBmomkRRKzXtXk27V5Mo6kEUdTumvtn_sWnX1jwl7lUYgbd7AJNG30XstUtP3NitaOTEfdxxN87b7X83oL59n08v_g9XzKqa</recordid><startdate>200311</startdate><enddate>200311</enddate><creator>Jodoin, Julie</creator><creator>Demeule, Michel</creator><creator>Fenart, Laurence</creator><creator>Cecchelli, Roméo</creator><creator>Farmer, Sarah</creator><creator>Linton, Kenneth J.</creator><creator>Higgins, Christopher F.</creator><creator>Béliveau, Richard</creator><general>Blackwell Science Ltd</general><general>Blackwell</general><general>Wiley</general><scope>IQODW</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>7TK</scope><scope>1XC</scope><orcidid>https://orcid.org/0000-0001-9285-0579</orcidid></search><sort><creationdate>200311</creationdate><title>P‐glycoprotein in blood–brain barrier endothelial cells: interaction and oligomerization with caveolins</title><author>Jodoin, Julie ; Demeule, Michel ; Fenart, Laurence ; Cecchelli, Roméo ; Farmer, Sarah ; Linton, Kenneth J. ; Higgins, Christopher F. ; Béliveau, Richard</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5101-f597ed5922a508b312513a0b9fcf33995e7794addacf2f6416e22dd6974e3dba3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Animals</topic><topic>Astrocytes - cytology</topic><topic>Astrocytes - metabolism</topic><topic>ATP Binding Cassette Transporter, Subfamily B, Member 1 - genetics</topic><topic>ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism</topic><topic>Binding Sites - genetics</topic><topic>Binding Sites - physiology</topic><topic>Biochemistry, Molecular Biology</topic><topic>Biological and medical sciences</topic><topic>Blood-Brain Barrier - metabolism</topic><topic>blood–brain barrier</topic><topic>brain</topic><topic>Brain - blood supply</topic><topic>Capillaries - cytology</topic><topic>Cattle</topic><topic>caveolae</topic><topic>Caveolae - chemistry</topic><topic>Caveolae - metabolism</topic><topic>caveolin</topic><topic>Caveolin 1</topic><topic>Caveolin 2</topic><topic>Caveolins - metabolism</topic><topic>Cells, Cultured</topic><topic>Cerebral circulation. Blood-brain barrier. Choroid plexus. Cerebrospinal fluid. Circumventricular organ. Meninges</topic><topic>Coculture Techniques</topic><topic>Dogs</topic><topic>endothelial cell</topic><topic>Endothelium, Vascular - cytology</topic><topic>Endothelium, Vascular - metabolism</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Kidney - cytology</topic><topic>Kidney - metabolism</topic><topic>Life Sciences</topic><topic>Macromolecular Substances</topic><topic>Models, Biological</topic><topic>Mutagenesis, Site-Directed</topic><topic>Protein Binding - physiology</topic><topic>Protein Transport - physiology</topic><topic>P‐glycoprotein</topic><topic>Rats</topic><topic>Vertebrates: nervous system and sense organs</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Jodoin, Julie</creatorcontrib><creatorcontrib>Demeule, Michel</creatorcontrib><creatorcontrib>Fenart, Laurence</creatorcontrib><creatorcontrib>Cecchelli, Roméo</creatorcontrib><creatorcontrib>Farmer, Sarah</creatorcontrib><creatorcontrib>Linton, Kenneth J.</creatorcontrib><creatorcontrib>Higgins, Christopher F.</creatorcontrib><creatorcontrib>Béliveau, Richard</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>Hyper Article en Ligne (HAL)</collection><jtitle>Journal of neurochemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Jodoin, Julie</au><au>Demeule, Michel</au><au>Fenart, Laurence</au><au>Cecchelli, Roméo</au><au>Farmer, Sarah</au><au>Linton, Kenneth J.</au><au>Higgins, Christopher F.</au><au>Béliveau, Richard</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>P‐glycoprotein in blood–brain barrier endothelial cells: interaction and oligomerization with caveolins</atitle><jtitle>Journal of neurochemistry</jtitle><addtitle>J Neurochem</addtitle><date>2003-11</date><risdate>2003</risdate><volume>87</volume><issue>4</issue><spage>1010</spage><epage>1023</epage><pages>1010-1023</pages><issn>0022-3042</issn><eissn>1471-4159</eissn><coden>JONRA9</coden><abstract>P‐glycoprotein (P‐gp), an adenosine triphosphate (ATP)‐binding cassette transporter which acts as a drug efflux pump, is highly expressed at the blood–brain barrier (BBB) where it plays an important role in brain protection. Recently, P‐gp has been reported to be located in the caveolae of multidrug‐resistant cells. In this study, we investigated the localization and the activity of P‐gp in the caveolae of endothelial cells of the BBB. We used an in vitro model of the BBB which is formed by co‐culture of bovine brain capillary endothelial cells (BBCEC) with astrocytes. Caveolar microdomains isolated from BBCEC are enriched in P‐gp, cholesterol, caveolin‐1, and caveolin‐2. Moreover, P‐gp interacts with caveolin‐1 and caveolin‐2; together, they form a high molecular mass complex. P‐gp in isolated caveolae is able to bind its substrates, and the caveolae‐disrupting agents filipin III and nystatin decrease P‐gp transport activity. In addition, mutations in the caveolin‐binding motif present in P‐gp reduced the interaction of P‐gp with caveolin‐1 and increased the transport activity of P‐gp. Thus, P‐gp expressed at the BBB is mainly localized in caveolae and its activity may be modulated by interaction with caveolin‐1.</abstract><cop>Oxford, UK</cop><pub>Blackwell Science Ltd</pub><pmid>14622130</pmid><doi>10.1046/j.1471-4159.2003.02081.x</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0001-9285-0579</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Journal of neurochemistry, 2003-11, Vol.87 (4), p.1010-1023 |
| issn | 0022-3042 1471-4159 |
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| subjects | Animals Astrocytes - cytology Astrocytes - metabolism ATP Binding Cassette Transporter, Subfamily B, Member 1 - genetics ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism Binding Sites - genetics Binding Sites - physiology Biochemistry, Molecular Biology Biological and medical sciences Blood-Brain Barrier - metabolism blood–brain barrier brain Brain - blood supply Capillaries - cytology Cattle caveolae Caveolae - chemistry Caveolae - metabolism caveolin Caveolin 1 Caveolin 2 Caveolins - metabolism Cells, Cultured Cerebral circulation. Blood-brain barrier. Choroid plexus. Cerebrospinal fluid. Circumventricular organ. Meninges Coculture Techniques Dogs endothelial cell Endothelium, Vascular - cytology Endothelium, Vascular - metabolism Fundamental and applied biological sciences. Psychology Kidney - cytology Kidney - metabolism Life Sciences Macromolecular Substances Models, Biological Mutagenesis, Site-Directed Protein Binding - physiology Protein Transport - physiology P‐glycoprotein Rats Vertebrates: nervous system and sense organs |
| title | P‐glycoprotein in blood–brain barrier endothelial cells: interaction and oligomerization with caveolins |
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