Mechanisms of Intestinal Serotonin Transporter (SERT) Upregulation by TGF-β1 Induced Non-Smad Pathways
TGF-β1 is an important multifunctional cytokine with numerous protective effects on intestinal mucosa. The influence of TGF-β1 on serotonin transporter (SERT) activity, the critical mechanism regulating the extracellular availability of serotonin (5-HT), is not known. Current studies were designed t...
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| creator | Nazir, Saad Kumar, Anoop Chatterjee, Ishita Anbazhagan, Arivarasu N Gujral, Tarunmeet Priyamvada, Shubha Saksena, Seema Alrefai, Waddah A Dudeja, Pradeep K Gill, Ravinder K |
| description | TGF-β1 is an important multifunctional cytokine with numerous protective effects on intestinal mucosa. The influence of TGF-β1 on serotonin transporter (SERT) activity, the critical mechanism regulating the extracellular availability of serotonin (5-HT), is not known. Current studies were designed to examine acute effects of TGF-β1 on SERT. Model human intestinal Caco-2 cells grown as monolayer's or as cysts in 3D culture and ex vivo mouse model were utilized. Treatment of Caco-2 cells with TGF-β1 (10 ng/ml, 60 min) stimulated SERT activity (~2 fold, P |
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The influence of TGF-β1 on serotonin transporter (SERT) activity, the critical mechanism regulating the extracellular availability of serotonin (5-HT), is not known. Current studies were designed to examine acute effects of TGF-β1 on SERT. Model human intestinal Caco-2 cells grown as monolayer's or as cysts in 3D culture and ex vivo mouse model were utilized. Treatment of Caco-2 cells with TGF-β1 (10 ng/ml, 60 min) stimulated SERT activity (~2 fold, P<0.005). This stimulation of SERT function was dependent upon activation of TGF-β1 receptor (TGFRI) as SB-431542, a specific TGF-βRI inhibitor blocked the SERT stimulation. SERT activation in response to TGF-β1 was attenuated by inhibition of PI3K and occurred via enhanced recruitment of SERT-GFP to apical surface in a PI3K dependent manner. The exocytosis inhibitor brefeldin A (2.5 μM) attenuated the TGF-β1-mediated increase in SERT function. TGF-β1 increased the association of SERT with the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) syntaxin 3 (STX3) and promoted exocytosis of SERT. Caco-2 cells grown as cysts in 3D culture recapitulated the effects of TGF-β1 showing increased luminal staining of SERT. Ussing chamber studies revealed increase in 3H-5-HT uptake in mouse ileum treated ex vivo with TGF-β1 (10 ng/ml, 1h). These data demonstrate a novel mechanism rapidly regulating intestinal SERT via PI3K and STX3. Since decreased SERT is implicated in various gastro-intestinal disorders e.g IBD, IBS and diarrhea, understanding mechanisms stimulating SERT function by TGF-β1 offers a novel therapeutic strategy to treat GI disorders.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0120447</identifier><identifier>PMID: 25954931</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>1-Phosphatidylinositol 3-kinase ; Activation ; Acute effects ; Animals ; Brefeldin A ; Caco-2 Cells ; Cell culture ; Cysts ; Diarrhea ; Disorders ; Epidermal growth factor ; Exocytosis ; Gastroenterology ; Hepatology ; Humans ; Ileum ; Inflammation ; Inflammatory bowel disease ; Inhibitors ; Intestinal Mucosa - metabolism ; Intestine ; Kinases ; Medicine ; Mice, Inbred C57BL ; Mucosa ; N-Ethylmaleimide-sensitive protein ; Phosphatidylinositol 3-Kinases - metabolism ; Physiology ; Protein Interaction Maps ; Protein Transport ; Proteins ; Qa-SNARE Proteins - metabolism ; Receptors, Transforming Growth Factor beta - metabolism ; Rodents ; Serotonin ; Serotonin - metabolism ; Serotonin Plasma Membrane Transport Proteins - genetics ; Serotonin Plasma Membrane Transport Proteins - metabolism ; Serotonin transporter ; Signal Transduction ; Smad protein ; SNAP receptors ; Stimulation ; Studies ; Syntaxin ; Three dimensional models ; Transfection ; Transforming Growth Factor beta1 - metabolism ; Transforming growth factor-b1 ; Up-Regulation</subject><ispartof>PloS one, 2015-05, Vol.10 (5), p.e0120447-e0120447</ispartof><rights>This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication: https://creativecommons.org/publicdomain/zero/1.0/ (the “License”) 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-c5077-516eb14332034a97f0d3a7efafb378e25a5c1f8460587ce71eb63460d370ecee3</citedby><cites>FETCH-LOGICAL-c5077-516eb14332034a97f0d3a7efafb378e25a5c1f8460587ce71eb63460d370ecee3</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/PMC4425666/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4425666/$$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/25954931$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Dahiya, Rajvir</contributor><creatorcontrib>Nazir, Saad</creatorcontrib><creatorcontrib>Kumar, Anoop</creatorcontrib><creatorcontrib>Chatterjee, Ishita</creatorcontrib><creatorcontrib>Anbazhagan, Arivarasu N</creatorcontrib><creatorcontrib>Gujral, Tarunmeet</creatorcontrib><creatorcontrib>Priyamvada, Shubha</creatorcontrib><creatorcontrib>Saksena, Seema</creatorcontrib><creatorcontrib>Alrefai, Waddah A</creatorcontrib><creatorcontrib>Dudeja, Pradeep K</creatorcontrib><creatorcontrib>Gill, Ravinder K</creatorcontrib><title>Mechanisms of Intestinal Serotonin Transporter (SERT) Upregulation by TGF-β1 Induced Non-Smad Pathways</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>TGF-β1 is an important multifunctional cytokine with numerous protective effects on intestinal mucosa. The influence of TGF-β1 on serotonin transporter (SERT) activity, the critical mechanism regulating the extracellular availability of serotonin (5-HT), is not known. Current studies were designed to examine acute effects of TGF-β1 on SERT. Model human intestinal Caco-2 cells grown as monolayer's or as cysts in 3D culture and ex vivo mouse model were utilized. Treatment of Caco-2 cells with TGF-β1 (10 ng/ml, 60 min) stimulated SERT activity (~2 fold, P<0.005). This stimulation of SERT function was dependent upon activation of TGF-β1 receptor (TGFRI) as SB-431542, a specific TGF-βRI inhibitor blocked the SERT stimulation. SERT activation in response to TGF-β1 was attenuated by inhibition of PI3K and occurred via enhanced recruitment of SERT-GFP to apical surface in a PI3K dependent manner. The exocytosis inhibitor brefeldin A (2.5 μM) attenuated the TGF-β1-mediated increase in SERT function. TGF-β1 increased the association of SERT with the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) syntaxin 3 (STX3) and promoted exocytosis of SERT. Caco-2 cells grown as cysts in 3D culture recapitulated the effects of TGF-β1 showing increased luminal staining of SERT. Ussing chamber studies revealed increase in 3H-5-HT uptake in mouse ileum treated ex vivo with TGF-β1 (10 ng/ml, 1h). These data demonstrate a novel mechanism rapidly regulating intestinal SERT via PI3K and STX3. Since decreased SERT is implicated in various gastro-intestinal disorders e.g IBD, IBS and diarrhea, understanding mechanisms stimulating SERT function by TGF-β1 offers a novel therapeutic strategy to treat GI disorders.</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>Activation</subject><subject>Acute effects</subject><subject>Animals</subject><subject>Brefeldin A</subject><subject>Caco-2 Cells</subject><subject>Cell culture</subject><subject>Cysts</subject><subject>Diarrhea</subject><subject>Disorders</subject><subject>Epidermal growth factor</subject><subject>Exocytosis</subject><subject>Gastroenterology</subject><subject>Hepatology</subject><subject>Humans</subject><subject>Ileum</subject><subject>Inflammation</subject><subject>Inflammatory bowel disease</subject><subject>Inhibitors</subject><subject>Intestinal Mucosa - metabolism</subject><subject>Intestine</subject><subject>Kinases</subject><subject>Medicine</subject><subject>Mice, Inbred C57BL</subject><subject>Mucosa</subject><subject>N-Ethylmaleimide-sensitive protein</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Physiology</subject><subject>Protein Interaction Maps</subject><subject>Protein Transport</subject><subject>Proteins</subject><subject>Qa-SNARE Proteins - metabolism</subject><subject>Receptors, Transforming Growth Factor beta - metabolism</subject><subject>Rodents</subject><subject>Serotonin</subject><subject>Serotonin - metabolism</subject><subject>Serotonin Plasma Membrane Transport Proteins - genetics</subject><subject>Serotonin Plasma Membrane Transport Proteins - metabolism</subject><subject>Serotonin transporter</subject><subject>Signal Transduction</subject><subject>Smad protein</subject><subject>SNAP receptors</subject><subject>Stimulation</subject><subject>Studies</subject><subject>Syntaxin</subject><subject>Three dimensional models</subject><subject>Transfection</subject><subject>Transforming Growth Factor beta1 - 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Rajvir</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mechanisms of Intestinal Serotonin Transporter (SERT) Upregulation by TGF-β1 Induced Non-Smad Pathways</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2015-05-08</date><risdate>2015</risdate><volume>10</volume><issue>5</issue><spage>e0120447</spage><epage>e0120447</epage><pages>e0120447-e0120447</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>TGF-β1 is an important multifunctional cytokine with numerous protective effects on intestinal mucosa. The influence of TGF-β1 on serotonin transporter (SERT) activity, the critical mechanism regulating the extracellular availability of serotonin (5-HT), is not known. Current studies were designed to examine acute effects of TGF-β1 on SERT. Model human intestinal Caco-2 cells grown as monolayer's or as cysts in 3D culture and ex vivo mouse model were utilized. Treatment of Caco-2 cells with TGF-β1 (10 ng/ml, 60 min) stimulated SERT activity (~2 fold, P<0.005). This stimulation of SERT function was dependent upon activation of TGF-β1 receptor (TGFRI) as SB-431542, a specific TGF-βRI inhibitor blocked the SERT stimulation. SERT activation in response to TGF-β1 was attenuated by inhibition of PI3K and occurred via enhanced recruitment of SERT-GFP to apical surface in a PI3K dependent manner. The exocytosis inhibitor brefeldin A (2.5 μM) attenuated the TGF-β1-mediated increase in SERT function. TGF-β1 increased the association of SERT with the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) syntaxin 3 (STX3) and promoted exocytosis of SERT. Caco-2 cells grown as cysts in 3D culture recapitulated the effects of TGF-β1 showing increased luminal staining of SERT. Ussing chamber studies revealed increase in 3H-5-HT uptake in mouse ileum treated ex vivo with TGF-β1 (10 ng/ml, 1h). These data demonstrate a novel mechanism rapidly regulating intestinal SERT via PI3K and STX3. Since decreased SERT is implicated in various gastro-intestinal disorders e.g IBD, IBS and diarrhea, understanding mechanisms stimulating SERT function by TGF-β1 offers a novel therapeutic strategy to treat GI disorders.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25954931</pmid><doi>10.1371/journal.pone.0120447</doi><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_plos_journals_1982585145 |
| 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 | 1-Phosphatidylinositol 3-kinase Activation Acute effects Animals Brefeldin A Caco-2 Cells Cell culture Cysts Diarrhea Disorders Epidermal growth factor Exocytosis Gastroenterology Hepatology Humans Ileum Inflammation Inflammatory bowel disease Inhibitors Intestinal Mucosa - metabolism Intestine Kinases Medicine Mice, Inbred C57BL Mucosa N-Ethylmaleimide-sensitive protein Phosphatidylinositol 3-Kinases - metabolism Physiology Protein Interaction Maps Protein Transport Proteins Qa-SNARE Proteins - metabolism Receptors, Transforming Growth Factor beta - metabolism Rodents Serotonin Serotonin - metabolism Serotonin Plasma Membrane Transport Proteins - genetics Serotonin Plasma Membrane Transport Proteins - metabolism Serotonin transporter Signal Transduction Smad protein SNAP receptors Stimulation Studies Syntaxin Three dimensional models Transfection Transforming Growth Factor beta1 - metabolism Transforming growth factor-b1 Up-Regulation |
| title | Mechanisms of Intestinal Serotonin Transporter (SERT) Upregulation by TGF-β1 Induced Non-Smad Pathways |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-29T05%3A13%3A12IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Mechanisms%20of%20Intestinal%20Serotonin%20Transporter%20(SERT)%20Upregulation%20by%20TGF-%CE%B21%20Induced%20Non-Smad%20Pathways&rft.jtitle=PloS%20one&rft.au=Nazir,%20Saad&rft.date=2015-05-08&rft.volume=10&rft.issue=5&rft.spage=e0120447&rft.epage=e0120447&rft.pages=e0120447-e0120447&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0120447&rft_dat=%3Cproquest_plos_%3E1680211611%3C/proquest_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1982585145&rft_id=info:pmid/25954931&rft_doaj_id=oai_doaj_org_article_12782c60cbba4f8a833f48afd21e1251&rfr_iscdi=true |