Exchange factors directly activated by cAMP mediate melanocortin 4 receptor-induced gene expression
G s protein-coupled receptors regulate many vital body functions by activation of cAMP response elements (CRE) via cAMP-dependent kinase A (PKA)-mediated phosphorylation of the CRE binding protein (CREB). Melanocortin 4 receptors (MC4R) are prototypical G s -coupled receptors that orchestrate the hy...
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| Veröffentlicht in: | Scientific reports 2016-09, Vol.6 (1), p.32776-32776, Article 32776 |
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| creator | Glas, Evi Mückter, Harald Gudermann, Thomas Breit, Andreas |
| description | G
s
protein-coupled receptors regulate many vital body functions by activation of cAMP response elements (CRE) via cAMP-dependent kinase A (PKA)-mediated phosphorylation of the CRE binding protein (CREB). Melanocortin 4 receptors (MC4R) are prototypical G
s
-coupled receptors that orchestrate the hypothalamic control of food-intake and metabolism. Remarkably, the significance of PKA for MC4R-induced CRE-dependent transcription in hypothalamic cells has not been rigorously interrogated yet. In two hypothalamic cell lines, we observed that blocking PKA activity had only weak or no effects on reporter gene expression. In contrast, inhibitors of exchange factors directly activated by cAMP-1/2 (EPAC-1/2) mitigated MC4R-induced CRE reporter activation and mRNA induction of the CREB-dependent genes c-fos and thyrotropin-releasing hormone. Furthermore, we provide first evidence that extracellular-regulated kinases-1/2 (ERK-1/2) activated by EPACs and not PKA are the elusive CREB kinases responsible for MC4R-induced CREB/CRE activation in hypothalamic cells. Overall, these data emphasize the pivotal role of EPACs rather than PKA in hypothalamic gene expression elicited by a prototypical G
s
-coupled receptor. |
| doi_str_mv | 10.1038/srep32776 |
| format | Article |
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s
-coupled receptors that orchestrate the hypothalamic control of food-intake and metabolism. Remarkably, the significance of PKA for MC4R-induced CRE-dependent transcription in hypothalamic cells has not been rigorously interrogated yet. In two hypothalamic cell lines, we observed that blocking PKA activity had only weak or no effects on reporter gene expression. In contrast, inhibitors of exchange factors directly activated by cAMP-1/2 (EPAC-1/2) mitigated MC4R-induced CRE reporter activation and mRNA induction of the CREB-dependent genes c-fos and thyrotropin-releasing hormone. Furthermore, we provide first evidence that extracellular-regulated kinases-1/2 (ERK-1/2) activated by EPACs and not PKA are the elusive CREB kinases responsible for MC4R-induced CREB/CRE activation in hypothalamic cells. Overall, these data emphasize the pivotal role of EPACs rather than PKA in hypothalamic gene expression elicited by a prototypical G
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-coupled receptor.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/srep32776</identifier><identifier>PMID: 27612207</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/80/86/2363 ; 692/163/2743/393 ; 96 ; 96/95 ; c-Fos protein ; Cell lines ; Cyclic AMP response element-binding protein ; Extracellular signal-regulated kinase ; Food intake ; Gene expression ; Guanine nucleotide-binding protein ; Humanities and Social Sciences ; Hypothalamus ; Kinases ; Melanocortin ; Melanocortin MC4 receptors ; multidisciplinary ; Phosphorylation ; Protein kinase A ; Regulatory sequences ; Reporter gene ; Science ; Thyroid-stimulating hormone ; Thyrotropin-releasing hormone ; Transcription</subject><ispartof>Scientific reports, 2016-09, Vol.6 (1), p.32776-32776, Article 32776</ispartof><rights>The Author(s) 2016</rights><rights>Copyright Nature Publishing Group Sep 2016</rights><rights>Copyright © 2016, The Author(s) 2016 The Author(s)</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c504t-5f224e96bdccf2a02ef28613a9dbf9e901edf805b1dea398f3f451284070ed153</citedby><cites>FETCH-LOGICAL-c504t-5f224e96bdccf2a02ef28613a9dbf9e901edf805b1dea398f3f451284070ed153</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/PMC5017209/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5017209/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27901,27902,41096,42165,51551,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27612207$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Glas, Evi</creatorcontrib><creatorcontrib>Mückter, Harald</creatorcontrib><creatorcontrib>Gudermann, Thomas</creatorcontrib><creatorcontrib>Breit, Andreas</creatorcontrib><title>Exchange factors directly activated by cAMP mediate melanocortin 4 receptor-induced gene expression</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>G
s
protein-coupled receptors regulate many vital body functions by activation of cAMP response elements (CRE) via cAMP-dependent kinase A (PKA)-mediated phosphorylation of the CRE binding protein (CREB). Melanocortin 4 receptors (MC4R) are prototypical G
s
-coupled receptors that orchestrate the hypothalamic control of food-intake and metabolism. Remarkably, the significance of PKA for MC4R-induced CRE-dependent transcription in hypothalamic cells has not been rigorously interrogated yet. In two hypothalamic cell lines, we observed that blocking PKA activity had only weak or no effects on reporter gene expression. In contrast, inhibitors of exchange factors directly activated by cAMP-1/2 (EPAC-1/2) mitigated MC4R-induced CRE reporter activation and mRNA induction of the CREB-dependent genes c-fos and thyrotropin-releasing hormone. Furthermore, we provide first evidence that extracellular-regulated kinases-1/2 (ERK-1/2) activated by EPACs and not PKA are the elusive CREB kinases responsible for MC4R-induced CREB/CRE activation in hypothalamic cells. Overall, these data emphasize the pivotal role of EPACs rather than PKA in hypothalamic gene expression elicited by a prototypical G
s
-coupled receptor.</description><subject>631/80/86/2363</subject><subject>692/163/2743/393</subject><subject>96</subject><subject>96/95</subject><subject>c-Fos protein</subject><subject>Cell lines</subject><subject>Cyclic AMP response element-binding protein</subject><subject>Extracellular signal-regulated kinase</subject><subject>Food intake</subject><subject>Gene expression</subject><subject>Guanine nucleotide-binding protein</subject><subject>Humanities and Social Sciences</subject><subject>Hypothalamus</subject><subject>Kinases</subject><subject>Melanocortin</subject><subject>Melanocortin MC4 receptors</subject><subject>multidisciplinary</subject><subject>Phosphorylation</subject><subject>Protein kinase A</subject><subject>Regulatory sequences</subject><subject>Reporter gene</subject><subject>Science</subject><subject>Thyroid-stimulating hormone</subject><subject>Thyrotropin-releasing hormone</subject><subject>Transcription</subject><issn>2045-2322</issn><issn>2045-2322</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>BENPR</sourceid><recordid>eNplkV1PHSEQhklTU431wj9gSLypTbYC-8lNE2O0mmjsRb0mLAxHzB7Ywq7x_HvHHD05rdwMMM-8zPAScsjZD87K7jQnGEvRts0nsidYVReiFOLz1n6XHOT8yHDVQlZcfiG7om24EKzdI-bi2TzosADqtJliytT6BGYaVhTP_klPYGm_oubs9jddgvV4gXHQIZqYJh9oRZGHEWsLH-xskF9AAArPY4KcfQxfyY7TQ4aDt7hP7i8v_pxfFTd3v67Pz24KU7NqKmonRAWy6a0xTmgmwImu4aWWtncSJONgXcfqnlvQpexc6aqai65iLQPL63Kf_FzrjnOPrRoIU9KDGpNf6rRSUXv1byb4B7WIT6pmvBVMosC3N4EU_86QJ7X02cCA00Kcs-Idl_hvsnxFj_9DH-OcAo6HlJSsEazpkDpZUybFjEa5TTOcqVf31MY9ZI-2u9-Q714h8H0NZEyhY2nryQ9qL7k6pT4</recordid><startdate>20160909</startdate><enddate>20160909</enddate><creator>Glas, Evi</creator><creator>Mückter, Harald</creator><creator>Gudermann, Thomas</creator><creator>Breit, Andreas</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88I</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20160909</creationdate><title>Exchange factors directly activated by cAMP mediate melanocortin 4 receptor-induced gene expression</title><author>Glas, Evi ; Mückter, Harald ; Gudermann, Thomas ; Breit, Andreas</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c504t-5f224e96bdccf2a02ef28613a9dbf9e901edf805b1dea398f3f451284070ed153</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>631/80/86/2363</topic><topic>692/163/2743/393</topic><topic>96</topic><topic>96/95</topic><topic>c-Fos protein</topic><topic>Cell lines</topic><topic>Cyclic AMP response element-binding protein</topic><topic>Extracellular signal-regulated kinase</topic><topic>Food intake</topic><topic>Gene expression</topic><topic>Guanine nucleotide-binding protein</topic><topic>Humanities and Social Sciences</topic><topic>Hypothalamus</topic><topic>Kinases</topic><topic>Melanocortin</topic><topic>Melanocortin MC4 receptors</topic><topic>multidisciplinary</topic><topic>Phosphorylation</topic><topic>Protein kinase A</topic><topic>Regulatory sequences</topic><topic>Reporter gene</topic><topic>Science</topic><topic>Thyroid-stimulating hormone</topic><topic>Thyrotropin-releasing hormone</topic><topic>Transcription</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Glas, Evi</creatorcontrib><creatorcontrib>Mückter, Harald</creatorcontrib><creatorcontrib>Gudermann, Thomas</creatorcontrib><creatorcontrib>Breit, Andreas</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest SciTech 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>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Science Database</collection><collection>Biological Science Database</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>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Scientific reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Glas, Evi</au><au>Mückter, Harald</au><au>Gudermann, Thomas</au><au>Breit, Andreas</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Exchange factors directly activated by cAMP mediate melanocortin 4 receptor-induced gene expression</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2016-09-09</date><risdate>2016</risdate><volume>6</volume><issue>1</issue><spage>32776</spage><epage>32776</epage><pages>32776-32776</pages><artnum>32776</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><abstract>G
s
protein-coupled receptors regulate many vital body functions by activation of cAMP response elements (CRE) via cAMP-dependent kinase A (PKA)-mediated phosphorylation of the CRE binding protein (CREB). Melanocortin 4 receptors (MC4R) are prototypical G
s
-coupled receptors that orchestrate the hypothalamic control of food-intake and metabolism. Remarkably, the significance of PKA for MC4R-induced CRE-dependent transcription in hypothalamic cells has not been rigorously interrogated yet. In two hypothalamic cell lines, we observed that blocking PKA activity had only weak or no effects on reporter gene expression. In contrast, inhibitors of exchange factors directly activated by cAMP-1/2 (EPAC-1/2) mitigated MC4R-induced CRE reporter activation and mRNA induction of the CREB-dependent genes c-fos and thyrotropin-releasing hormone. Furthermore, we provide first evidence that extracellular-regulated kinases-1/2 (ERK-1/2) activated by EPACs and not PKA are the elusive CREB kinases responsible for MC4R-induced CREB/CRE activation in hypothalamic cells. Overall, these data emphasize the pivotal role of EPACs rather than PKA in hypothalamic gene expression elicited by a prototypical G
s
-coupled receptor.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>27612207</pmid><doi>10.1038/srep32776</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 631/80/86/2363 692/163/2743/393 96 96/95 c-Fos protein Cell lines Cyclic AMP response element-binding protein Extracellular signal-regulated kinase Food intake Gene expression Guanine nucleotide-binding protein Humanities and Social Sciences Hypothalamus Kinases Melanocortin Melanocortin MC4 receptors multidisciplinary Phosphorylation Protein kinase A Regulatory sequences Reporter gene Science Thyroid-stimulating hormone Thyrotropin-releasing hormone Transcription |
| title | Exchange factors directly activated by cAMP mediate melanocortin 4 receptor-induced gene expression |
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