BQ788 reveals glial ET B receptor modulation of neuronal cholinergic and nitrergic pathways to inhibit intestinal motility: Linked to postoperative ileus
ET-1 signalling modulates intestinal motility and inflammation, but the role of ET-1/ET receptor signalling is poorly understood. Enteric glia modulate normal motility and inflammation. We investigated whether glial ET signalling regulates neural-motor pathways of intestinal motility and inflammatio...
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| Veröffentlicht in: | British journal of pharmacology 2023-10, Vol.180 (19), p.2550-2576 |
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| creator | Mazzotta, Elvio Grants, Iveta Villalobos-Hernandez, Egina Chaudhuri, Samhita McClain, Jonathon L Seguella, Luisa Kendig, Derek M Blakeney, Bryan A Murthy, Srinivasa K Schneider, Reiner Leven, Patrick Wehner, Sven Harzman, Alan Grider, John R Gulbransen, Brian D Christofi, Fedias L |
| description | ET-1 signalling modulates intestinal motility and inflammation, but the role of ET-1/ET
receptor signalling is poorly understood. Enteric glia modulate normal motility and inflammation. We investigated whether glial ET
signalling regulates neural-motor pathways of intestinal motility and inflammation.
We studied ET
signalling using: ET
drugs (ET-1, SaTX, BQ788), activity-dependent stimulation of neurons (high K
-depolarization, EFS), gliotoxins, Tg (Ednrb-EGFP)EP59Gsat/Mmucd mice, cell-specific mRNA in Sox10
;Rpl22-HAflx or ChAT
;Rpl22-HAflx mice, Sox10
::GCaMP5g-tdT, Wnt1
::GCaMP5g-tdT mice, muscle tension recordings, fluid-induced peristalsis, ET-1 expression, qPCR, western blots, 3-D LSM-immunofluorescence co-labelling studies in LMMP-CM and a postoperative ileus (POI) model of intestinal inflammation.
In the muscularis externa ET
receptor is expressed exclusively in glia. ET-1 is expressed in RiboTag (ChAT)-neurons, isolated ganglia and intra-ganglionic varicose-nerve fibres co-labelled with peripherin or SP. ET-1 release provides activity-dependent glial ET
receptor modulation of Ca
waves in neural evoked glial responses. BQ788 reveals amplification of glial and neuronal Ca
responses and excitatory cholinergic contractions, sensitive to L-NAME. Gliotoxins disrupt SaTX-induced glial-Ca
waves and prevent BQ788 amplification of contractions. The ET
receptor is linked to inhibition of contractions and peristalsis. Inflammation causes glial ET
up-regulation, SaTX-hypersensitivity and glial amplification of ET
signalling. In vivo BQ788 (i.p., 1 mg·kg
) attenuates intestinal inflammation in POI.
Enteric glial ET-1/ET
signalling provides dual modulation of neural-motor circuits to inhibit motility. It inhibits excitatory cholinergic and stimulates inhibitory nitrergic motor pathways. Amplification of glial ET
receptors is linked to muscularis externa inflammation and possibly pathogenic mechanisms of POI. |
| doi_str_mv | 10.1111/bph.16145 |
| format | Article |
| fullrecord | <record><control><sourceid>pubmed_cross</sourceid><recordid>TN_cdi_crossref_primary_10_1111_bph_16145</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>37198101</sourcerecordid><originalsourceid>FETCH-LOGICAL-c971-3621a390d3f1decf23f03aeb6638fd69404b5da02e1f33d94bbe9df19ee96a453</originalsourceid><addsrcrecordid>eNo9kMtOwzAQRS0EoqWw4AeQtyxSPHWe7GhVHlIlhNR95MTjxpDGke0U9VP4W1wKzOZqZs48dAm5BjaFEHdV30whhTg5IWOIszRKeA6nZMwYyyKAPB-RC-feGQvNLDknI55BkQODMfmav2V5Ti3uULSOblotWrpc03ko1dh7Y-nWyKEVXpuOGkU7HKzpAlQ3ptUd2o2uqegk7bS3x6wXvvkUe0e9obprdKV9UI_O68Pg1njdar-_pyvdfaA8YL1x3vRow5kdUt3i4C7JmQov4dWvTsj6cblePEer16eXxcMqqosMIp7OQPCCSa5AYq1mXDEusEpTniuZFjGLq0QKNkNQnMsiriospIICsUhFnPAJuT2ura1xzqIqe6u3wu5LYOXB3TK4W_64G9ibI9sP1RblP_lnJ_8Glfp5Cg</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>BQ788 reveals glial ET B receptor modulation of neuronal cholinergic and nitrergic pathways to inhibit intestinal motility: Linked to postoperative ileus</title><source>Wiley-Blackwell Open Access Backfiles</source><source>MEDLINE</source><source>Wiley Online Library</source><source>Alma/SFX Local Collection</source><source>EZB Electronic Journals Library</source><creator>Mazzotta, Elvio ; Grants, Iveta ; Villalobos-Hernandez, Egina ; Chaudhuri, Samhita ; McClain, Jonathon L ; Seguella, Luisa ; Kendig, Derek M ; Blakeney, Bryan A ; Murthy, Srinivasa K ; Schneider, Reiner ; Leven, Patrick ; Wehner, Sven ; Harzman, Alan ; Grider, John R ; Gulbransen, Brian D ; Christofi, Fedias L</creator><creatorcontrib>Mazzotta, Elvio ; Grants, Iveta ; Villalobos-Hernandez, Egina ; Chaudhuri, Samhita ; McClain, Jonathon L ; Seguella, Luisa ; Kendig, Derek M ; Blakeney, Bryan A ; Murthy, Srinivasa K ; Schneider, Reiner ; Leven, Patrick ; Wehner, Sven ; Harzman, Alan ; Grider, John R ; Gulbransen, Brian D ; Christofi, Fedias L</creatorcontrib><description>ET-1 signalling modulates intestinal motility and inflammation, but the role of ET-1/ET
receptor signalling is poorly understood. Enteric glia modulate normal motility and inflammation. We investigated whether glial ET
signalling regulates neural-motor pathways of intestinal motility and inflammation.
We studied ET
signalling using: ET
drugs (ET-1, SaTX, BQ788), activity-dependent stimulation of neurons (high K
-depolarization, EFS), gliotoxins, Tg (Ednrb-EGFP)EP59Gsat/Mmucd mice, cell-specific mRNA in Sox10
;Rpl22-HAflx or ChAT
;Rpl22-HAflx mice, Sox10
::GCaMP5g-tdT, Wnt1
::GCaMP5g-tdT mice, muscle tension recordings, fluid-induced peristalsis, ET-1 expression, qPCR, western blots, 3-D LSM-immunofluorescence co-labelling studies in LMMP-CM and a postoperative ileus (POI) model of intestinal inflammation.
In the muscularis externa ET
receptor is expressed exclusively in glia. ET-1 is expressed in RiboTag (ChAT)-neurons, isolated ganglia and intra-ganglionic varicose-nerve fibres co-labelled with peripherin or SP. ET-1 release provides activity-dependent glial ET
receptor modulation of Ca
waves in neural evoked glial responses. BQ788 reveals amplification of glial and neuronal Ca
responses and excitatory cholinergic contractions, sensitive to L-NAME. Gliotoxins disrupt SaTX-induced glial-Ca
waves and prevent BQ788 amplification of contractions. The ET
receptor is linked to inhibition of contractions and peristalsis. Inflammation causes glial ET
up-regulation, SaTX-hypersensitivity and glial amplification of ET
signalling. In vivo BQ788 (i.p., 1 mg·kg
) attenuates intestinal inflammation in POI.
Enteric glial ET-1/ET
signalling provides dual modulation of neural-motor circuits to inhibit motility. It inhibits excitatory cholinergic and stimulates inhibitory nitrergic motor pathways. Amplification of glial ET
receptors is linked to muscularis externa inflammation and possibly pathogenic mechanisms of POI.</description><identifier>ISSN: 0007-1188</identifier><identifier>EISSN: 1476-5381</identifier><identifier>DOI: 10.1111/bph.16145</identifier><identifier>PMID: 37198101</identifier><language>eng</language><publisher>England</publisher><subject>Animals ; Cholinergic Agents - metabolism ; Gastrointestinal Motility ; Gliotoxin - metabolism ; Ileus - drug therapy ; Ileus - etiology ; Ileus - metabolism ; Inflammation - metabolism ; Mice ; Neuroglia ; Neurons - metabolism</subject><ispartof>British journal of pharmacology, 2023-10, Vol.180 (19), p.2550-2576</ispartof><rights>2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c971-3621a390d3f1decf23f03aeb6638fd69404b5da02e1f33d94bbe9df19ee96a453</citedby><cites>FETCH-LOGICAL-c971-3621a390d3f1decf23f03aeb6638fd69404b5da02e1f33d94bbe9df19ee96a453</cites><orcidid>0000-0003-2773-6846</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27915,27916</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37198101$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mazzotta, Elvio</creatorcontrib><creatorcontrib>Grants, Iveta</creatorcontrib><creatorcontrib>Villalobos-Hernandez, Egina</creatorcontrib><creatorcontrib>Chaudhuri, Samhita</creatorcontrib><creatorcontrib>McClain, Jonathon L</creatorcontrib><creatorcontrib>Seguella, Luisa</creatorcontrib><creatorcontrib>Kendig, Derek M</creatorcontrib><creatorcontrib>Blakeney, Bryan A</creatorcontrib><creatorcontrib>Murthy, Srinivasa K</creatorcontrib><creatorcontrib>Schneider, Reiner</creatorcontrib><creatorcontrib>Leven, Patrick</creatorcontrib><creatorcontrib>Wehner, Sven</creatorcontrib><creatorcontrib>Harzman, Alan</creatorcontrib><creatorcontrib>Grider, John R</creatorcontrib><creatorcontrib>Gulbransen, Brian D</creatorcontrib><creatorcontrib>Christofi, Fedias L</creatorcontrib><title>BQ788 reveals glial ET B receptor modulation of neuronal cholinergic and nitrergic pathways to inhibit intestinal motility: Linked to postoperative ileus</title><title>British journal of pharmacology</title><addtitle>Br J Pharmacol</addtitle><description>ET-1 signalling modulates intestinal motility and inflammation, but the role of ET-1/ET
receptor signalling is poorly understood. Enteric glia modulate normal motility and inflammation. We investigated whether glial ET
signalling regulates neural-motor pathways of intestinal motility and inflammation.
We studied ET
signalling using: ET
drugs (ET-1, SaTX, BQ788), activity-dependent stimulation of neurons (high K
-depolarization, EFS), gliotoxins, Tg (Ednrb-EGFP)EP59Gsat/Mmucd mice, cell-specific mRNA in Sox10
;Rpl22-HAflx or ChAT
;Rpl22-HAflx mice, Sox10
::GCaMP5g-tdT, Wnt1
::GCaMP5g-tdT mice, muscle tension recordings, fluid-induced peristalsis, ET-1 expression, qPCR, western blots, 3-D LSM-immunofluorescence co-labelling studies in LMMP-CM and a postoperative ileus (POI) model of intestinal inflammation.
In the muscularis externa ET
receptor is expressed exclusively in glia. ET-1 is expressed in RiboTag (ChAT)-neurons, isolated ganglia and intra-ganglionic varicose-nerve fibres co-labelled with peripherin or SP. ET-1 release provides activity-dependent glial ET
receptor modulation of Ca
waves in neural evoked glial responses. BQ788 reveals amplification of glial and neuronal Ca
responses and excitatory cholinergic contractions, sensitive to L-NAME. Gliotoxins disrupt SaTX-induced glial-Ca
waves and prevent BQ788 amplification of contractions. The ET
receptor is linked to inhibition of contractions and peristalsis. Inflammation causes glial ET
up-regulation, SaTX-hypersensitivity and glial amplification of ET
signalling. In vivo BQ788 (i.p., 1 mg·kg
) attenuates intestinal inflammation in POI.
Enteric glial ET-1/ET
signalling provides dual modulation of neural-motor circuits to inhibit motility. It inhibits excitatory cholinergic and stimulates inhibitory nitrergic motor pathways. Amplification of glial ET
receptors is linked to muscularis externa inflammation and possibly pathogenic mechanisms of POI.</description><subject>Animals</subject><subject>Cholinergic Agents - metabolism</subject><subject>Gastrointestinal Motility</subject><subject>Gliotoxin - metabolism</subject><subject>Ileus - drug therapy</subject><subject>Ileus - etiology</subject><subject>Ileus - metabolism</subject><subject>Inflammation - metabolism</subject><subject>Mice</subject><subject>Neuroglia</subject><subject>Neurons - metabolism</subject><issn>0007-1188</issn><issn>1476-5381</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kMtOwzAQRS0EoqWw4AeQtyxSPHWe7GhVHlIlhNR95MTjxpDGke0U9VP4W1wKzOZqZs48dAm5BjaFEHdV30whhTg5IWOIszRKeA6nZMwYyyKAPB-RC-feGQvNLDknI55BkQODMfmav2V5Ti3uULSOblotWrpc03ko1dh7Y-nWyKEVXpuOGkU7HKzpAlQ3ptUd2o2uqegk7bS3x6wXvvkUe0e9obprdKV9UI_O68Pg1njdar-_pyvdfaA8YL1x3vRow5kdUt3i4C7JmQov4dWvTsj6cblePEer16eXxcMqqosMIp7OQPCCSa5AYq1mXDEusEpTniuZFjGLq0QKNkNQnMsiriospIICsUhFnPAJuT2ura1xzqIqe6u3wu5LYOXB3TK4W_64G9ibI9sP1RblP_lnJ_8Glfp5Cg</recordid><startdate>202310</startdate><enddate>202310</enddate><creator>Mazzotta, Elvio</creator><creator>Grants, Iveta</creator><creator>Villalobos-Hernandez, Egina</creator><creator>Chaudhuri, Samhita</creator><creator>McClain, Jonathon L</creator><creator>Seguella, Luisa</creator><creator>Kendig, Derek M</creator><creator>Blakeney, Bryan A</creator><creator>Murthy, Srinivasa K</creator><creator>Schneider, Reiner</creator><creator>Leven, Patrick</creator><creator>Wehner, Sven</creator><creator>Harzman, Alan</creator><creator>Grider, John R</creator><creator>Gulbransen, Brian D</creator><creator>Christofi, Fedias L</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><orcidid>https://orcid.org/0000-0003-2773-6846</orcidid></search><sort><creationdate>202310</creationdate><title>BQ788 reveals glial ET B receptor modulation of neuronal cholinergic and nitrergic pathways to inhibit intestinal motility: Linked to postoperative ileus</title><author>Mazzotta, Elvio ; Grants, Iveta ; Villalobos-Hernandez, Egina ; Chaudhuri, Samhita ; McClain, Jonathon L ; Seguella, Luisa ; Kendig, Derek M ; Blakeney, Bryan A ; Murthy, Srinivasa K ; Schneider, Reiner ; Leven, Patrick ; Wehner, Sven ; Harzman, Alan ; Grider, John R ; Gulbransen, Brian D ; Christofi, Fedias L</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c971-3621a390d3f1decf23f03aeb6638fd69404b5da02e1f33d94bbe9df19ee96a453</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Animals</topic><topic>Cholinergic Agents - metabolism</topic><topic>Gastrointestinal Motility</topic><topic>Gliotoxin - metabolism</topic><topic>Ileus - drug therapy</topic><topic>Ileus - etiology</topic><topic>Ileus - metabolism</topic><topic>Inflammation - metabolism</topic><topic>Mice</topic><topic>Neuroglia</topic><topic>Neurons - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mazzotta, Elvio</creatorcontrib><creatorcontrib>Grants, Iveta</creatorcontrib><creatorcontrib>Villalobos-Hernandez, Egina</creatorcontrib><creatorcontrib>Chaudhuri, Samhita</creatorcontrib><creatorcontrib>McClain, Jonathon L</creatorcontrib><creatorcontrib>Seguella, Luisa</creatorcontrib><creatorcontrib>Kendig, Derek M</creatorcontrib><creatorcontrib>Blakeney, Bryan A</creatorcontrib><creatorcontrib>Murthy, Srinivasa K</creatorcontrib><creatorcontrib>Schneider, Reiner</creatorcontrib><creatorcontrib>Leven, Patrick</creatorcontrib><creatorcontrib>Wehner, Sven</creatorcontrib><creatorcontrib>Harzman, Alan</creatorcontrib><creatorcontrib>Grider, John R</creatorcontrib><creatorcontrib>Gulbransen, Brian D</creatorcontrib><creatorcontrib>Christofi, Fedias L</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>British journal of pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mazzotta, Elvio</au><au>Grants, Iveta</au><au>Villalobos-Hernandez, Egina</au><au>Chaudhuri, Samhita</au><au>McClain, Jonathon L</au><au>Seguella, Luisa</au><au>Kendig, Derek M</au><au>Blakeney, Bryan A</au><au>Murthy, Srinivasa K</au><au>Schneider, Reiner</au><au>Leven, Patrick</au><au>Wehner, Sven</au><au>Harzman, Alan</au><au>Grider, John R</au><au>Gulbransen, Brian D</au><au>Christofi, Fedias L</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>BQ788 reveals glial ET B receptor modulation of neuronal cholinergic and nitrergic pathways to inhibit intestinal motility: Linked to postoperative ileus</atitle><jtitle>British journal of pharmacology</jtitle><addtitle>Br J Pharmacol</addtitle><date>2023-10</date><risdate>2023</risdate><volume>180</volume><issue>19</issue><spage>2550</spage><epage>2576</epage><pages>2550-2576</pages><issn>0007-1188</issn><eissn>1476-5381</eissn><abstract>ET-1 signalling modulates intestinal motility and inflammation, but the role of ET-1/ET
receptor signalling is poorly understood. Enteric glia modulate normal motility and inflammation. We investigated whether glial ET
signalling regulates neural-motor pathways of intestinal motility and inflammation.
We studied ET
signalling using: ET
drugs (ET-1, SaTX, BQ788), activity-dependent stimulation of neurons (high K
-depolarization, EFS), gliotoxins, Tg (Ednrb-EGFP)EP59Gsat/Mmucd mice, cell-specific mRNA in Sox10
;Rpl22-HAflx or ChAT
;Rpl22-HAflx mice, Sox10
::GCaMP5g-tdT, Wnt1
::GCaMP5g-tdT mice, muscle tension recordings, fluid-induced peristalsis, ET-1 expression, qPCR, western blots, 3-D LSM-immunofluorescence co-labelling studies in LMMP-CM and a postoperative ileus (POI) model of intestinal inflammation.
In the muscularis externa ET
receptor is expressed exclusively in glia. ET-1 is expressed in RiboTag (ChAT)-neurons, isolated ganglia and intra-ganglionic varicose-nerve fibres co-labelled with peripherin or SP. ET-1 release provides activity-dependent glial ET
receptor modulation of Ca
waves in neural evoked glial responses. BQ788 reveals amplification of glial and neuronal Ca
responses and excitatory cholinergic contractions, sensitive to L-NAME. Gliotoxins disrupt SaTX-induced glial-Ca
waves and prevent BQ788 amplification of contractions. The ET
receptor is linked to inhibition of contractions and peristalsis. Inflammation causes glial ET
up-regulation, SaTX-hypersensitivity and glial amplification of ET
signalling. In vivo BQ788 (i.p., 1 mg·kg
) attenuates intestinal inflammation in POI.
Enteric glial ET-1/ET
signalling provides dual modulation of neural-motor circuits to inhibit motility. It inhibits excitatory cholinergic and stimulates inhibitory nitrergic motor pathways. Amplification of glial ET
receptors is linked to muscularis externa inflammation and possibly pathogenic mechanisms of POI.</abstract><cop>England</cop><pmid>37198101</pmid><doi>10.1111/bph.16145</doi><tpages>27</tpages><orcidid>https://orcid.org/0000-0003-2773-6846</orcidid></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0007-1188 |
| ispartof | British journal of pharmacology, 2023-10, Vol.180 (19), p.2550-2576 |
| issn | 0007-1188 1476-5381 |
| language | eng |
| recordid | cdi_crossref_primary_10_1111_bph_16145 |
| source | Wiley-Blackwell Open Access Backfiles; MEDLINE; Wiley Online Library; Alma/SFX Local Collection; EZB Electronic Journals Library |
| subjects | Animals Cholinergic Agents - metabolism Gastrointestinal Motility Gliotoxin - metabolism Ileus - drug therapy Ileus - etiology Ileus - metabolism Inflammation - metabolism Mice Neuroglia Neurons - metabolism |
| title | BQ788 reveals glial ET B receptor modulation of neuronal cholinergic and nitrergic pathways to inhibit intestinal motility: Linked to postoperative ileus |
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