PI 3-kinase- and ERK-MAPK-dependent mechanisms underlie Glucagon-Like Peptide-1-mediated activation of Sprague Dawley colonic myenteric neurons

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dc.check.date2020-05-23
dc.check.infoAccess to this article is restricted until 12 months after publication by request of the publisher.en
dc.contributor.authorO'Brien, Rebecca L.
dc.contributor.authorBuckley, Maria M.
dc.contributor.authorKelliher, Amy
dc.contributor.authorO'Malley, Dervla
dc.contributor.funderUniversity College Corken
dc.contributor.funderCollege of Medicine and Health, University College Cork
dc.date.accessioned2019-06-11T08:35:55Z
dc.date.available2019-06-11T08:35:55Z
dc.date.issued2019-05-23
dc.date.updated2019-06-11T08:27:06Z
dc.description.abstractBackground: Glucagon-like peptide (GLP-1) can modify colonic function, with beneficial effects reported in the functional bowel disorder, irritable bowel syndrome (IBS). IBS pathophysiology is characterized by hyper-activation of the hypothalamic-pituitary-adrenal stress axis and altered microbial profiles. This study aims to characterize the neuronal and functional effects of GLP-1 in healthy rat colons to aid understanding of its beneficial effects in moderating bowel dysfunction. Methods: Immunofluorescent and calcium imaging of myenteric neurons prepared from Sprague Dawley rat colons was carried out to elucidate the neuromodulatory actions of the GLP-1 receptor agonist, exendin-4 (Ex-4). Colonic contractile activity was assessed using organ bath physiological recordings. Key results: Ex-4 induced an elevation of intracellular calcium arising from store release and influx via voltage-gated calcium channels. Ex-4 activated both ERK-MAPK and PI 3-kinase signaling cascades. Neuronal activation was found to underlie suppression of contractile activity in colonic circular muscle. Although the stress hormone, corticotropin-releasing factor (CRF) potentiated the neuronal response to Ex-4, and the functional effects of Ex-4 on colonic circular muscle activity were not altered. Conclusions and inferences: Ex-4 evoked neurally regulated suppression of rat colonic circular muscle activity. In myenteric neurons, the neurostimulatory effects of Ex-4 were dependent upon activation of PI 3-kinase and ERK-MAPK signaling cascades. No further change in circular muscle function was noted in the presence of CRF suggesting that stress does not impact on colonic function in health. Further studies in a model of IBS are needed to determine whether mechanisms are modified in the context of bowel dysfunction.en
dc.description.sponsorshipUniversity College Cork (School of Medicine Translational Research Access Programme (TRAP) funding 2012)en
dc.description.statusPeer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationO'Brien, R., Buckley, M. M., Kelliher, A. and O'Malley, D. (2019) 'PI 3-kinase- and ERK-MAPK-dependent mechanisms underlie Glucagon-Like Peptide-1-mediated activation of Sprague Dawley colonic myenteric neurons', Neurogastroenterology and Motility. doi: 10.1111/nmo.13631en
dc.identifier.doi10.1111/nmo.13631en
dc.identifier.eissn1365-2982
dc.identifier.endpage11en
dc.identifier.issn1350-1925
dc.identifier.journaltitleNeurogastroenterology and Motilityen
dc.identifier.startpage1en
dc.identifier.urihttps://hdl.handle.net/10468/8041
dc.language.isoenen
dc.publisherJohn Wiley & Sons Ltd.en
dc.relation.urihttps://onlinelibrary.wiley.com/doi/abs/10.1111/nmo.13631
dc.rights© 2019, John Wiley & Sons Ltd. This is the peer reviewed version of the following article: O'Brien, R., Buckley, M. M., Kelliher, A. and O'Malley, D. (2019) 'PI 3-kinase- and ERK-MAPK-dependent mechanisms underlie Glucagon-Like Peptide-1-mediated activation of Sprague Dawley colonic myenteric neurons', Neurogastroenterology and Motility. doi: 10.1111/nmo.13631, which has been published in final form at https://doi.org/10.1111/nmo.13631. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.en
dc.subjectCircular smooth muscleen
dc.subjectMyenteric neuronsen
dc.subjectERK-MAPKen
dc.subjectGLP-1 receptorsen
dc.subjectVoltage-gated calcium channelsen
dc.titlePI 3-kinase- and ERK-MAPK-dependent mechanisms underlie Glucagon-Like Peptide-1-mediated activation of Sprague Dawley colonic myenteric neuronsen
dc.typeArticle (peer-reviewed)en
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