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IBS pathophysiology is characterized by hyper\u2010activation of the hypothalamic\u2010pituitary\u2010adrenal stress axis and altered microbial profiles. This study aims to characterize the neuronal and functional effects of GLP\u20101 in healthy rat colons to aid understanding of its beneficial effects in moderating bowel dysfunction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Immunofluorescent and calcium imaging of myenteric neurons prepared from Sprague Dawley rat colons was carried out to elucidate the neuromodulatory actions of the GLP\u20101 receptor agonist, exendin\u20104 (Ex\u20104). Colonic contractile activity was assessed using organ bath physiological recordings.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key results<\/jats:title><jats:p>Ex\u20104 induced an elevation of intracellular calcium arising from store release and influx via voltage\u2010gated calcium channels. Ex\u20104 activated both ERK\u2010MAPK and PI 3\u2010kinase signaling cascades. Neuronal activation was found to underlie suppression of contractile activity in colonic circular muscle. Although the stress hormone, corticotropin\u2010releasing factor (CRF) potentiated the neuronal response to Ex\u20104, and the functional effects of Ex\u20104 on colonic circular muscle activity were not altered.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and inferences<\/jats:title><jats:p>Ex\u20104 evoked neurally regulated suppression of rat colonic circular muscle activity. In myenteric neurons, the neurostimulatory effects of Ex\u20104 were dependent upon activation of PI 3\u2010kinase and ERK\u2010MAPK 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.<\/jats:p><\/jats:sec>","DOI":"10.1111\/nmo.13631","type":"journal-article","created":{"date-parts":[[2019,5,23]],"date-time":"2019-05-23T19:00:17Z","timestamp":1558638017000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["PI 3\u2010kinase\u2010 and ERK\u2010MAPK\u2010dependent mechanisms underlie Glucagon\u2010Like Peptide\u20101\u2010mediated activation of Sprague Dawley colonic myenteric neurons"],"prefix":"10.1111","volume":"31","author":[{"given":"Rebecca","family":"O'Brien","sequence":"first","affiliation":[{"name":"Department of Physiology University College Cork Cork Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9097-1334","authenticated-orcid":false,"given":"Maria M.","family":"Buckley","sequence":"additional","affiliation":[{"name":"Department of Physiology University College Cork Cork Ireland"},{"name":"APC Microbiome Ireland University College Cork Cork Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amy","family":"Kelliher","sequence":"additional","affiliation":[{"name":"Department of Physiology University College Cork Cork Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7031-4879","authenticated-orcid":false,"given":"Dervla","family":"O'Malley","sequence":"additional","affiliation":[{"name":"Department of Physiology University College Cork Cork Ireland"},{"name":"APC Microbiome Ireland University College Cork Cork Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2019,5,23]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/jdi.12478"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2982.2007.01079.x"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1136\/gut.46.5.622"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1136\/gut.2004.059741"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1113\/EP087443"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2012.02.029"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2036.2008.03870.x"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinre.2016.12.007"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.3892\/ijmm.2013.1252"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2982.2009.01412.x"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.peptides.2010.01.004"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2011.04.020"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2005.11.033"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1097\/MCO.0b013e32833b6471"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1751-2980.2009.00392.x"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1097\/00042737-199805000-00011"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.138.10.4445"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2003.059659"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.2000.278.6.G924"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.autneu.2006.06.007"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2009.175067"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2008-0726"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.2337\/db13-1440"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2982.2010.01476.x"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0167-0115(00)00220-2"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1026678925120"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1159\/000051874"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00031.2014"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2008.11.002"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.2337\/db11-1019"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep43522"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13098-015-0075-7"},{"issue":"3","key":"e_1_2_9_34_1","first-page":"136","article-title":"The gut microbiome and irritable bowel syndrome: State of art review. 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