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

Thumbnail Image
Files
Date
2019-05-23
Authors
O'Brien, Rebecca L.
Buckley, Maria M.
Kelliher, Amy
O'Malley, Dervla
Journal Title
Journal ISSN
Volume Title
Publisher
John Wiley & Sons Ltd.
Published Version
10.1111/nmo.13631
Research Projects
Organizational Units
Journal Issue
Abstract
Background: 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.
Description
Keywords
Circular smooth muscle , Myenteric neurons , ERK-MAPK , GLP-1 receptors , Voltage-gated calcium channels
Citation
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
URI
https://hdl.handle.net/10468/8041
Collections
Physiology - Journal Articles
Copyright
© 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.