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

• Published in: Neurogastroenterology and motility Vol. 31; no. 8; pp. 1 - 11
• Main Authors: O'Brien, Rebecca, Buckley, Maria M., Kelliher, Amy, O'Malley, Dervla
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.08.2019
• Subjects: Calcium (intracellular); Calcium channels; Calcium channels (voltage-gated); Calcium imaging; Calcium influx; Circular smooth muscle; Colon; Corticotropin-releasing hormone; ERK‐MAPK; Extracellular signal-regulated kinase; GLP‐1 receptors; Glucagon; Hypothalamus; Intestine; Irritable bowel syndrome; MAP kinase; Muscle contraction; Muscle function; Myenteric neurons; Neurons; Peptides; Pituitary; Voltage‐gated calcium channels; Voltage-gated calcium channels; GLP-1 receptors; Myenteric neurons; Circular smooth muscle; ERK-MAPK
• ISSN: 1350-1925; 1365-2982
• DOI: 10.1111/nmo.13631

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. A glucagon‐like peptide‐1 receptor agonist suppressed colonic contractile activity in a healthy Sprague Dawley rat. This was mediated by activation of myenteric neurons. The stress hormone, corticotropin‐releasing factor, did not further modify colonic contractile activity but may be important in a model of bowel dysfunction.