Work

A specialized population of intramuscular interstitial cells of Cajal regulates motility within the mouse oesophagogastric junction

Year: 2025

Type: article

Abstract: The oesophagogastric junction (EGJ) is a high‐pressure zone consisting of the lower oesophageal sphincter (LES), distal oesophagus and crural diaphragm. Phasic electrical activity associated with phasic contractions has been demonstrated in the human distal oesophagus as well as in the dog proximal LES but is absent from the dog distal LES where phasic contractions are also absent. As electrical slow waves are dependent on activation of anoctamin 1 (ANO1) channels in interstitial cells of Cajal (ICC), we hypothesized that differences in contractile activity between regions may be correlated to differences in ICC Ca2+ signalling behaviours. Using ICC‐specific GCaMP6f mice we found that unlike the LES where only asynchronous Ca2+ transients were observed, two distinct ICC Ca2+ signalling behaviours were present within the distal oesophagus. Type I intramuscular interstitial cells of Cajal (ICC‐IM) exhibited localized asynchronous Ca2+ transients that were insensitive to ANO1 or voltage‐dependent Ca2+ channel (VDCC) inhibition but abolished by inhibiting endoplasmic reticulum (ER) Ca2+ release. In contrast type II ICC‐IM exhibited rhythmic, whole‐cell Ca2+ transients that were inhibited by ANO1 or VDCC antagonists revealing the underlying asynchronous Ca2+ release events. Phasic contractile activity in the mouse distal oesophagus was also inhibited by ANO1 and VDCC antagonists, suggesting a link between type II ICC‐IM Ca2+ signalling and contraction. mRNA encoding IP3R1 and ANO1 channels was expressed in ICC‐IM. These data suggest that type II ICC‐IM are responsible for generating rhythmic, phasic activity in the distal oesophagus and that Ca2+ release occurs in ICC‐IM via IP3 receptors (IP3Rs), which in turn activates ANO1, causing depolarization, Ca2+ influx via VDCCs and contraction. image Key points The oesophagogastric junction (EGJ) is a high‐pressure zone that prevents acid reflux into the oesophagus. Disrupted EGJ motility is associated with gastro‐oesophageal reflux disease or achalasia. The lower oesophageal sphincter (LES) generates tone, whereas the adjacent distal oesophagus exhibits phasic contractions. Both activities are dependent on anoctamin 1 (ANO1) and voltage‐dependent Ca2+ channels (VDCCs). Only intramuscular interstitial cells of Cajal (ICC‐IM) are present in the EGJ, yet two distinct ICC Ca2+ signalling behaviours were apparent. Type I ICC‐IM exhibited localized asynchronous Ca2+ transients, whereas type II ICC‐IM exhibited rhythmic whole‐cell Ca2+ transients that were inhibited by ANO1 and VDCC antagonists revealing the underlying asynchronous Ca2+ transients that were abolished by IP3 receptor (IP3R) inhibition. mRNA encoding IP3R1 and ANO1 was expressed in all ICC, suggesting that Ca2+ release via IP3Rs leads to ANO1 activation, depolarization and subsequent Ca2+ influx via VDCCs. Type II ICC‐IM likely participate in generating pacemaker activity and regulating EGJ function.

Source: The Journal of Physiology

DOI: 10.1113/jp288125

Authors: Emer P. Ni Bhraonain, Karen I. Hannigan, Jack A. Turner, Grace A. Wildbore, Kenton M. Sanders, Caroline A. Cobine

Institution: University of Nevada, Reno

Language: English

Topic: Gastrointestinal motility and disorders

Subfield: Gastroenterology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: green

Funders: Honeywell Hometown Solutions, National Institutes of Health, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases