Cajal肌内间质细胞的一个特殊群体调节小鼠食管胃交界处的运动。

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

作者信息

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

机构信息

Department of Physiology and Cell Biology, Reno School of Medicine, University of Nevada, Reno, Nevada, USA.

Department of Pharmacology, Reno School of Medicine, University of Nevada, Reno, Nevada, USA.

出版信息

J Physiol. 2025 May 5. doi: 10.1113/JP288125.

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 Ca signalling behaviours. Using ICC-specific GCaMP6f mice we found that unlike the LES where only asynchronous Ca transients were observed, two distinct ICC Ca signalling behaviours were present within the distal oesophagus. Type I intramuscular interstitial cells of Cajal (ICC-IM) exhibited localized asynchronous Ca transients that were insensitive to ANO1 or voltage-dependent Ca channel (VDCC) inhibition but abolished by inhibiting endoplasmic reticulum (ER) Ca release. In contrast type II ICC-IM exhibited rhythmic, whole-cell Ca transients that were inhibited by ANO1 or VDCC antagonists revealing the underlying asynchronous Ca 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 Ca signalling and contraction. mRNA encoding IPR1 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 Ca release occurs in ICC-IM via IP receptors (IPRs), which in turn activates ANO1, causing depolarization, Ca influx via VDCCs and contraction. 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 Ca channels (VDCCs). Only intramuscular interstitial cells of Cajal (ICC-IM) are present in the EGJ, yet two distinct ICC Ca signalling behaviours were apparent. Type I ICC-IM exhibited localized asynchronous Ca transients, whereas type II ICC-IM exhibited rhythmic whole-cell Ca transients that were inhibited by ANO1 and VDCC antagonists revealing the underlying asynchronous Ca transients that were abolished by IP receptor (IPR) inhibition. mRNA encoding IPR1 and ANO1 was expressed in all ICC, suggesting that Ca release via IPRs leads to ANO1 activation, depolarization and subsequent Ca influx via VDCCs. Type II ICC-IM likely participate in generating pacemaker activity and regulating EGJ function.

摘要

食管胃交界(EGJ)是一个高压区,由食管下括约肌(LES)、食管远端和膈脚组成。与节律性收缩相关的阶段性电活动已在人类食管远端以及犬类LES近端得到证实,但在犬类LES远端不存在,该部位也没有节律性收缩。由于电慢波依赖于Cajal间质细胞(ICC)中anoctamin 1(ANO1)通道的激活,我们推测不同区域之间收缩活动的差异可能与ICC钙信号传导行为的差异相关。使用ICC特异性GCaMP6f小鼠,我们发现与仅观察到异步钙瞬变的LES不同,食管远端存在两种不同的ICC钙信号传导行为。I型肌内Cajal间质细胞(ICC-IM)表现出局部异步钙瞬变,对ANO1或电压依赖性钙通道(VDCC)抑制不敏感,但通过抑制内质网(ER)钙释放可消除。相比之下,II型ICC-IM表现出节律性的全细胞钙瞬变,被ANO1或VDCC拮抗剂抑制,揭示了潜在的异步钙释放事件。小鼠食管远端的节律性收缩活动也被ANO1和VDCC拮抗剂抑制,表明II型ICC-IM钙信号传导与收缩之间存在联系。编码IPR1和ANO1通道的mRNA在ICC-IM中表达。这些数据表明,II型ICC-IM负责在食管远端产生节律性的阶段性活动,并且钙释放通过IP受体(IPR)在ICC-IM中发生,进而激活ANO1,导致去极化、通过VDCCs的钙内流和收缩。要点:食管胃交界(EGJ)是一个防止胃酸反流至食管的高压区。EGJ运动功能紊乱与胃食管反流病或贲门失弛缓症相关。食管下括约肌(LES)产生张力,而相邻的食管远端表现出节律性收缩。这两种活动均依赖于anoctamin 1(ANO1)和电压依赖性钙通道(VDCCs)。EGJ中仅存在肌内Cajal间质细胞(ICC-IM),但有两种不同的ICC钙信号传导行为明显。I型ICC-IM表现出局部异步钙瞬变,而II型ICC-IM表现出节律性的全细胞钙瞬变,被ANO1和VDCC拮抗剂抑制,揭示了潜在的异步钙瞬变,通过IP受体(IPR)抑制可消除。编码IPR1和ANO1的mRNA在所有ICC中表达,表明通过IPR的钙释放导致ANO1激活、去极化以及随后通过VDCCs的钙内流。II型ICC-IM可能参与产生起搏活动并调节EGJ功能。

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