# Control of motility in the lower esophageal sphincter

> **NIH NIH R01** · UNIVERSITY OF NEVADA RENO · 2021 · $436,175

## Abstract

Program Director/Principal Investigator (Last, First, Middle): Cobine, Caroline, A
Project Summary
The lower esophageal sphincter (LES) is a thickened region of muscle between the distal esophagus and
proximal stomach. The LES develops contractile tone that forms a protective barrier and restricts acidic contents
of the stomach from being refluxed into and damaging the esophagus. LES tone is thought to be ‘myogenic’,
but LES muscles are not just composed of smooth muscle cells (SMCs) and neurons. Rather, interstitial cells of
Cajal (ICC) are electrically coupled to SMCs and regulate the excitability of SMCs. For example, we found that
responses to nitrergic input, an important regulator of relaxation after swallowing, are reduced in animals with
loss of ICC (W/WV mice). This concept was criticized because manometric measurements in W/WV mice
displayed evidence of nitrergic relaxation. An important observation in these studies, but not investigated or
discussed in terms of mechanism, was that the LES in W/WV mice is hypotensive, suggesting that ICC provide
important functions in the LES, such as development and maintenance of tone. This project seeks to better
understand the mechanism of LES tone. Preliminary findings suggest that activation of Ca2+-dependent Cl-
channels (CaCC encoded by Ano1), most highly expressed by ICC in the LES, are responsible for a significant
portion of tone in these muscles. Ano1 channels are activated by spontaneous Ca2+ transients in ICC. The
inward current activated by Ca2+ causes depolarization of the syncytium and increases the open probability of
voltage-dependent Ca2+ channels in SMCs. The degree of contraction by this mechanism appears also to be
regulated by a mechanism known as Ca2+ sensitization, a process suggested in previous papers, but previous
findings are subject to other explanations. Here we propose to investigate the following: 1. Determine the
molecular and functional apparatus responsible for the electromechanical and pharmacomechanical regulation
of tone in the LES, 2. Examine how inputs from intrinsic neurons modulate the electromechanical and
pharmacomechanical mechanisms underlying LES tone. This study will utilize a variety of cutting-edge
techniques, such as transgenic mice, optogenetic monitoring of Ca2+ transients and biochemical analysis of
phosphorylation steps that either increase or inhibit Ca2+ sensitivity in SMCs. Many of these pre-clinical studies
will be performed on mice, but we will also perform parallel studies on Cynomolgus monkey LES, a primate with
significant genetic homology to humans.
OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page Continuation Format Page

## Key facts

- **NIH application ID:** 10279048
- **Project number:** 1R01DK129528-01
- **Recipient organization:** UNIVERSITY OF NEVADA RENO
- **Principal Investigator:** Caroline Ann Cobine
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $436,175
- **Award type:** 1
- **Project period:** 2021-09-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10279048

## Citation

> US National Institutes of Health, RePORTER application 10279048, Control of motility in the lower esophageal sphincter (1R01DK129528-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10279048. Licensed CC0.

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