# Deciphering Ion Channel Mechanisms Underlying Mechanosensitivity in the Gut

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $485,513

## Abstract

Gastrointestinal (GI) motility is controlled by intestinal pacemaker cells, smooth muscle cells and the enteric
nervous system (ENS) acting independently as the “second brain” in the gut. ENS abnormalities cause many
GI motility disorders. In 1899, Bayliss and Starling proposed the classic “The law of the intestine” stating that
“excitation at any point of the gut excites contraction above, inhibition below”, suggesting that distinct intrinsic
excitatory and inhibitory intestinal motor behaviors can be elicited by mechanical forces. Recent studies have
also demonstrated that mechanosensitivity is required to drive intestinal motor behaviors such as the colonic
migrating motor complex (CMMC) resulting from either direct activation of ENS or by serotonin release from
enterochromaffin cells (ECs) in the gut epithelium by mechanical forces. However, the molecules, cells, and
neural circuits governing the process of mechanosensitivity in the gut still remain poorly understood.
Membrane-bound ion channels play an essential role in mechanotransduction. Recent exciting studies have
identified the mechanosensitive Piezo channels as molecular sensors for mechanical forces in the skin and
have significantly advanced our knowledge about the role of the Piezo channels in our senses of light touch
and mechanical pain. However, The role of Piezo channels involved in the mechanosensitivity in the gut and
other visceral organs is poorly understood. Preliminary studies showed that chemical activation of Piezo1
promotes colon contraction and increases CMMC frequency, suggesting that Piezo1 is functionally expressed
by both cholinergic excitatory and nitrergic enteric neural circuits. More importantly, Piezo1 is required for
normal colonic motility in vivo. We thus hypothesize that Piezo1 is a molecular sensor for mechanical forces in
the GI tract and potentially could serve as a therapeutic drug target for treating GI motility disorders such as
slow transit constipation.
To test this hypothesis, we will take a multidisciplinary approach using live-cell Ca2+ imaging, patch-clamp
recordings and pharmacological approaches in combination to mouse genetics and intestinal motor behavioral
methods to elucidate the cellular and molecular mechanisms underlying the Piezo1-mediated
mechanosensitivity in both ENS and intestinal epithelium. Successful completion of these studies will advance
our understanding of the previously unrecognized roles of Piezo1 and Piezo1-expressing enteric neurons and
ECs in controlling GI motility. More importantly, these studies will offer new opportunities for developing
effective and safer medicines for GI motility disorders.

## Key facts

- **NIH application ID:** 10116046
- **Project number:** 2R01DK103901-05A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Hongzhen Hu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $485,513
- **Award type:** 2
- **Project period:** 2015-07-15 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10116046

## Citation

> US National Institutes of Health, RePORTER application 10116046, Deciphering Ion Channel Mechanisms Underlying Mechanosensitivity in the Gut (2R01DK103901-05A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10116046. Licensed CC0.

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