# Mechanotransduction in Intestinal Smooth Muscle Cells

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2021 · $357,750

## Abstract

PROJECT SUMMARY
In electro-mechanical organs, such as the gastrointestinal (GI) tract, ion channels are required to generate
electrical activity that drives contractions. In turn, mechanical forces affect ion channel function and therefore
electrical activity, which is termed mechano-electric feedback. Therefore, ion channel mechanosensitivity is
important for normal function, and abnormalities can lead to disease. In the previous grant cycles we have
shown that a mechano-sensitive voltage-gated sodium channel NaV1.5, encoded by SCN5A, is present in
gastrointestinal smooth muscle cells of the human small bowel and colon. Further, SCN5A mutations are
associated with irritable bowel syndrome (IBS). The contribution of NaV1.5 current density and
mechanosensitivity to normal and abnormal mechano-electric feedback is not known. The central hypothesis
of this proposal is that NaV1.5 mechanosensitivity and current density are critical for control of human GI
smooth muscle excitability, and both are regulated and targetable. We will test the central hypothesis in 3
specific aims (SAs). We will determine in: SA1 how IBS NaV1.5 mutations affect mechanosensitivity and how
changes in mechanosensitivity affect mechano-electric feedback; SA2 how NaV1.5 pore determines
mechanosensitivity and mechanosensitivity block by certain drugs; SA3 how NaV1.5 is regulated by miRNAs in
smooth muscle cells and the effects of NaV1.5 regulation by miRNA and drugs on GI smooth muscle cell
function. The SAs are supported by extensive preliminary data. 1) 30% of IBS-associated SCN5A mutations
result abnormal mechanosensitivity reducing mechano-electric feedback. 2) NaV1.5 mechanosensitivity
depends on ion channel pore, and NaV1.5 mechanosensitivity blockade by drugs such as ranolazine is
mechanistically separate from peak current block. 3) In GI smooth muscle from slow transit constipation
patients NaV1.5 is down-regulated while a small set of miRNAs is upregulated and miRNA let-7f correlates with
NaV1.5 expression, down-regulates NaV1.5 current and alters electrical slow wave activity. 4) Patients on
ranolazine have delayed colon transit and rat GI transit is delayed by ranolazine. To investigate the central
hypothesis we use a wide variety of cutting-edge techniques, including whole-cell and single-channel voltage-
and current-clamp electrophysiology and optogenetics in combination with ultra-fast pressure delivery,
CRISPR-Cas to introduce patient mutations into cells, bacterial NaV channels with designer functional domains,
Western blots, IHC, delivery of miRNA mimics by lentivirus, rat organotypic cultures, and a prospective clinical
trial. Successful completion of the proposed studies has both basic significance and clinical impact. As a result
of the work done in the previous grant cycles and the preliminary data presented in this proposal, we will
significantly advance our understanding of the molecular mechanisms of NaV1.5 channel mechanosensitivity,
the contribution of ...

## Key facts

- **NIH application ID:** 10144989
- **Project number:** 5R01DK052766-23
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Arthur Beyder
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $357,750
- **Award type:** 5
- **Project period:** 1997-09-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10144989

## Citation

> US National Institutes of Health, RePORTER application 10144989, Mechanotransduction in Intestinal Smooth Muscle Cells (5R01DK052766-23). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10144989. Licensed CC0.

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