# Phenotypic diversity of interstitial cells of Cajal and colonic motor functions

> **NIH NIH R01** · UNIVERSITY OF NEVADA RENO · 2020 · $398,206

## Abstract

Summary
Colonic motility is the product of myogenic, neurogenic and endocrinogenic factors that regulate the excitability
of smooth muscle cells (SMCs). The traditional concept of ‘myogenic’ has been revised to include regulatory
inputs from interstitial cells (interstitial cells of Cajal (ICC) and PDGFRa+ cells). These cells are electrically
coupled to SMCs, forming the SIP syncytium. While much has been learned about ICC in other organs of the
GI tract, very little is known about the 4 types of ICC in colonic muscles. We developed reporter strains and
mice with exclusive expression of optogenetic Ca2+ sensors in ICC. Using these mice it is possible to isolate
specific types of ICC for physiological and molecular studies and to image Ca2+ transients in ICC in situ. Our
preliminary data show that all ICC in the colon employ brief Ca2+ entry and release events (i.e. Ca2+ transients)
to activate Ca2+-activated Cl- channels (CaCC), encoded by Ano1, in ICC. Activation of CaCC initiates inward
current, and this has a depolarizing or excitatory impact on the SIP syncytium. Ca2+ transients occur
spontaneously in colonic ICC, but they are also regulated by neural and hormonal inputs. Our overarching
hypothesis is that Ca2+ transients in ICC are the ‘myogenic’ mechanism that establishes patterning of
contractions in colonic muscles. Neural and hormonal modulation of ICC Ca2+ transients establish organ level
mixing and propulsive motility. We will address the following questions to investigate this hypothesis: 1. What
specific Ca2+ handling behaviors are manifest in the 4 classes of colonic ICC? 2. Is the behavior of ICC affected
by neural and hormonal inputs and during colonic motility behaviors such as colonic migrating motor complexes
(CMMC)? 3. What is the relationship between Ca2+ transients in ICC and the electrical and mechanical events
that generate colonic motility? Ca2+ transients in ICC of GCaMP6f-Kit mice will be imaged in situ using confocal
microscopy while recording movements and intracellular electrical activity. Preliminary data show that basal
electrical and contractile patterning in colonic muscles are disrupted by ANO1 channel antagonists. These data
demonstrate the key importance of ICC in colonic motor activity, because ICC express ANO1 exclusively in GI
muscles. Colonic dysmotilities have been associated with reduced populations of ICC. Therefore, we will utilize
animal models with reduced ICC to explore how deficiencies in these cells affect local propagating and mixing
contractions and propulsive contractions, such as CMMC. Ca2+ transients will also be characterized in animals
with reduced ICC to determine how loss of these cells affects spontaneous Ca2+ signaling and neural and
hormonal regulation. This study will be the first comprehensive evaluation of the pacemaker activity of colonic
ICC, and the first to show that ICC are responsible for developing basal motor patterning in colonic motility.
Completion of the specific aims wi...

## Key facts

- **NIH application ID:** 9882264
- **Project number:** 5R01DK120759-02
- **Recipient organization:** UNIVERSITY OF NEVADA RENO
- **Principal Investigator:** Sal Baker
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $398,206
- **Award type:** 5
- **Project period:** 2019-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9882264

## Citation

> US National Institutes of Health, RePORTER application 9882264, Phenotypic diversity of interstitial cells of Cajal and colonic motor functions (5R01DK120759-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9882264. Licensed CC0.

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