# Ion channels in the tubulovesicles

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $344,524

## Abstract

Gastric acid secretion from parietal cells is essential for food digestion and pathogen elimination in the
stomach. Dysregulation of gastric acid homeostasis underlies a spectrum of acid-related diseases,
including atrophic gastritis, gastric cancer, peptic and duodenal ulcers, and gastroesophageal reflux
disease (GERD); GERD alone affects at least 20% of the US population. Histamine, the primary
transmitter that “switches on” H+ secretion into the stomach lumen, acts by relocating the H+-K+-ATPase
proton pump from cytoplasmic tubulovesicles (TVs) onto the apical canalicular membranes via vesicular
transport and fusion. However, the mechanisms by which histamine induces the exocytosis of TVs
remain unclear. Most types of regulated exocytosis, including neurotransmitter release, are Ca2+-dependent, but it remains controversial whether Ca2+ is involved in histamine-triggered TV exocytosis.
Human mutations of Transient Receptor Potential Mucolipin-1 (ML1), a Ca2+-permeable channel of
intracellular membranes, cause achlorhydria (low acid secretion). Using super-resolution confocal
imaging, and by developing a new patch-clamp method to record directly from canalicular and
tubulovesicular membranes and a new organelle-targeted Ca2+ imaging method to detect Ca2+ release
from TVs, we identified ML1 as a likely histamine-triggered Ca2+ release channel in TVs. The central goal
of this proposal is to investigate the roles of ML1 in TV exocytosis and to use mouse models to explore
the potential clinical use of ML1 agonists and inhibitors in controlling acid secretion in vivo. Using an
integrative approach with Ca2+ imaging, electrophysiology, voltage imaging, electron microscopy, small
molecule channel agonists and inhibitors, and transgenic mouse models, we will test the hypothesis that
histamine-cAMP-PKA signaling activate ML1 and the TV K+ channel KCNQ1 to trigger TV exocytosis
and acid secretion. Aim 1 is to test the roles of ML1 and PKA in histamine-induced secretion of gastric
acids. Aim 2 is to investigate the roles of KCNQ1 channels in histamine-induced gastric acid secretion.
Finally, Aim 3 is to determine the roles of ML1 and KCNQ1 channels in controlling gastric acid levels in
vivo. Our long-term goal of the proposed research is to lay the groundwork necessary to develop new
therapeutic strategies for acid-related diseases.

## Key facts

- **NIH application ID:** 9851867
- **Project number:** 5R01DK115474-03
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** MOHAMMED AKAABOUNE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $344,524
- **Award type:** 5
- **Project period:** 2017-12-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9851867

## Citation

> US National Institutes of Health, RePORTER application 9851867, Ion channels in the tubulovesicles (5R01DK115474-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9851867. Licensed CC0.

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