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Dev Cell. 2017 May 8;41(3):262-273.e6. doi: 10.1016/j.devcel.2017.04.003.

Gastric Acid Secretion from Parietal Cells Is Mediated by a Ca2+ Efflux Channel in the Tubulovesicle.

Author information

1
Department of Molecular, Cellular, and Developmental Biology, University of Michigan, 3089 Natural Science Building (Kraus), 830 North University, Ann Arbor, MI 48109, USA.
2
Department of Molecular, Cellular, and Developmental Biology, University of Michigan, 3089 Natural Science Building (Kraus), 830 North University, Ann Arbor, MI 48109, USA; Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, China.
3
National Center for Advancing Translational Sciences, National Institute of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
4
Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
5
Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
6
Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
7
Department of Molecular, Cellular, and Developmental Biology, University of Michigan, 3089 Natural Science Building (Kraus), 830 North University, Ann Arbor, MI 48109, USA. Electronic address: haoxingx@umich.edu.

Abstract

Gastric acid secretion by parietal cells requires trafficking and exocytosis of H/K-ATPase-rich tubulovesicles (TVs) toward apical membranes in response to histamine stimulation via cyclic AMP elevation. Here, we found that TRPML1 (ML1), a protein that is mutated in type IV mucolipidosis (ML-IV), is a tubulovesicular channel essential for TV exocytosis and acid secretion. Whereas ML-IV patients are reportedly achlorhydric, transgenic overexpression of ML1 in mouse parietal cells induced constitutive acid secretion. Gastric acid secretion was blocked and stimulated by ML1 inhibitors and agonists, respectively. Organelle-targeted Ca2+ imaging and direct patch-clamping of apical vacuolar membranes revealed that ML1 mediates a PKA-activated conductance on TV membranes that is required for histamine-induced Ca2+ release from TV stores. Hence, we demonstrated that ML1, acting as a Ca2+ channel in TVs, links transmitter-initiated cyclic nucleotide signaling with Ca2+-dependent TV exocytosis in parietal cells, providing a regulatory mechanism that could be targeted to manage acid-related gastric diseases.

KEYWORDS:

Ca(2+) release; TRPML1; cAMP; exocytosis; membrane trafficking; tubulovesicle

PMID:
28486130
PMCID:
PMC5497767
DOI:
10.1016/j.devcel.2017.04.003
[Indexed for MEDLINE]
Free PMC Article

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