Gastric Acid Secretion from Parietal Cells Is Mediated by a Ca 2+ Efflux Channel in the Tubulovesicle

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...

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Published in:Developmental cell 2017-05, Vol.41 (3), p.262
Main Authors: Sahoo, Nirakar, Gu, Mingxue, Zhang, Xiaoli, Raval, Neel, Yang, Junsheng, Bekier, Michael, Calvo, Raul, Patnaik, Samarjit, Wang, Wuyang, King, Greyson, Samie, Mohammad, Gao, Qiong, Sahoo, Sasmita, Sundaresan, Sinju, Keeley, Theresa M, Wang, Yanzhuang, Marugan, Juan, Ferrer, Marc, Samuelson, Linda C, Merchant, Juanita L, Xu, Haoxing
Format: Article
Language:English
Subjects:
Animals
Biological Transport - physiology
Calcium - metabolism
Cell Membrane - metabolism
Exocytosis - physiology
Gastric Acid - secretion
H(+)-K(+)-Exchanging ATPase - metabolism
Histamine - metabolism
Mice
Parietal Cells, Gastric - metabolism
Parietal Cells, Gastric - secretion
Signal Transduction - physiology
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Summary: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 Ca 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 Ca release from TV stores. Hence, we demonstrated that ML1, acting as a Ca channel in TVs, links transmitter-initiated cyclic nucleotide signaling with Ca -dependent TV exocytosis in parietal cells, providing a regulatory mechanism that could be targeted to manage acid-related gastric diseases.
ISSN:1878-1551
DOI:10.1016/j.devcel.2017.04.003