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Δευτέρα 8 Μαΐου 2017

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

Publication date: 8 May 2017
Source:Developmental Cell, Volume 41, Issue 3
Author(s): Nirakar Sahoo, Mingxue Gu, Xiaoli Zhang, Neel Raval, Junsheng Yang, Michael Bekier, Raul Calvo, Samarjit Patnaik, Wuyang Wang, Greyson King, Mohammad Samie, Qiong Gao, Sasmita Sahoo, Sinju Sundaresan, Theresa M. Keeley, Yanzhuang Wang, Juan Marugan, Marc Ferrer, Linda C. Samuelson, Juanita L. Merchant, Haoxing Xu
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.

Graphical abstract

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Teaser

Acid secretion from the parietal cells of the stomach is essential for food digestion. Sahoo et al. identified TRPML1 as a histamine-activated Ca2+ channel in the tubulovesicles required for gastric acid secretion. Synthetic agonists and inhibitors of TRPML1 may be developed to control acid secretion and treat acid-related gastric diseases.


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