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

Therapeutic Approaches


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(2+) 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(2+) release from TV stores. Hence, we demonstrated that ML1, acting as a Ca(2+) channel in TVs, links transmitter-initiated cyclic nucleotide signaling with Ca(2+)-dependent TV exocytosis in parietal cells, providing a regulatory mechanism that could be targeted to manage acid-related gastric diseases.


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-Alegre, Marc; Samuelson, Linda C; Merchant, Juanita L; Xu, Haoxing;

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