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

• DOI: 10.1016/j.devcel.2017.04.003
• Publication Date: 2017-05-08T16:32:40Z
• Authors: 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
• Keywords: Parietal cell; Apical membrane

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.