| Literature DB >> 28486130 |
Nirakar Sahoo1, Mingxue Gu1, Xiaoli Zhang1, Neel Raval1, Junsheng Yang2, Michael Bekier1, Raul Calvo3, Samarjit Patnaik3, Wuyang Wang1, Greyson King1, Mohammad Samie1, Qiong Gao1, Sasmita Sahoo1, Sinju Sundaresan4, Theresa M Keeley5, Yanzhuang Wang1, Juan Marugan3, Marc Ferrer3, Linda C Samuelson6, Juanita L Merchant4, Haoxing Xu7.
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.Entities:
Keywords: Ca(2+) release; TRPML1; cAMP; exocytosis; membrane trafficking; tubulovesicle
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Year: 2017 PMID： 28486130 PMCID： PMC5497767 DOI： 10.1016/j.devcel.2017.04.003
Source DB: PubMed Journal: Dev Cell ISSN： 1534-5807 Impact factor: 12.270