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

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. MerchantHaoxing Xu

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)262-273.e6
JournalDevelopmental Cell
Volume41
Issue number3
DOIs
StatePublished - May 8 2017
Externally publishedYes

Keywords

  • Ca release
  • TRPML1
  • cAMP
  • exocytosis
  • membrane trafficking
  • tubulovesicle

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology

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