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

Dev Cell. 2017 May 8;41(3):262-273.e6. doi: 10.1016/j.devcel.2017.04.003.

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.

Keywords: Ca(2+) release; TRPML1; cAMP; exocytosis; membrane trafficking; tubulovesicle.

MeSH terms

  • Animals
  • Biological Transport / physiology
  • Calcium / metabolism*
  • Cell Membrane / metabolism*
  • Exocytosis / physiology*
  • Gastric Acid / metabolism*
  • H(+)-K(+)-Exchanging ATPase / metabolism
  • Histamine / metabolism
  • Mice
  • Parietal Cells, Gastric / metabolism*
  • Signal Transduction / physiology

Substances

  • Histamine
  • H(+)-K(+)-Exchanging ATPase
  • Calcium