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 Merchant; Haoxing Xu

doi:10.1016/j.devcel.2017.04.003

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

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

Authors

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

Affiliations

¹ Department of Molecular, Cellular, and Developmental Biology, University of Michigan, 3089 Natural Science Building (Kraus), 830 North University, Ann Arbor, MI 48109, USA.
² Department of Molecular, Cellular, and Developmental Biology, University of Michigan, 3089 Natural Science Building (Kraus), 830 North University, Ann Arbor, MI 48109, USA; Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, China.
³ National Center for Advancing Translational Sciences, National Institute of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
⁴ Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
⁵ Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
⁶ Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
⁷ Department of Molecular, Cellular, and Developmental Biology, University of Michigan, 3089 Natural Science Building (Kraus), 830 North University, Ann Arbor, MI 48109, USA. Electronic address: haoxingx@umich.edu.

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

Abstract

MeSH terms

Substances

Grants and funding