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

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

Research output: Contribution to journal › Article › peer-review

47 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 language	English (US)
Pages (from-to)	262-273.e6
Journal	Developmental Cell
Volume	41
Issue number	3
DOIs	https://doi.org/10.1016/j.devcel.2017.04.003
State	Published - May 8 2017
Externally published	Yes

Keywords

Ca release
TRPML1
cAMP
exocytosis
membrane trafficking
tubulovesicle

ASJC Scopus subject areas

Molecular Biology
General Biochemistry, Genetics and Molecular Biology
Developmental Biology
Cell Biology

Access to Document

10.1016/j.devcel.2017.04.003

Cite this

Sahoo, N., Gu, M., Zhang, X., Raval, N., Yang, J., Bekier, M., Calvo, R., Patnaik, S., Wang, W., King, G., Samie, M., Gao, Q., Sahoo, S., Sundaresan, S., Keeley, T. M., Wang, Y., Marugan, J., Ferrer, M., Samuelson, L. C., ... Xu, H. (2017). Gastric Acid Secretion from Parietal Cells Is Mediated by a Ca²⁺ Efflux Channel in the Tubulovesicle. Developmental Cell, 41(3), 262-273.e6. https://doi.org/10.1016/j.devcel.2017.04.003

Sahoo, N, Gu, M, Zhang, X, Raval, N, Yang, J, Bekier, M, Calvo, R, Patnaik, S, Wang, W, King, G, Samie, M, Gao, Q, Sahoo, S, Sundaresan, S, Keeley, TM, Wang, Y, Marugan, J, Ferrer, M, Samuelson, LC, Merchant, JL & Xu, H 2017, 'Gastric Acid Secretion from Parietal Cells Is Mediated by a Ca²⁺ Efflux Channel in the Tubulovesicle', Developmental Cell, vol. 41, no. 3, pp. 262-273.e6. https://doi.org/10.1016/j.devcel.2017.04.003

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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.",

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author = "Nirakar Sahoo and Mingxue Gu and Xiaoli Zhang and Neel Raval and Junsheng Yang and Michael Bekier and Raul Calvo and Samarjit Patnaik and Wuyang Wang and Greyson King and Mohammad Samie and Qiong Gao and Sasmita Sahoo and Sinju Sundaresan and Keeley, \{Theresa M.\} and Yanzhuang Wang and Juan Marugan and Marc Ferrer and Samuelson, \{Linda C.\} and Merchant, \{Juanita L.\} and Haoxing Xu",

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AU - Raval, Neel

AU - Yang, Junsheng

AU - Bekier, Michael

AU - Calvo, Raul

AU - Patnaik, Samarjit

AU - Wang, Wuyang

AU - King, Greyson

AU - Samie, Mohammad

AU - Gao, Qiong

AU - Sahoo, Sasmita

AU - Sundaresan, Sinju

AU - Keeley, Theresa M.

AU - Wang, Yanzhuang

AU - Marugan, Juan

AU - Ferrer, Marc

AU - Samuelson, Linda C.

AU - Merchant, Juanita L.

AU - Xu, Haoxing

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AB - 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.

KW - Ca release

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