A role for the Ca2+ channel TRPML1 in gastric acid secretion, based on analysis of knockout mice

Manjari Chandra, Hua Zhou, Qin Li, Shmuel Muallem, Sandra L. Hofmann, Abigail A. Soyombo

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Background & Aims: Mutations in TRPML1, a lysosomal Ca 2+-permeable TRP channel, lead to mucolipidosis type IV, a neurodegenerative lysosomal storage disease. An unusual feature of mucolipidosis type IV is constitutive achlorhydria. We produced Trpml1-/- (null) mice to investigate the requirement for this protein in gastric acid secretion. Methods: Trpml1-null mice were generated by gene targeting. The expression of Trpml1 and its role in acid secretion by gastric parietal cells were analyzed using biochemical, histologic, and ultrastructural approaches. Results: Trpml1 is expressed by parietal cells and localizes predominantly to the lysosomes; it was dynamically palmitoylated and dephosphorylated in vivo following histamine stimulation of acid secretion. Trpml1-null mice had significant impairments in basal and histamine-stimulated gastric acid secretion and markedly reduced levels of the gastric proton pump. Histologic and ultrastructural analyses revealed that Trpml1-/- parietal cells were enlarged, had multivesicular and multi-lamellated lysosomes, and maintained an abnormal intracellular canalicular membrane. The intralysosomal Ca2+ content and receptor-mediated Ca2+ signaling were, however, unaffected in Trpml1-/- gastric glands, indicating that Trpml1 does not function in the regulation of lysosomal Ca2+. Conclusions: Loss of Trpml1 causes reduced levels and mislocalization of the gastric proton pump and alters the secretory canaliculi, causing hypochlorhydria and hypergastrinemia. The lysosomal enlargement and defective intracellular canaliculi formation observed in Trpml1-/- parietal cells indicate that Trpml1 functions in the formation and trafficking of the tubulovesicles. This study provides direct evidence for the regulation of gastric acid secretion by a TRP channel; TRPML1 is an important protein in parietal cell apical membrane trafficking.

Original languageEnglish (US)
Pages (from-to)857-867
Number of pages11
JournalGastroenterology
Volume140
Issue number3
DOIs
StatePublished - Mar 2011

Fingerprint

Gastric Acid
Knockout Mice
Mucolipidoses
Achlorhydria
Proton Pumps
Lysosomes
Histamine
Stomach
Gastric Parietal Cells
Lysosomal Storage Diseases
Intracellular Membranes
Acids
Gene Targeting
Gastric Mucosa
Proteins
Cell Membrane
Mutation

Keywords

  • Apical Membrane Trafficking
  • Mucolipin-1
  • Stomach
  • Vesicles

ASJC Scopus subject areas

  • Gastroenterology

Cite this

A role for the Ca2+ channel TRPML1 in gastric acid secretion, based on analysis of knockout mice. / Chandra, Manjari; Zhou, Hua; Li, Qin; Muallem, Shmuel; Hofmann, Sandra L.; Soyombo, Abigail A.

In: Gastroenterology, Vol. 140, No. 3, 03.2011, p. 857-867.

Research output: Contribution to journalArticle

Chandra, Manjari ; Zhou, Hua ; Li, Qin ; Muallem, Shmuel ; Hofmann, Sandra L. ; Soyombo, Abigail A. / A role for the Ca2+ channel TRPML1 in gastric acid secretion, based on analysis of knockout mice. In: Gastroenterology. 2011 ; Vol. 140, No. 3. pp. 857-867.
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AU - Soyombo, Abigail A.

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AB - Background & Aims: Mutations in TRPML1, a lysosomal Ca 2+-permeable TRP channel, lead to mucolipidosis type IV, a neurodegenerative lysosomal storage disease. An unusual feature of mucolipidosis type IV is constitutive achlorhydria. We produced Trpml1-/- (null) mice to investigate the requirement for this protein in gastric acid secretion. Methods: Trpml1-null mice were generated by gene targeting. The expression of Trpml1 and its role in acid secretion by gastric parietal cells were analyzed using biochemical, histologic, and ultrastructural approaches. Results: Trpml1 is expressed by parietal cells and localizes predominantly to the lysosomes; it was dynamically palmitoylated and dephosphorylated in vivo following histamine stimulation of acid secretion. Trpml1-null mice had significant impairments in basal and histamine-stimulated gastric acid secretion and markedly reduced levels of the gastric proton pump. Histologic and ultrastructural analyses revealed that Trpml1-/- parietal cells were enlarged, had multivesicular and multi-lamellated lysosomes, and maintained an abnormal intracellular canalicular membrane. The intralysosomal Ca2+ content and receptor-mediated Ca2+ signaling were, however, unaffected in Trpml1-/- gastric glands, indicating that Trpml1 does not function in the regulation of lysosomal Ca2+. Conclusions: Loss of Trpml1 causes reduced levels and mislocalization of the gastric proton pump and alters the secretory canaliculi, causing hypochlorhydria and hypergastrinemia. The lysosomal enlargement and defective intracellular canaliculi formation observed in Trpml1-/- parietal cells indicate that Trpml1 functions in the formation and trafficking of the tubulovesicles. This study provides direct evidence for the regulation of gastric acid secretion by a TRP channel; TRPML1 is an important protein in parietal cell apical membrane trafficking.

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