A role for the Ca2+ channel TRPML1 in gastric acid secretion, based on analysis of knockout mice.
OBJECTIVE
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 Ca(2+) content and receptor-mediated Ca(2+) signaling were, however, unaffected in Trpml1(-/-) gastric glands, indicating that Trpml1 does not function in the regulation of lysosomal Ca(2+).


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.
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8593, USA.
Manjari
M
Chandra
Hua
H
Zhou
Qin
Q
Li
Shmuel
S
Muallem
Sandra L
SL
Hofmann
Abigail A
AA
Soyombo
D000126:Achlorhydria / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D004195:Disease Models, Animal; D005744:Gastric Acid / Q000378:metabolism*; D005755:Gastrins / Q000097:blood; D017506:H(+)-K(+)-Exchanging ATPase / Q000378:metabolism; D006632:Histamine / Q000378:metabolism; D006984:Hypertrophy; D054878:Lipoylation; D008247:Lysosomes / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009081:Mucolipidoses / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D010295:Parietal Cells, Gastric / Q000378:metabolism* / Q000648:ultrastructure; D010766:Phosphorylation; D021381:Protein Transport; D050053:TRPM Cation Channels / Q000172:deficiency* / Q000235:genetics; D013997:Time Factors; D050051:Transient Receptor Potential Channels
D005755:Gastrins; C512321:Mcoln1 protein, mouse; D050053:TRPM Cation Channels; D050051:Transient Receptor Potential Channels; D006632:Histamine; D017506:H(+)-K(+)-Exchanging ATPase; D002118:Calcium