A tyrosine-based signal targets H/K-ATPase to a regulated compartment and is required for the cessation of gastric acid secretion.
Gastric acid secretion is mediated by the H/K-ATPase of parietal cells. Activation of acid secretion involves insertion of H/K-ATPase into the parietal cell plasmalemma, while its cessation is associated with reinternalization of the H/K-ATPase into an intracellular storage compartment. The cytoplasmic tail of the H/K-ATPase beta subunit includes a four residue sequence homologous to tyrosine-based endocytosis signals. We generated transgenic mice expressing H/K-ATPase beta subunit in which this motif's tyrosine residue is mutated to alanine. Gastric glands from animals expressing mutant beta subunit constitutively secrete acid and continuously express H/K-ATPase at their cell surfaces. Thus, the beta subunit's tyrosine-based signal is required for the internalization of H/K-ATPase and for the termination of acid secretion. As a consequence of chronic hyperacidity, the mice develop gastric ulcers and a hypertrophic gastropathy resembling Menetrier's disease.
Courtois-Coutry
N
N
Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Roush
D
D
Rajendran
V
V
McCarthy
J B
JB
Geibel
J
J
Kashgarian
M
M
Caplan
M J
MJ
D000818:Animals; D019556:COS Cells; D002118:Calcium / Q000378:metabolism; D003587:Cytomegalovirus / Q000235:genetics; D017931:DNA Primers; D004705:Endocytosis; D005744:Gastric Acid / Q000378:metabolism*; D005753:Gastric Mucosa / Q000166:cytology / Q000201:enzymology; D017506:H(+)-K(+)-Exchanging ATPase / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D046911:Macromolecular Substances; D051379:Mice; D008822:Mice, Transgenic; D016253:Microscopy, Immunoelectron; D016297:Mutagenesis, Site-Directed; D010295:Parietal Cells, Gastric / Q000201:enzymology / Q000502:physiology* / Q000648:ultrastructure; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D014443:Tyrosine
D017931:DNA Primers; D046911:Macromolecular Substances; D011994:Recombinant Proteins; D014443:Tyrosine; D017506:H(+)-K(+)-Exchanging ATPase; D002118:Calcium