N-methyl d-Aspartate Channels Link Ammonia and Epithelial Cell Death Mechanisms in Helicobacter pylori Infection
Author(s)Seo, Ji Hye; Peek, Richard M.; Hagen, Susan J.; Fox, James G
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Background & Aims: Helicobacter pylori infection is a risk factor for gastric cancer. Ammonia/ammonium (A/A) is a cytotoxin generated by H pylori that kills gastric epithelial cells. We investigated whether A/A cytotoxicity occurs by activating N-methyl d-aspartate (NMDA) channels, which results in Ca2+permeation and epithelial cell death. Methods: Gastric epithelial cells were cultured to confluence and then incubated with A/A and NMDA channel or cell signaling antagonists. Cells were incubated with wild-type H pylori or mutant strains that do not produce A/A. Changes in intracellular Ca2+were examined in living cells by confocal microscopy. Biochemical and histochemical techniques were used to examine the relationship between A/A-induced cell death and intracellular levels of Ca2+. Results: A/A increased Ca2+permeation in gastric epithelial cells; the increase was blocked by NMDA receptor and cell signaling antagonists. Wild-type, but not mutant H pylori, also caused extensive Ca2+permeation of gastric epithelial cells, which was blocked when NMDA-receptor expression was repressed. Ca2+that entered cells was initially cytoplasmic and activated proteases. Later, the Ca2+was sequestered to cytoplasmic vacuoles that are dilatations of the endoplasmic reticulum. Inositol-3-phosphatedependent release of Ca2+from the endoplasmic reticulum and protease activity damaged mitochondria, reduced levels of adenosine triphosphate, and transcriptionally up-regulated cell death effectors. Expression of the NMDA receptor was altered in stomachs of mice infected with H pylori. Conclusions: A/A affects gastric epithelial cell viability by allowing excessive Ca2+permeation through NMDA channels. NMDA channels might thereby regulate cell survival and death pathways during development of gastric cancers associated with H pylori infection.
DepartmentMassachusetts Institute of Technology. Division of Comparative Medicine
Seo, Ji Hye et al. “N-Methyl d-Aspartate Channels Link Ammonia and Epithelial Cell Death Mechanisms in Helicobacter Pylori Infection.” Gastroenterology 141, 6 (December 2011): 2064–2075 © 2011 AGA Institute
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