N-methyl d-Aspartate Channels Link Ammonia and Epithelial Cell Death Mechanisms in Helicobacter pylori Infection
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...
| Main Authors: | , , , |
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| Other Authors: | |
| Format: | Article |
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Elsevier BV
2018
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| Online Access: | http://hdl.handle.net/1721.1/117648 https://orcid.org/0000-0001-9307-6116 |
| Summary: | 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. |
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