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...
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| 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 |
| _version_ | 1826188000314261504 |
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| author | Seo, Ji Hye Peek, Richard M. Hagen, Susan J. Fox, James G |
| author2 | Massachusetts Institute of Technology. Division of Comparative Medicine |
| author_facet | Massachusetts Institute of Technology. Division of Comparative Medicine Seo, Ji Hye Peek, Richard M. Hagen, Susan J. Fox, James G |
| author_sort | Seo, Ji Hye |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T07:53:04Z |
| format | Article |
| id | mit-1721.1/117648 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T07:53:04Z |
| publishDate | 2018 |
| publisher | Elsevier BV |
| record_format | dspace |
| spelling | mit-1721.1/1176482022-09-23T09:25:10Z N-methyl d-Aspartate Channels Link Ammonia and Epithelial Cell Death Mechanisms in Helicobacter pylori Infection Seo, Ji Hye Peek, Richard M. Hagen, Susan J. Fox, James G Massachusetts Institute of Technology. Division of Comparative Medicine Fox, James G 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. National Institutes of Health (U.S.) (Grant R01AI/RR037750) 2018-09-06T15:59:58Z 2018-09-06T15:59:58Z 2011-09 2010-12 2018-08-29T15:24:12Z Article http://purl.org/eprint/type/JournalArticle 0016-5085 1528-0012 http://hdl.handle.net/1721.1/117648 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 https://orcid.org/0000-0001-9307-6116 http://dx.doi.org/10.1053/j.gastro.2011.08.048 Gastroenterology Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier BV PMC |
| spellingShingle | Seo, Ji Hye Peek, Richard M. Hagen, Susan J. Fox, James G N-methyl d-Aspartate Channels Link Ammonia and Epithelial Cell Death Mechanisms in Helicobacter pylori Infection |
| title | N-methyl d-Aspartate Channels Link Ammonia and Epithelial Cell Death Mechanisms in Helicobacter pylori Infection |
| title_full | N-methyl d-Aspartate Channels Link Ammonia and Epithelial Cell Death Mechanisms in Helicobacter pylori Infection |
| title_fullStr | N-methyl d-Aspartate Channels Link Ammonia and Epithelial Cell Death Mechanisms in Helicobacter pylori Infection |
| title_full_unstemmed | N-methyl d-Aspartate Channels Link Ammonia and Epithelial Cell Death Mechanisms in Helicobacter pylori Infection |
| title_short | N-methyl d-Aspartate Channels Link Ammonia and Epithelial Cell Death Mechanisms in Helicobacter pylori Infection |
| title_sort | n methyl d aspartate channels link ammonia and epithelial cell death mechanisms in helicobacter pylori infection |
| url | http://hdl.handle.net/1721.1/117648 https://orcid.org/0000-0001-9307-6116 |
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