The Endoplasmic Reticulum Stress-Responsive Protein GRP78 Protects Neurons Against Excitotoxicity and Apoptosis: Suppression of Oxidative Stress and Stabilization of Calcium Homeostasis
Abstract
The 78-kDa glucose-regulated protein (GRP78) is localized in the endoplasmic reticulum (ER), and its expression is increased by environmental stressors in many types of nonneuronal cells. We report that levels of GRP78 are increased in cultured rat hippocampal neurons exposed to glutamate and oxidative insults (Fe2+ and amyloid beta-peptide) and that treatment of cultures with a GRP78 antisense oligodeoxynucleotide increases neuronal death following exposure to each insult. GRP78 antisense treatment enhanced apoptosis of differentiated PC12 cells following NGF withdrawal or exposure to staurosporine. Pretreatment of hippocampal cells with 2-deoxy-d-glucose, a potent inducer of GRP78 expression, protected neurons against excitotoxic and oxidative injury. GRP78 expression may function to suppress oxidative stress and stabilize calcium homeostasis because treatment with GRP78 antisense resulted in increased levels of reactive oxygen species and intracellular calcium following exposure to glutamate and oxidative insults in hippocampal neurons. Dantrolene (a blocker of ER calcium release), uric acid (an antioxidant), and zVAD-fmk (a caspase inhibitor) each protected neurons against the death-enhancing action of GRP78 antisense. The data suggest that ER stress plays a role in neuronal cell death induced by an array of insults and that GRP78 serves a neuroprotective function.
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GRP78 has previously exhibited several neuroprotective roles within endoplasmic reticulum-stress response pathways, by guarding against oxidative stress and glutamate excitotoxicity due to prolonged cerebral ischemia.
“whereas GRP78 has previously exhibited several neuroprotective roles within endoplasmic reticulum–stress response pathways, by guarding against oxidative stress and glutamate excitotoxicity due to prolonged cerebral ischemia.”
From High vulnerability of medial prefrontal pyramidal neurons in post-stroke, vascular, Alzheimer's disease, and aging-related dementias (2026) · cites this paper as [23]
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“Sections were blocked with 10% normal goat serum for 1 hour and then incubated overnight at 4 b OCSP Classification: there were no differences found between stroke territory distributions of post-stroke with no dementia and post-stroke dementia cases( p > 0.05). c Only eight cases were included for post-stroke non-dem…”
Influential
- Authors
- Yu, Z., Luo, H., Fu, W., & Mattson, M. P.
- Affiliations
- University of Kentucky (US)
- Venue
- Experimental Neurology
- Publisher
- Elsevier BV
- Published
- 1999-02
- Volume
- 155
- Issue
- 2
- Pages
- 302-314
- ISSN
- 0014-4886 (ISSN-L)
- OpenAlex
- W2049876394
- Cited by
- 438
- References
- 74
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 3 · 2023: 7 · 2022: 3 · 2021: 7 · 2020: 7 · 2019: 14 · 2018: 10 · 2017: 11 · 2016: 11 · 2015: 16 · 2014: 16 · 2013: 16 · 2012: 19
- FWCI
- 9.43
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Experimental Neurology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ag014554-07, 5r01ns035253-03)
- National Institute on Aging (AG14554, P01AG005119, AG0 5119)
- National Institute of Neurological Disorders and Stroke (NS 35253)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- GRP78, endoplasmic reticulum stress, excitotoxicity, oxidative stress, neuronal apoptosis, neuroprotection, calcium homeostasis, reactive oxygen species, glutamate, amyloid-beta, iron, staurosporine, NGF withdrawal, dantrolene, uric acid, caspase inhibition, hippocampal neurons, PC12 cells, antisense oligodeoxynucleotides
- MeSH terms
- Endoplasmic Reticulum Chaperone BiP, Animals, Calcium, Carrier Proteins, Endoplasmic Reticulum, Ferric Compounds, Heat-Shock Proteins, Hippocampus, Homeostasis, Immunohistochemistry, Mitochondria, Neurons, Blotting, Western, PC12 Cells, Apoptosis, Reactive Oxygen Species, Oxidative Stress, Glutamic Acid, Molecular Chaperones, Excitatory Amino Acids, Rats
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