The endoplasmic reticulum stress-responsive protein GRP78 protects neurons against excitotoxicity and apoptosis: Suppression of oxidative stress and stabilization of calcium homeostasis

Zaifang Yu, Hong Luo, Weiming Fu, Mark P. Mattson

Research output: Contribution to journalArticle

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 (Fe(2+) and amyloid β-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 PC 12 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.

Original languageEnglish (US)
Pages (from-to)302-314
Number of pages13
JournalExperimental Neurology
Volume155
Issue number2
DOIs
StatePublished - Feb 1999
Externally publishedYes

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Endoplasmic Reticulum Stress
Heat-Shock Proteins
Oxidative Stress
Homeostasis
Apoptosis
Calcium
Neurons
Endoplasmic Reticulum
Glutamic Acid
Dantrolene
Caspase Inhibitors
Staurosporine
Oligodeoxyribonucleotides
Deoxyglucose
Nerve Growth Factor
Uric Acid
Amyloid
Reactive Oxygen Species
Cell Death
Antioxidants

Keywords

  • Alzheimer's disease
  • Amyloid
  • Caspase
  • Dantrolene
  • Glutathione
  • Mitochondrial transmembrane potential
  • Neurotrophic factors
  • Staurosporine

ASJC Scopus subject areas

  • Neurology
  • Neuroscience(all)

Cite this

The endoplasmic reticulum stress-responsive protein GRP78 protects neurons against excitotoxicity and apoptosis : Suppression of oxidative stress and stabilization of calcium homeostasis. / Yu, Zaifang; Luo, Hong; Fu, Weiming; Mattson, Mark P.

In: Experimental Neurology, Vol. 155, No. 2, 02.1999, p. 302-314.

Research output: Contribution to journalArticle

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