4-hydroxynonenal, an aldehydic product of lipid peroxidation, impairs signal transduction associated with muscarinic acetylcholine and metabotropic glutamate receptors: Possible action on Gα(q/11)

Emmanuelle M. Blanc, Jeremiah F. Kelly, Robert J. Mark, Georg Waeg, Mark P. Mattson

Research output: Contribution to journalArticlepeer-review

Abstract

Considerable data indicate that oxidative stress and membrane lipid peroxidation contribute to neuronal degeneration in an array of age-related neurodegenerative disorders. In contrast, the impact of subtoxic levels of membrane lipid peroxidation on neuronal function is largely unknown. We now report that 4-hydroxynonanal (HNE), an aldehydic product of lipid peroxidation, disrupts coupling of muscarinic cholinergic recaptors and metabotropic glutamate recaptots to phospholipase C-linked GTP-binding proteins in cultured rat cerebrocortical neurons. At subtoxic concentrations, HNE markedly inhibited GTPase activity, inositol phosphate release, and elevation of intracellular calcium levels induced by carbachol (muscarinic agonist) and (RS)-3,5-dihydroxyphenyl glycine (metabotropic glutamate receptor agonist). Maximal impairment of agonist-induced responses occurred within 30 min of exposure to HNE. Other aldehydes, including malondialdehyde, had little effect on agonist-induced responses. Antioxidants that suppress lipid peroxidation did not prevent impairment of agonist-induced responses by HNE, whereas glutathione, which is known to bind and detoxify HNE, did prevent impairment of agonist-induced responses. HNE itself did not induce oxidative stress. Immunoprecipitation-western blot analysis using an antibody to HNE-protein conjugates showed that HNE can bind to Gα(q/11). HNE also significantly suppressed inositol phosphate release induced by aluminum fluoride. Collectively, our data suggest that HNE plays a role in altering receptor-G protein coupling in neurons under conditions of oxidative stress that may occur both normally, and before cell degeneration and death in pathological settings.

Original languageEnglish (US)
Pages (from-to)570-580
Number of pages11
JournalJournal of Neurochemistry
Volume69
Issue number2
StatePublished - Aug 1997
Externally publishedYes

Keywords

  • Alzheimer's disease
  • Antioxidants
  • Calcium homeostasis
  • Cerebral ischemia
  • Endoplasmic reticulum
  • Glutathione
  • Inositol phosphate
  • Phospholipase C
  • Stroke
  • Vitamin E

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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