4-Hydroxynonenal, an Aldehydic Product of Lipid Peroxidation, Impairs Signal Transduction Associated with Muscarinic Acetylcholine and Metabotropic Glutamate Receptors: Possible Action on Gαq/11 |
| |
Authors: | Emmanuelle M Blanc Jeremiah F Kelly Robert J Mark †Georg Waeg Mark P Mattson |
| |
Institution: | Sanders-Brown Center on Aging and Department of Anatomy and Neurobiology, University of Kentucky, Lexington, Kentucky;and; Gerontology Research Center, NIH, Baltimore, Maryland, U.S.A.;and; Institute for Biochemistry, University of Graz, Graz, Austria |
| |
Abstract: | 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-hydroxy-nonenal (HNE), an aldehydic product of lipid peroxidation, disrupts coupling of muscarinic cholinergic receptors and metabotropic glutamate receptors 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 Gαq/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. |
| |
Keywords: | Alzheimer's disease Antioxidants Calcium homeostasis Cerebral ischemia Endoplasmic reticulum Glutathione Inositol phosphate Phospholipase C Stroke Vitamin E |
|
|