4-HYDROXYNONENAL, AN ALDEHYDIC PRODUCT OF LIPID-PEROXIDATION, IMPAIRSSIGNAL-TRANSDUCTION ASSOCIATED WITH MUSCARINIC ACETYLCHOLINE AND METABOTROPIC GLUTAMATE RECEPTORS - POSSIBLE ACTION ON G-ALPHA(Q 11)/

Considerable data indicate that oxidative stress and membrane lipid pe roxidation contribute to neuronal degeneration in an array of age-rela ted neurodegenerative disorders. In contrast, the impact of subtoxic l evels of membrane lipid peroxidation on neuronal function is largely u nknown. We now report that 4-hydroxynonenal (HNE), an aldehydic produc t of lipid peroxidation, disrupts coupling of muscarinic cholinergic r eceptors and metabotropic glutamate receptors to phospholipase C-linke d GTP-binding proteins in cultured rat cerebrocortical neurons. At sub toxic concentrations, HNE markedly inhibited GTPase activity, inositol phosphate release, and elevation of intracellular calcium levels indu ced by carbachol (muscarinic agonist) and (RS)-3,5-dihydroxyphenyl gly cine (metabotropic glutamate receptor agonist). Maximal impairment of agonist-induced responses occurred within 30 min of exposure to HNE. O ther aldehydes, including malondialdehyde, had little effect on agonis t-induced responses. Antioxidants that suppress lipid peroxidation did not prevent impairment of agonist-induced responses by HNE, whereas g lutathione, which is known to bind and detoxify HNE, did prevent impai rment of agonist-induced responses. HNE itself did not induce oxidativ e stress. Immunoprecipitation-western blot analysis using an antibody to HNE-protein conjugates showed that HNE can bind to G alpha(q/11). H NE also significantly suppressed inositol phosphate release induced by aluminum fluoride. Collectively, our data suggest that HNE plays a ro le in altering receptor-G protein coupling in neurons under conditions of oxidative stress that may occur both normally, and before cell deg eneration and death in pathological settings.