Nitric oxide causes glutamate release from brain synaptosomes.
We determined the ability of pathological levels of nitric oxide (NO) to cause glutamate release from isolated rat brain nerve terminals using a fluorometric assay. It was found that NO (0.7 and 2 microM) produced (4 and 10 nmol/mg of synaptosomal protein) Ca2+-independent glutamate release from synaptosomes (after 1 min of exposure). Spermine/NO complex (spermine NONOate; a slow NO donor) and potassium cyanide (an inhibitor of cytochrome oxidase) also caused Ca2+-independent glutamate release. Preincubation of synaptosomes with 5 microM 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (an inhibitor of soluble guanylyl cyclase) had no effect on NO-induced Ca2+-independent glutamate release. Ca2+-independent glutamate release produced by NO was greater in a low-oxygen medium. NO, spermine NONOate, and potassium cyanide inhibited synaptosomal respiration with a similar order of potency with respect to their ability to cause glutamate release. Because NO has been shown previously to inhibit reversibly cytochrome oxidase in competition with oxygen, our findings in this study suggest that NO (and cyanide) causes glutamate release following inhibition of mitochondrial respiration at the level of cytochrome oxidase. Thus, elevated NO production leading to mitochondrial dysfunction, glutamate release, and excitotoxicty may contribute to neuronal death in neurological diseases.
McNaught
K S
KS
Department of Biochemistry, University of Cambridge, England, UK.
Brown
G C
GC
D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D003470:Culture Media / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D009569:Nitric Oxide / Q000494:pharmacology*; D009589:Nitrogen Oxides; D010100:Oxygen / Q000378:metabolism; D011190:Potassium Cyanide / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013096:Spermine / Q000031:analogs & derivatives / Q000494:pharmacology; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*
D003470:Culture Media; D009589:Nitrogen Oxides; C091861:spermine nitric oxide complex; D013096:Spermine; D009569:Nitric Oxide; D018698:Glutamic Acid; D015761:4-Aminopyridine; D011190:Potassium Cyanide; D010100:Oxygen