Nitric oxide inhibits complex I following AMPA receptor activation via peroxynitrite.
We investigated the role of nitric oxide (NO) on mitochondrial complexes activity, following short-term non-desensitizing activation of AMPA receptors with kainate (KA) plus cyclothiazide (CTZ), in cultured rat hippocampal neurons. In these conditions, we observed a decrease in the activity of mitochondrial complexes I, II/III, and IV. A selective neuronal nitric oxide synthase inhibitor, 7-Nitroindazole, prevented the decrease in the activity of mitochondrial complex I, but not for the other complexes. Exposure to KA plus CTZ also increased cyclic GMP levels significantly, and led to increased levels of 3-nitrotyrosine, a biomarker for peroxynitrite production. Taken together, our results suggest that non-desensitizing activation of AMPA receptors causes inhibition of mitochondrial complex I via peroxynitrite.
Araújo
Inês M
IM
Center for Neuroscience and Cell Biology, Department of Zoology, University of Coimbra, 3004-517 Coimbra, Portugal.
Verdasca
Maria J
MJ
Ambrósio
António F
AF
Carvalho
Caetana M
CM
D000704:Analysis of Variance; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001581:Benzothiadiazines / Q000494:pharmacology; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D004347:Drug Interactions; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology; D007150:Immunohistochemistry / Q000379:methods; D007608:Kainic Acid / Q000494:pharmacology; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects*; D009569:Nitric Oxide / Q000494:pharmacology*; D030421:Peroxynitrous Acid / Q000494:pharmacology*; D017494:Proton Pumps / Q000145:classification / Q000378:metabolism*; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D000959:Antihypertensive Agents; D001581:Benzothiadiazines; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; C489787:MAP2 protein, rat; D008869:Microtubule-Associated Proteins; D017494:Proton Pumps; D011810:Quinoxalines; D018091:Receptors, AMPA; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D006152:Cyclic GMP; C004639:cyclothiazide; D007608:Kainic Acid; D019331:NG-Nitroarginine Methyl Ester