NADPH oxidase is required for NMDA receptor-dependent activation of ERK in hippocampal area CA1.
Previous studies have shown that N-methyl-D-aspartate (NMDA) receptor activation results in production of reactive oxygen species (ROS) and activation of extracellular signal-regulated kinase (ERK) in hippocampal area CA1. In addition, application of ROS to hippocampal slices has been shown to result in activation of ERK in area CA1. To determine whether these events were linked causally, we investigated whether ROS are required for NMDA receptor-dependent activation of ERK. In agreement with previous studies, we found that treatment of hippocampal slices with NMDA resulted in activation of ERK in area CA1. The NMDA receptor-dependent activation of ERK was either blocked or attenuated by a number of antioxidants, including the general antioxidant N-acetyl-L-cysteine (L-NAC), the superoxide-scavenging enzyme superoxide dismutase (SOD), the membrane-permeable SOD mimetic Mn(III) tetrakis (4-benzoic acid) porphyrin (MnTBAP), the hydrogen peroxide-scavenging enzyme catalase, and the catalase mimetic ebselen. The NMDA receptor-dependent activation of ERK also was blocked by the NADPH oxidase inhibitor diphenylene iodonium (DPI) and was absent in mice that lacked p47(phox), one of the required protein components of NADPH oxidase. Taken together, our results suggest that ROS production, especially superoxide production via NADPH oxidase, is required for NMDA receptor-dependent activation of ERK in hippocampal area CA1.
Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, USA.
Kenneth T
KT
Kishida
Maryland
M
Pao
Steven M
SM
Holland
Eric
E
Klann
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001393:Azoles / Q000494:pharmacology; D015153:Blotting, Western / Q000379:methods; D002374:Catalase / Q000494:pharmacology; D002395:Catecholamines / Q000494:pharmacology; D018491:Dopamine Agonists; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000145:classification / Q000378:metabolism*; D016166:Free Radical Scavengers / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology* / Q000201:enzymology; D048288:Imidazolines / Q000494:pharmacology; D066298:In Vitro Techniques; D054833:Isoindoles; D008239:Lysine / Q000031:analogs & derivatives / Q000494:pharmacology; D008665:Metalloporphyrins / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D016202:N-Methylaspartate / Q000494:pharmacology; D019255:NADPH Oxidases / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D016566:Organoselenium Compounds / Q000494:pharmacology; D018408:Patch-Clamp Techniques / Q000379:methods; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D013482:Superoxide Dismutase / Q000494:pharmacology
D001393:Azoles; D002395:Catecholamines; D018491:Dopamine Agonists; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D016166:Free Radical Scavengers; D048288:Imidazolines; D054833:Isoindoles; D008665:Metalloporphyrins; C086501:N-acetylcysteine lysinate; D016566:Organoselenium Compounds; D017382:Reactive Oxygen Species; D016194:Receptors, N-Methyl-D-Aspartate; C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin; C042986:ebselen; D016202:N-Methylaspartate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; C011775:(3,4-dihydroxyphenylamino)-2-imidazoline; D002374:Catalase; D013482:Superoxide Dismutase; D019255:NADPH Oxidases; D048049:Extracellular Signal-Regulated MAP Kinases; D008239:Lysine; D019331:NG-Nitroarginine Methyl Ester; D000111:Acetylcysteine