title: NADPH oxidase-mediated Rac1 GTP activity is necessary for nongenomic actions of the mineralocorticoid receptor in the CA1 region of the rat hippocampus.
abstract: Mineralocorticoid receptors (MRs) in the central nervous system play important roles in spatial memory, fear memory, salt sensitivity, and hypertension. Corticosterone binds to MRs to induce presynaptic vesicle release and postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor aggregation, which are necessary for induction of long-term potentiation under psychological stress. On the other hand, cognitive dysfunction is an important problem clinically in patients with hypertension, diabetes, and cerebral infarction, and all of these conditions are associated with an increase in reactive oxygen species (ROS) generation. Oxidative stress has been shown to modify the genomic actions of MRs in the peripheral organs; however, there have been no reports until now about the relation between the nongenomic actions of MRs and ROS in the central nervous system. In this study, we investigated the relationship between ROS and the nongenomic actions of MR. We examined the nongenomic actions of MR by measuring the slope of the field excitatory postsynaptic potentials and found that ROS induced an additive increase of these potentials, which was accompanied by Rac1 GTP activation and ERK1/2 phosphorylation. An NADPH oxidase inhibitor, apocynin, blocked the nongenomic actions of MRs. A Rac1 inhibitor, NSC23766, was also found to block synaptic enhancement and ERK1/2 phosphorylation induced by NADPH and corticosterone. We concluded that NADPH oxidase activity and Rac1 GTP activity are indispensable for the nongenomic actions of MRs and that Rac1 GTP activation induces ERK1/2 phosphorylation in the brain.
authors: Department of Nephrology, University of Tokyo Faculty of Medicine, Tokyo, Japan.
authors: Fumiko
authors: F
authors: Kawakami-Mori
authors: Tatsuo
authors: T
authors: Shimosawa
authors: Shengyu
authors: S
authors: Mu
authors: Hong
authors: H
authors: Wang
authors: Sayoko
authors: S
authors: Ogura
authors: Yutaka
authors: Y
authors: Yatomi
authors: Toshiro
authors: T
authors: Fujita
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D003345:Corticosterone / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000378:metabolism* / Q000502:physiology; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology
chemical_list: D000098:Acetophenones; D000634:Aminoquinolines; D004791:Enzyme Inhibitors; C487513:NSC 23766; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D018161:Receptors, Mineralocorticoid; C056165:acetovanillone; D019255:NADPH Oxidases; C499134:Rac1 protein, rat; D020830:rac1 GTP-Binding Protein; D003345:Corticosterone