Peroxynitrite donor impairs excitability of hippocampal CA1 neurons by inhibiting voltage-gated potassium currents.
Nitric oxide (NO) reacts rapidly with superoxide anion and produces peroxynitrite (ONOO(-)), which is a highly reactive free radical that has been shown to mediate much of the toxicity of NO. ONOO(-) has also been implicated as playing a role in the pathology of various brain disorders. The aim of this study was to investigate the actions of ONOO(-) on voltage-activated potassium currents and its effect on membrane excitability in hippocampal CA1 neurons. SIN-1(3-morpholino-sydnonimine), which leads to the simultaneous generation of superoxide anion and NO, and then forms the highly reactive species ONOO(-), induced a dose-dependent inhibition in amplitudes of transient potassium currents (I(A)) and delayed rectifier potassium currents (I(K)). SIN-1 (500 microM) produced a hyperpolarizing shift in the activation-voltage curve of both I(A) and I(K) and delayed the recovery of I(A) from inactivity, but did not have a marked effect on the inactivation parameters of I(A). However, co-treatment with SIN-1 and Mn(III)tetrakis(4-benzoic acid)porphyrin chloride (MnTBAP, 100 microM), an ONOO(-) scavenger, had no effects on I(A) and I(K) currents. SIN-1 (500 microM) led to increase in action potential duration and decrease in action potential firing rate. The results suggest that changes of I(A) and I(K) currents induced by ONOO(-) in hippocampal neurons have influence on excitability of hippocampal CA1 neurons, which are related to its neurotoxicity.
Liu
Zhao Wei
ZW
Key Lab of Bioactive Materials, Ministry of Education, College of Life Science, Tianjin 300071, China.
Lei
Ting
T
Zhang
Tao
T
Yang
Zhuo
Z
D000818:Animals; D016166:Free Radical Scavengers / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology; D066298:In Vitro Techniques; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D008981:Molsidomine / Q000031:analogs & derivatives* / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D030421:Peroxynitrous Acid; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar
D016166:Free Radical Scavengers; D008665:Metalloporphyrins; D020030:Nitric Oxide Donors; D024642:Potassium Channels, Voltage-Gated; C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin; D030421:Peroxynitrous Acid; C002385:linsidomine; D008981:Molsidomine