Inhibition of Qi site of mitochondrial complex III with antimycin A decreases persistent and transient sodium currents via reactive oxygen species and protein kinase C in rat hippocampal CA1 cells.
Hypoxia-induced inhibition of Qi site of mitochondrial complex III under hypoxia has received attention, but its downstream pathways remain unclear. In this paper, we used Qi site inhibitor antimycin A to mimic the inhibition of the Qi site of mitochondrial complex III and studied the effects of the inhibition of this site on persistent sodium currents, transient sodium currents, and neuronal excitability in rat hippocampal CA1 cells with whole cell patch-clamp methods. The results showed that antimycin A decreased the amplitude of both persistent and transient sodium currents; antioxidant 2-mercaptopropionylglycine or 1,10 phenanthroline abolished the effect of antimycin A; the complex III Qo site inhibitor stigmatellin, the protein kinase C inhibitor chelerythrine, but not the protein kinase A inhibitor H89, canceled the effect of antimycin A; antimycin A decreased the amplitude of both persistent and transient sodium currents only at more depolarized membrane potentials and the decrease percentage of both persistent and transient sodium currents after antimycin A at potentials above -50 mV increased with the change in potentials toward more depolarized direction; exogenous application of H2O2 inhibited the amplitude of both persistent and transient sodium currents; the amount of current required to trigger spikes was increased and the number of spikes produced by varying levels of currents was decreased by antimycin A. These results suggest that the inhibition of Qi site of mitochondrial complex III decreases both persistent and transient sodium currents via reactive oxygen species and protein kinase C in rat hippocampal CA1 cells.
Lai
Bin
B
State Key Laboratory of Medical Neurobiology, Fudan University Shanghai Medical College, 138 Yixueyuan Road, Shanghai 200032, People's Republic of China.
Zhang
Li
L
Dong
Lian-Yan
LY
Zhu
Yan-Hua
YH
Sun
Feng-Yan
FY
Zheng
Ping
P
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000968:Antimycin A / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D002534:Hypoxia, Brain / Q000378:metabolism / Q000503:physiopathology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009924:Organ Culture Techniques; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D011493:Protein Kinase C / Q000187:drug effects* / Q000378:metabolism; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D000975:Antioxidants; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D015222:Sodium Channels; D000968:Antimycin A; D012964:Sodium; D006861:Hydrogen Peroxide; D011493:Protein Kinase C; D014450:Electron Transport Complex III