Hydrogen-peroxide-induced toxicity of rat striatal neurones involves activation of a non-selective cation channel.
Striatal neurones are particularly vulnerable to hypoxia/ischaemia-induced damage, and free radicals are thought to be prime mediators of this neuronal destruction. It has been shown that hydrogen peroxide (H2O2), through the production of free radicals, induces rat insulinoma cell death by activation of a non-selective cation channel, which leads to irreversible cell depolarization and unregulated Ca2+ entry into the cell. In the study presented here, we demonstrate that a subpopulation of striatal neurones (medium spiny neurones) is depolarized by H2O2 through the production of free radicals. Cell-attached recordings from rat cultured striatal neurones demonstrate that exposure to H2O2 opens a large-conductance channel that is characterized by extremely long open times (seconds). Inside-out recordings show that cytoplasmically applied beta-nicotinamide adenine dinucleotide activates a channel with little voltage dependence, a linear current-voltage relationship and a single-channel conductance of between 70 and 90 pS. This channel is permeable to Na+, K+ and Ca2+ ions. Fura-2 imaging from cultured striatal neurones reveals that H2O2 exposure induces a biphasic intracellular Ca2+ increase in a subpopulation of neurones, the second, later phase resulting in Ca2+ overload. This later component of the Ca2+ response is dependent on the presence of extracellular Ca2+ and is independent of synaptic activity or voltage-gated Ca2+ channel opening. Consequently, this channel may be an important contributor to free radical-induced selective striatal neurone destruction. These results are remarkably similar to those observed for insulinoma cells and suggest that this family of non-selective cation channels has a widespread distribution in mammalian tissues.
Smith
M A
MA
Department of Biomedical Sciences, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, UK.
Herson
P S
PS
Lee
K
K
Pinnock
R D
RD
Ashford
M L J
ML
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002412:Cations / Q000378:metabolism*; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D004594:Electrophysiology; D006861:Hydrogen Peroxide / Q000506:poisoning*; D007425:Intracellular Membranes / Q000378:metabolism; D007473:Ion Channels / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D016877:Oxidants / Q000506:poisoning*; D051381:Rats; D017207:Rats, Sprague-Dawley
D002412:Cations; D007473:Ion Channels; D016877:Oxidants; D006861:Hydrogen Peroxide; D002118:Calcium