Acidosis-induced zinc-dependent death of cultured cerebellar granule neurons.
Severe acidosis caused death of cultured cerebellar granule neurons (CGNs). Acidosis was accompanied by a progressive increase of the intracellular zinc ions ([Zn(2+)](i)) and decrease of [Ca(2+)](i). Zn(2+) chelator, N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN), prevented the increase of [Zn(2+)](i) and acidosis-induced neuronal death. However, neuronal death was insensitive to blockade of ASIC1 channels with amiloride, as CGNs display considerably lower expression of ASIC1a than other neurons. The antioxidant trolox and menadione significantly protected neurons from acidotic death. Earlier, we demonstrated that menadione rescues neurons from the deleterious effect of inhibition of mitochondrial complex I (Isaev et al. Neuroreport 15:2227-2231, 2004). We speculate that excessive Zn(2+)-dependent production of reactive oxygen species by mitochondrial complex I may be a general motive for the induction of cell death in CGNs under acidotic conditions.
Isaev
Nikolay K
NK
A.N. Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow, Russia, 119992. isaev@genebee.msu.su
Stelmashook
Elena V
EV
Lukin
Sergey V
SV
Freyer
Dorette
D
Mergenthaler
Philipp
P
Zorov
Dmitry B
DB
D062565:Acid Sensing Ion Channels; D000138:Acidosis / Q000235:genetics / Q000473:pathology*; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003594:Cytoplasmic Granules / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D005021:Ethylamines / Q000494:pharmacology; D005453:Fluorescence; D005786:Gene Expression Regulation / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism; D024483:Vitamin K 3 / Q000494:pharmacology; D015032:Zinc / Q000494:pharmacology*
D062565:Acid Sensing Ion Channels; C568268:Asic1 protein, rat; D005021:Ethylamines; C511824:N,N,N',N'-tetrakis(2-pyridylmethyl)ethane-1,2-diamine; D009419:Nerve Tissue Proteins; D011725:Pyridines; D012333:RNA, Messenger; D015222:Sodium Channels; D024483:Vitamin K 3; D015032:Zinc