Mitogen-activated protein kinase/extracellular signal-regulated kinase attenuates 3-hydroxykynurenine-induced neuronal cell death.
3-Hydroxykynurenine (3-HK), an endogenous tryptophan metabolite, is known to have toxic effects in brain. However, the molecular mechanism of the toxicity has not been well identified. In this study, we investigated the involvement of MAPK/extracellular signal-regulated kinase (ERK) in the 3-HK-induced neuronal cell damage. Our results showed that 3-HK induced apoptotic neuronal cell death and ERK phosphorylation occurred during cell death. Inhibition of ERK activation using PD98059 considerably increased cell death. Furthermore, cell death was preceded by mitochondrial malfunction including collapse of mitochondrial membrane potential (DeltaPsi(m)) and cytochrome c release from mitochondria to the cytosol. Interestingly, inhibition of ERK dramatically increased mitochondrial malfunction, and enhanced caspase activation, resulting in enhanced neuronal cell death. Thus, our results show that ERK plays a protective role by maintaining mitochondrial function and regulating caspase activity under conditions of cellular stress.
Lee
Hyun Jung
HJ
Department of Anatomy, College of Medicine, Chung-Ang University, Seoul, South Korea.
Bach
Jae-Hyung
JH
Chae
Hee-Sun
HS
Lee
Sang Hyung
SH
Joo
Wan Seok
WS
Choi
Se Hoon
SH
Kim
Kyung Yong
KY
Lee
Won Bok
WB
Kim
Sung Su
SS
D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007737:Kynurenine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000633:toxicity*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology*
D004791:Enzyme Inhibitors; C005045:3-hydroxykynurenine; D007737:Kynurenine; D020928:Mitogen-Activated Protein Kinases