Homocysteine–NMDA receptor-mediated activation of extracellular signal-regulated kinase leads to neuronal cell death
Version of Record online: 5 JUN 2009
© 2009 The Authors. Journal Compilation © 2009 International Society for Neurochemistry
Journal of Neurochemistry
Volume 110, Issue 3, pages 1095–1106, August 2009
How to Cite
Poddar, R. and Paul, S. (2009), Homocysteine–NMDA receptor-mediated activation of extracellular signal-regulated kinase leads to neuronal cell death. Journal of Neurochemistry, 110: 1095–1106. doi: 10.1111/j.1471-4159.2009.06207.x
- Issue online: 13 JUL 2009
- Version of Record online: 5 JUN 2009
- Received May 21, 2009; revised manuscript received May 29, 2009; accepted May 29, 2009.
- Ca2+ influx;
- cAMP response-element binding protein;
- extracellular signal-regulated mitogen-activated protein kinase;
- neuronal cell death;
- NMDA receptors
Hyperhomocysteinemia is an independent risk factor for stroke and neurological abnormalities. However, the underlying cellular mechanisms by which elevated homocysteine can promote neuronal death is not clear. In the present study we have examined the role of NMDA receptor-mediated activation of the extracellular signal-regulated kinase-mitogen-activated protein (ERK-MAP) kinase pathway in homocysteine-dependent neurotoxicity. The study demonstrates that in neurons l-homocysteine-induced cell death was mediated through activation of NMDA receptors. The study also shows that homocysteine-dependent NMDA receptor stimulation and resultant Ca2+ influx leads to rapid and sustained phosphorylation of ERK-MAP kinase. Inhibition of ERK phosphorylation attenuates homocysteine-mediated neuronal cell death thereby demonstrating that activation of ERK-MAP kinase signaling pathway is an intermediate step that couples homocysteine-mediated NMDA receptor stimulation to neuronal death. The findings also show that cAMP response-element binding protein (CREB), a pro-survival transcription factor and a downstream target of ERK, is only transiently activated following homocysteine exposure. The sustained activation of ERK but a transient activation of CREB together suggest that exposure to homocysteine initiates a feedback loop that shuts off CREB signaling without affecting ERK phosphorylation and thereby facilitates homocysteine-mediated neurotoxicity.