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Potent homocysteine-induced ERK phosphorylation in cultured neurons depends on self-sensitization via system Xc(-).

Abstract：

:Homocysteine is increased during pathological conditions, endangering vascular and cognitive functions, and elevated homocysteine during pregnancy may be correlated with an increased incidence of schizophrenia in the offspring. This study showed that millimolar homocysteine concentrations in saline medium cause phosphorylation of extracellular-signal regulated kinases 1 and 2 (ERK(1/2)) in cerebellar granule neurons, inhibitable by metabotropic but not ionotropic glutamate receptor antagonists. These findings are analogous to observations by Zieminska et al. (2003), that similar concentrations cause neuronal death. However, these concentrations are much higher than those occurring clinically during hyperhomocysteinemia. It is therefore important that a approximately 10-fold increase in potency occurred in the presence of the glutamate precursor glutamine, when ERK(1/2) phosphorylation became inhibitable by NMDA or non-NMDA antagonists and dependent upon epidermal growth factor (EGF) receptor transactivation. However, glutamate release to the medium was reduced, suggesting that reversal of the cystine/glutamate antiporter, system X(c)(-) could be involved in potentiation of the response by causing a localized release of initially accumulated homocysteine. In agreement with this hypothesis further enhancement of ERK(1/2) phosphorylation occurred in the additional presence of cystine. Pharmacological inhibition of system X(c)(-) prevented the effect of micromolar homocysteine concentrations, and U0126-mediated inhibition of ERK(1/2) phosphorylation enhanced homocysteine-induced death. In conclusion, homocysteine interacts with system X(c)(-) like quisqualate (Venkatraman et al. 1994), by "self-sensitization" with initial accumulation and subsequent release in exchange with cystine and/or glutamate, establishing high local homocysteine concentrations, which activate adjacent ionotropic glutamate receptors and cause neurotoxicity.

journal_name

Toxicol Appl Pharmacol

journal_title

Toxicology and applied pharmacology

authors

Gu L,Hu X,Xue Z,Yang J,Wan L,Ren Y,Hertz L,Peng L

doi

10.1016/j.taap.2009.10.010

subject

Has Abstract

pub_date

2010-01-15 00:00:00

pages

209-23

issue

eissn

0041-008X

issn

1096-0333

pii

S0041-008X(09)00440-2

journal_volume

242

pub_type

杂志文章

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Potent homocysteine-induced ERK phosphorylation in cultured neurons depends on self-sensitization via system Xc(-).