Potent homocysteine-induced ERK phosphorylation in cultured neurons depends on self-sensitization via system Xc{sup -}

Journal Article · Fri Jan 15 00:00:00 EST 2010 · Toxicology and Applied Pharmacology

OSTI ID:21344842

Li, Gu; Xiaoling, Hu; Zhanxia, Xue ^[1]; Jun, Yang; Lishu, Wan; Yan, Ren ^[2]; Hertz, Leif ^[1]

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1. Department of Clinical Pharmacology, College of Basic Medical Sciences, China Medical University, Shenyang (China)
2. Department of Neurology, First Affiliated Hospital, China Medical University, Shenyang (China)

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{sub 1/2}) in cerebellar granule neurons, inhibitable by metabotropic but not ionotropic glutamate receptor antagonists. These findings are analogous to observations by , that similar concentrations cause neuronal death. However, these concentrations are much higher than those occurring clinically during hyperhomocysteinemia. It is therefore important that a approx 10-fold increase in potency occurred in the presence of the glutamate precursor glutamine, when ERK{sub 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{sub c}{sup -} 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{sub 1/2} phosphorylation occurred in the additional presence of cystine. Pharmacological inhibition of system X{sub c}{sup -} prevented the effect of micromolar homocysteine concentrations, and U0126-mediated inhibition of ERK{sub 1/2} phosphorylation enhanced homocysteine-induced death. In conclusion, homocysteine interacts with system X{sub c}{sup -} 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.

• OSTI ID: 21344842
• Journal Information: Toxicology and Applied Pharmacology, Vol. 242, Issue 2; Other Information: DOI: 10.1016/j.taap.2009.10.010; PII: S0041-008X(09)00440-2; Copyright (c) 2009 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
CYSTINE
DEATH
GLUTAMINE
GROWTH FACTORS
HOMOCYSTEINE
HYPOTHESIS
NERVE CELLS
PHOSPHORYLATION
PHOSPHOTRANSFERASES
PRECURSOR
PREGNANCY
TOXICITY
AMIDES
AMINO ACIDS
ANIMAL CELLS
CARBOXYLIC ACIDS
CHEMICAL REACTIONS
DISULFIDES
ENZYMES
MITOGENS
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANIC SULFUR COMPOUNDS
PHOSPHORUS-GROUP TRANSFERASES
PROTEINS
SOMATIC CELLS
TRANSFERASES