Regulation of extracellular signal-regulated kinase by homocysteine in hippocampus

Neuroscience. 2005;133(4):925-35. doi: 10.1016/j.neuroscience.2005.03.034.


In several neurological disorders including hyperhomocysteinemia, homocysteine (Hcy) accumulates in the brain, and acts as a potent neurotoxin. However, the molecular mechanisms induced by increased levels of Hcy in brain are not well understood. Here we show an activation of the extracellular signal-regulated kinases (ERK1 and ERK2) and the downstream nuclear targets Elk-1 and calcium/cAMP response element binding protein, in the hippocampus of cystathionine beta synthase deficient mice, a murine model of hyperhomocysteinemia. An ex vivo model of hippocampal slices allowed us to reproduce Hcy -induced ERK activation and to unravel the mechanisms responsible of this activation. Of interest, N-methyl-d-aspartate (NMDA), non-NMDA and metabotropic glutamate receptor antagonists all blocked Hcy -induced ERK activation. Moreover, the ERK activation was blocked in the presence of Na+-channel blocker tetrodotoxin, indicating the existence of a trans-synaptic activity in ERK activation by Hcy in hippocampal slices. The effects of Hcy on ERK cascade activation were also dependent on calcium influx, CaMK-II, PKC as well as PKA activation. Thus, altogether these data support a role of Hcy on ERK activation, via complex mechanisms, starting with a control of glutamate release, which in turn activates ionotropic and metabotropic receptor subtypes and produces increases in intracellular calcium levels.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 6-Cyano-7-nitroquinoxaline-2,3-dione / pharmacology
  • Analysis of Variance
  • Animals
  • Blotting, Western / methods
  • Chelating Agents / pharmacology
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Dizocilpine Maleate / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Egtazic Acid / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Excitatory Amino Acid Antagonists / pharmacology
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology*
  • Glycine / analogs & derivatives
  • Glycine / pharmacology
  • Hippocampus / metabolism*
  • Homocysteine / blood
  • Homocysteine / deficiency
  • Homocysteine / pharmacology
  • Homocysteine / physiology*
  • Immunohistochemistry / methods
  • In Vitro Techniques
  • Male
  • Mice
  • Mice, Knockout
  • Signal Transduction / physiology*
  • Tetrodotoxin / pharmacology
  • Time Factors


  • Chelating Agents
  • Cyclic AMP Response Element-Binding Protein
  • Enzyme Inhibitors
  • Excitatory Amino Acid Antagonists
  • methyl-(4-carboxyphenyl)glycine
  • Homocysteine
  • Tetrodotoxin
  • Egtazic Acid
  • Dizocilpine Maleate
  • 6-Cyano-7-nitroquinoxaline-2,3-dione
  • Extracellular Signal-Regulated MAP Kinases
  • Glycine