Regulation of MAPK/ERK phosphorylation via ionotropic glutamate receptors in cultured rat striatal neurons

Eur J Neurosci. 2004 Mar;19(5):1207-16. doi: 10.1111/j.1460-9568.2004.03223.x.


Extracellular signals may regulate mitogen-activated protein kinase (MAPK) cascades through a receptor-mediated mechanism. As a signaling superhighway to the nucleus, active Ras-MAPK cascades phosphorylate transcription factors and facilitate gene expression. In cultured rat striatal neurons, the present work systemically examined the linkage between glutamate receptors and the extracellular signal-regulated kinase 1/2 (ERK1/2) subclass of MAPK. We found that glutamate induced a rapid and transient phosphorylation of ERK1/2. Similar responses of ERK1/2 phosphorylation were also induced by the ligands selective for each of three subtypes of ionotropic receptors (NMDA, AMPA and kainate), although not by the subgroup-selective agonists for three subgroups of metabotropic glutamate receptors after 8-9 days in culture. The ERK1/2 phosphorylation induced by all ionotropic receptor agents was dose-, time- and Ca(2+) influx-dependent and occurred in neurons, but not glia. The NMDA-, AMPA- and kainate-induced ERK1/2 phosphorylation was blocked only by the antagonists selective for respective subtypes. The ERK1/2 phosphorylation induced by these agents was also sensitive to the MAPK kinase 1 (MEK1) inhibitor PD98059 and the MEK1/2 inhibitor U0126. In a further attempt to evaluate the role of active ERK1/2 in activating a downstream transcription factor cAMP response element-binding protein (CREB), NMDA, AMPA, and kainate were found to increase CREB phosphorylation. The NMDA- and AMPA/kainate-induced CREB phosphorylation was completely and partially blocked by U0126, respectively. These results revealed a positive linkage between ionotropic glutamate receptors and MEK-sensitive ERK1/2 phosphorylation in striatal neurons. The active ERK1/2 cascade activates the downstream transcription factor CREB to participate in the regulation of gene expression.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cells, Cultured
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism*
  • Embryo, Mammalian
  • Excitatory Amino Acid Agonists / pharmacology
  • Excitatory Amino Acid Antagonists / pharmacology
  • Female
  • Mitogen-Activated Protein Kinase Kinases / metabolism*
  • Neurons / drug effects
  • Neurons / metabolism
  • Phosphorylation / drug effects
  • Pregnancy
  • Rats
  • Receptors, AMPA / agonists
  • Receptors, AMPA / antagonists & inhibitors
  • Receptors, AMPA / metabolism*
  • Receptors, Kainic Acid / agonists
  • Receptors, Kainic Acid / antagonists & inhibitors
  • Receptors, Kainic Acid / metabolism*
  • Receptors, N-Methyl-D-Aspartate / agonists
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / metabolism*


  • Excitatory Amino Acid Agonists
  • Excitatory Amino Acid Antagonists
  • Receptors, AMPA
  • Receptors, Kainic Acid
  • Receptors, N-Methyl-D-Aspartate
  • Mitogen-Activated Protein Kinase Kinases