Metabotropic glutamate receptor 5-regulated Elk-1 phosphorylation and immediate early gene expression in striatal neurons

J Neurochem. 2003 May;85(4):1006-17. doi: 10.1046/j.1471-4159.2003.01750.x.


The Galphaq protein-coupled metabotropic glutamate receptor subtype-5 (mGluR5) is densely expressed in medium spiny projection neurons of striatum. Emerging evidence suggests a significant role of mGluR5 in the addictive plasticity of striatal neurons that is likely derived from inducible cellular gene expression related to stimulation of mGluR5 and associative signaling proteins. In this study, we found that activation of mGluR5 with a selective agonist (RS)-2-chloro-5-hydroxy-phenylglycine (CHPG) induced a rapid and transient phosphorylation of a transcription regulator Elk-1 in cultured striatal neurons from rat E19 embryos or neonatal day-1 pups. The Elk-1 phosphorylation was dose-dependent and occurred in neurochemically identified GABAergic neurons, but not glia. A series of experiments further demonstrated that the CHPG-stimulated Elk-1 phosphorylation was mediated through selective activation of mGluR5-regulated phospholipase C and associative second messenger system, i.e. 1,4,5,-triphosphate-sensitive Ca2+ release. Moreover, the Elk-1 phosphorylation was partially dependent on mGluR5-mediated co-activation of NMDA, but not kainate/AMPA receptors and L-type voltage-operated Ca2+ channels. Using an immediate early gene c-fos as a report of inducible gene expression, we found that CHPG induced marked c-fos mRNA expression. The c-fos induction kinetically corresponded to the Elk-1 phosphorylation and was attenuated by antisense oligonucleotides that selectively knocked down Elk-1 proteins. These results indicate that glutamatergic tone on mGluR5 is positively coupled to Elk-1 phosphorylation in striatal neurons via multiple signaling mechanisms involving Ca2+ release and NMDA activation, and the mGluR5-mediated Elk-1 phosphorylation facilitates gene transcription.

Publication types

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

MeSH terms

  • Animals
  • Calcium / metabolism
  • Calcium Channel Blockers / pharmacology
  • Calcium Channels, L-Type / drug effects
  • Cells, Cultured
  • Corpus Striatum / cytology*
  • Corpus Striatum / embryology
  • DNA-Binding Proteins*
  • Dose-Response Relationship, Drug
  • Excitatory Amino Acid Agonists / pharmacology
  • Excitatory Amino Acid Antagonists / pharmacology
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology
  • Genes, Immediate-Early / physiology*
  • Glycine / analogs & derivatives*
  • Glycine / pharmacology
  • Neuroglia / drug effects
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Phenylacetates / pharmacology
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins / drug effects
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-fos / genetics
  • Proto-Oncogene Proteins c-fos / metabolism
  • RNA, Messenger / metabolism
  • Rats
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate / agonists
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors
  • Receptors, Metabotropic Glutamate / metabolism*
  • Transcription Factors*
  • Type C Phospholipases / metabolism
  • ets-Domain Protein Elk-1


  • 2-chloro-5-hydroxyphenylglycine
  • Calcium Channel Blockers
  • Calcium Channels, L-Type
  • DNA-Binding Proteins
  • Elk1 protein, rat
  • Excitatory Amino Acid Agonists
  • Excitatory Amino Acid Antagonists
  • Grm5 protein, rat
  • Phenylacetates
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-fos
  • RNA, Messenger
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate
  • Transcription Factors
  • ets-Domain Protein Elk-1
  • metabotropic glutamate receptor type 1
  • Type C Phospholipases
  • Calcium
  • Glycine