Interactions between ionotropic and metabotropic glutamate receptors regulate cAMP response element-binding protein phosphorylation in cultured striatal neurons

Neuroscience. 2002;115(2):395-402. doi: 10.1016/s0306-4522(02)00400-1.


The striatum is a key structure of basal ganglia controlling extrapyramidal motor activity and processing addictive plasticity of abused substances. Glutamatergic transmission that is enriched in the striatum regulates a variety of striatal neuronal activities via selective activation of ionotropic and metabotropic glutamate receptors (mGluRs). In this study, the interaction between N-methyl-D-aspartate (NMDA) receptors and group I mGluRs (mGluR1 and mGluR5 subtypes) in activating a phosphorylation cascade to a transcription factor cAMP response element-binding protein (CREB) was investigated in primary cultures of E18 or postnatal day 1 striatal neurons. We found that activation of NMDA receptors with NMDA rapidly and concentration-dependently increased the number of neurons expressing phosphorylated CREB (pCREB) as revealed by immunocytochemistry. The increased pCREB expression by NMDA was sensitive to an NMDA antagonist MK801. Co-incubation of a subthreshold dose of a group I mGluR agonist 3,5-dihydroxyphenylglycine (DHPG) that itself did not alter basal pCREB expression augmented NMDA-induced CREB phosphorylation. The mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride blocked the DHPG augmentation of NMDA-induced CREB phosphorylation, while the mGluR1 antagonist 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester did not. Interestingly, the protein kinase C inhibitors chelerythrine and Gö6983 also prevented DHPG from enhancing CREB phosphorylation induced by NMDA. Whereas a low dose of the protein kinase C activator phorbol 12-myristate 13-acetate mimicked the DHPG potentiation. These results indicate a facilitatory regulation of an NMDA cascade to CREB phosphorylation by concurrent glutamatergic tone on mGluR5, which is probably processed via an intracellular signaling pathway involving protein kinase C.

Publication types

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

MeSH terms

  • Animals
  • Calcium / metabolism
  • Carcinogens / pharmacology
  • Cells, Cultured
  • Corpus Striatum / cytology*
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Excitatory Amino Acid Agonists / pharmacology
  • Methoxyhydroxyphenylglycol / analogs & derivatives*
  • Methoxyhydroxyphenylglycol / pharmacology
  • N-Methylaspartate / pharmacology
  • Neurons / cytology
  • Neurons / metabolism*
  • Phosphorylation / drug effects
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase C / metabolism
  • Rats
  • Receptors, AMPA / antagonists & inhibitors
  • Receptors, AMPA / metabolism
  • Receptors, Glutamate / metabolism*
  • Receptors, Kainic Acid / antagonists & inhibitors
  • Receptors, Kainic Acid / metabolism
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Tetradecanoylphorbol Acetate / pharmacology
  • Up-Regulation / physiology


  • Carcinogens
  • Cyclic AMP Response Element-Binding Protein
  • Excitatory Amino Acid Agonists
  • Gluk1 kainate receptor
  • Receptors, AMPA
  • Receptors, Glutamate
  • Receptors, Kainic Acid
  • Receptors, N-Methyl-D-Aspartate
  • Methoxyhydroxyphenylglycol
  • N-Methylaspartate
  • Protein Kinase C
  • Tetradecanoylphorbol Acetate
  • Calcium
  • glutamate receptor ionotropic, AMPA 1
  • 3,4-dihydroxyphenylglycol