Regulation of transcription factor phosphorylation by metabotropic glutamate receptor-associated signaling pathways in rat striatal neurons

Neuroscience. 2002;114(3):557-65. doi: 10.1016/s0306-4522(02)00318-4.

Abstract

The group I metabotropic glutamate receptors (mGluRs) are positively coupled to phospholipase C. Through phospholipase C, group I mGluR activation increases intracellular concentrations of diacylglycerol which is known as a strong activator of protein kinase C (PKC). This study investigated the putative role of PKC in the regulation of transcription factor phosphorylation induced by group I mGluR activation in the rat striatum in vivo. We found that the group I agonist 3,5-dihydroxyphenylglycine (DHPG) injected into the dorsal striatum (caudate-putamen) increased phosphorylation of the two transcription factors, cAMP response element-binding protein (CREB) and Elk-1, and extracellular signal-regulated kinase 1/2 (ERK1/2) in the injected striatum. Inhibition of PKC with GF109203X significantly attenuated DHPG-stimulated CREB, Elk-1, and ERK1/2 phosphorylation. Activation of PKC with intracaudate injection of 12-O-tetradecanoylphorbol-13-acetate (TPA) mimicked DHPG actions in facilitating the phosphorylation of CREB, Elk-1, and ERK1/2. Blockade of N-methyl-D-aspartate (NMDA) glutamate receptors with the non-competitive antagonist MK801 or the competitive antagonist AP5 attenuated TPA-induced CREB, Elk-1, and ERK1/2 phosphorylation. Similarly, inhibition of Ca(2+)/calmodulin-dependent protein kinases (CaMK) with KN62 also resulted in a significant attenuation of TPA induction of the three phosphoproteins. The data obtained from this study indicate that selective activation of PKC is needed for the group I agonist-induced CREB, Elk-1, and ERK1/2 phosphorylation in striatal neurons. Activated PKC may, at least in part, facilitate the phosphorylation of transcription factors via an NMDA/CaMK-sensitive pathway.

Publication types

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

MeSH terms

  • Animals
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism*
  • Male
  • Neurons / drug effects
  • Neurons / metabolism*
  • Phosphorylation / drug effects
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase C / metabolism
  • Rats
  • Rats, Wistar
  • Receptors, Metabotropic Glutamate / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Transcription Factors / metabolism*

Substances

  • Receptors, Metabotropic Glutamate
  • Transcription Factors
  • metabotropic glutamate receptor type 1
  • Protein Kinase C