N-acetylaspartylglutamate stimulates metabotropic glutamate receptor 3 to regulate expression of the GABA(A) subunit in cerebellar granule cells

Subroto Ghose, Barbara Wroblewska, Lorenzo Corsi, Dennis R. Grayson, Angel L. De Blas, Stefano Vicini, Joseph H. Neale

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

We have shown that the vertebrate neuropeptide N- acetylaspartylglutamate (NAAG) meets the criteria for a neurotransmitter, including function as a selective metabotropic glutamate receptor (mGluR) 3 agonist. Short-term treatment of cerebellar granule cells with NAAG (30 μM) results in the transient increase in content of GABA(A) α6 subunit mRNA. Using quantitative PCR, this increase was determined to be up to 170% of control values. Similar effects are seen following treatment with trans-1- aminocyclopentane-1,3-dicarboxylate and glutamate and are blocked by the mGluR antagonists (2 S, 3 S, 4 S)-2-methyl-2-(carboxycyclopropyl) glycine and (2S)-α-ethylglutamic acid. The effect is pertussis toxin-sensitive. The increase in α6 subunit mRNA level can be simulated by activation of other receptors negatively linked to adenylate cyclase activity, such as adenosine A1, α2-adrenergic, muscarinic, and GABA(B) receptors. Forskolin stimulation of cyclic AMP (cAMP) levels abolished the effect of NAAG. The change in α6 levels induced by 30 μM NAAG can be inhibited in a dose-dependent manner by simultaneous application of increasing doses of the β-adrenergic receptor agonist isoproterenol. The increase in α6 mRNA content is followed by a fourfold increase in α6 protein level 6 h posttreatment. Under voltage- clamped conditions, NAAG-treated granule cells demonstrate an increase in the furosemide-induced inhibition of GABA-gated currents in a concentration- dependent manner, indicating an increase in functional α6-containing GABA(A) receptors. These data support the hypothesis that NAAG, acting through mGluR3, regulates expression of the GABA(A) α6 subunit via a cAMP-mediated pathway and that cAMP-coupled receptors for other neurotransmitters may similarly influence GABA(A) receptor subunit composition.

Original languageEnglish (US)
Pages (from-to)2326-2335
Number of pages10
JournalJournal of Neurochemistry
Volume69
Issue number6
DOIs
StatePublished - Dec 1997

Keywords

  • Cerebellar granule cells
  • Cyclic AMP
  • GABA(A) receptor
  • GABA(A) α6
  • Glutamate
  • Metabotropic glutamate receptor
  • N- Acetylaspartylglutamate
  • mGluR3
  • mRNA regulation

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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