Destabilization of glial fibrillary acidic protein mRNA in astrocytes by ammonia and protection by extracellular ATP

J. T. Neary, S. R. Whittemore, Q. Zhu, Michael D Norenberg

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

The expression of the astrocyte-specific intermediate filament protein, glial fibrillary acidic protein (GFAP), is decreased in hepatic encephalopathy and increased in numerous neurological conditions including brain injury. However, little is known about the molecular mechanisms that regulate GFAP expression. Here it is reported that treatment of cultured astrocytes with ammonium chloride reduces GFAP mRNA by up to 85% without inhibiting total RNA synthesis. The effect of NH4Cl was time and dose dependent. The reduction in GFAP mRNA was detected 3 h after initiation of ammonia treatment with a maximum effect observed at 24 h. Significant decreases in GFAP mRNA were observed at 2, 5, and 10 mM NH4Cl. Concurrent treatment with extracellular ATP prevented the loss of GFAP mRNA, possibly by activation of purinergic receptors. In addition, removal of ammonium chloride restored GFAP mRNA to normal levels. Nuclear runoff experiments indicated that NH4Cl did not inhibit GFAP mRNA transcription. Studies using α- amanitin, an inhibitor of RNA polymerase II, showed that NH4Cl decreased the stability of GFAP mRNA by ~50%. This destabilization of GFAP mRNA may be an important factor in the pathogenesis of hepatic encephalopathy. Because increased GFAP is an important component of reactive gliosis, understanding the mechanisms that destabilize GFAP mRNA may facilitate strategies to minimize the gliosis associated with brain injury.

Original languageEnglish
Pages (from-to)2021-2027
Number of pages7
JournalJournal of Neurochemistry
Volume63
Issue number6
StatePublished - Dec 1 1994

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Glial Fibrillary Acidic Protein
Ammonia
Astrocytes
Adenosine Triphosphate
Messenger RNA
Ammonium Chloride
Gliosis
Hepatic Encephalopathy
Brain Injuries
Brain
Amanitins
Intermediate Filament Proteins
Purinergic Receptors
RNA Polymerase II
Transcription
Runoff
Chemical activation
RNA

Keywords

  • Extracellular ATP
  • Glial fibrillary acidic protein
  • Gliosis
  • Hepatic encephalopathy
  • mRNA stability

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Destabilization of glial fibrillary acidic protein mRNA in astrocytes by ammonia and protection by extracellular ATP. / Neary, J. T.; Whittemore, S. R.; Zhu, Q.; Norenberg, Michael D.

In: Journal of Neurochemistry, Vol. 63, No. 6, 01.12.1994, p. 2021-2027.

Research output: Contribution to journalArticle

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