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Destabilization of Glial Fibrillary Acidic Protein mRNA in Astrocytes by Ammonia and Protection by Extracellular ATP
Author(s) -
Neary J. T.,
Whittemore S. R.,
Zhu Q.,
Norenberg M. D.
Publication year - 1994
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1994.63062021.x
Subject(s) - glial fibrillary acidic protein , gliosis , astrocyte , messenger rna , microbiology and biotechnology , biology , glutamine synthetase , extracellular , gfap stain , chemistry , biochemistry , endocrinology , glutamine , central nervous system , immunology , immunohistochemistry , amino acid , gene , neuroscience
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 NH 4 Cl 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 m M NH 4 Cl. 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 NH 4 Cl did not inhibit GFAP mRNA transcription. Studies using α‐amanitin, an inhibitor of RNA polymerase II, showed that NH 4 Cl 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.