Endothelin-1 reverses the histone deacetylase inhibitor-induced increase in glial glutamate transporter transcription without affecting histone acetylation levels.

Astrocytes play a crucial role in maintaining glutamate homeostasis in the intact central nervous system. This function is profoundly impaired in the acutely and chronically diseased brain as evidenced by the decreased expression of the glial glutamate transporters, GLT-1/EAAT-2 and/or GLAST/EAAT-1, and a subsequent increase in extracellular glutamate concentrations which in turn induce excitotoxic neuronal cell death. We recently provided evidence that these disease-related disturbances of glial glutamate transport might be mediated in part by endothelins. This family of peptides not only massively reduces basal expression of GLT-1/EAAT-2 and GLAST/EAAT-1 in cultured astrocytes, but also completely overrides the exogenously induced expression of both glutamate transporter subtypes. The observed potency of this effect now prompted us to investigate whether endothelins inhibit glial glutamate transporter expression through an epigenetic, protein acetylation-dependent mechanism. We found that treating cultured astrocytes with the histone deacetylase inhibitor, trichostatin A, promotes transcription of both the GLT-1 and GLAST genes. These stimulatory influences were associated with an overall increase in acetylation of histones H3 and H4. The additional presence of endothelin-1 completely prevented the trichostatin A-induced increases in GLT-1- and GLAST expression without profoundly altering H3 and H4 acetylation levels. We conclude that endothelins inhibit glial glutamate transporter expression through an acetylation/deacetylation-independent process. We further suggest that modulating the activity of histone deacetylases represent an additional mechanism by which disease-associated disturbances of glial glutamate transporter expression are mediated.