Increased expression of endoplasmic reticulum stress proteins following chronic valproate treatment of rat C6 glioma cells.

The anticonvulsant sodium valproate has been shown to be an effective treatment for bipolar disorder, however, its precise mechanism of action has yet to be determined. It has been suggested that adaptational changes in gene expression are critical for valproate's prophylactic effects. Previous studies in our lab have shown that one gene that may be regulated by valproate is the 78-kilodalton glucose-regulated protein (GRP78). We report that treatment of rat C6 glioma cells with valproate can also increase the expression of additional endoplasmic reticulum stress proteins, GRP94 and calreticulin. All three proteins showed similar concentration-dependent increases in messenger RNA abundance. Chronic (seven days) treatment significantly increased GRP78 and GRP94 messenger RNA expression, whereas calreticulin expression increased after both acute and chronic treatment. Increases in mRNA expression corresponded to a similar increase in protein expression. The roles of GRP78, GRP94 and calreticulin as molecular chaperones and calcium binding proteins, suggest that these results might have functional relevance to the therapeutic action of valproate.