Decrease in the AP-2 DNA-binding activity and in the protein expression of AP-2 alpha and AP-2 beta in frontal cortex of rats treated with lithium for 6 weeks.

Abstract

Lithium chloride (LiCl), when fed to rats for 6 weeks, has been reported to decrease brain mRNA, protein, and activity levels of arachidonic acid (AA)-selective cytosolic phospholipase A2 (cPLA2), without affecting secretory sPLA2 or Ca2+-independent iPLA2. We investigated whether transcription factors known to regulate cPLA2 gene expression are modulated by chronic lithium treatment. Male Fischer-344 rats were fed a LiCl-containing diet for 6 weeks to produce a therapeutically relevant brain lithium concentration. Control animals were fed a LiCl-free diet. Using a gelshift assay, we found that LiCl significantly decreased activating protein 2 (AP-2)-binding activity, and protein levels of the AP-2 alpha and AP-2 beta but not of the AP-2 gamma subunits in the frontal cortex. Activating protein 1 (AP-1)-binding activity was increased, whereas glucocorticoid response element, polyoma enhancer activator 3, and nuclear factor kappa B DNA-binding activities were not changed significantly. Since both cPLA2 and AP-2 can be activated by protein kinase C (PKC), we examined the frontal cortex protein levels of PKC alpha and PKC epsilon, as well as AA-dependent PKC activity. The protein levels of PKC alpha and PKC epsilon were decreased significantly, as was AA-dependent PKC activity, in the lithium-treated compared to control rats. Our results suggest that the reported decrease in brain gene expression of cPLA2 by chronic lithium may be mediated by reduced AP-2 transcriptional activity, and that decreased expression of PKC alpha and PKC epsilon contributes to lowering the AP-2 activity.