Opposite Effects of Proteasome Inhibitors in the Adrenergic Induction of Arylalkylamine N‐acetyltransferase in Rat Pinealocytes

Abstract

In the rat pineal gland, the steady‐state level of arylalkylamine N‐acetyltransferase (AANAT) protein is controlled by transcriptional and translational mechanisms as well as by proteasome‐mediated degradation. Studies with proteasome inhibitors, MG132 and clasto‐lactacystin β‐lactone (c‐lact), show two opposite effects of proteasomal inhibition on norepinephrine (NE)‐induction of Aanat. Addition of MG132 or c‐lact following NE stimulation causes an increase in AANAT protein level and enzyme activity without affecting the level of Aanat mRNA. In contrast, addition of inhibitors prior to NE stimulation reduces the NE‐stimulated Aanat mRNA, AANAT protein, and enzyme activity. The inhibitory effect of proteasomal inhibition on adrenergic‐induced Aanat transcription appears specific for Aanat because it has no effect on the adrenergic induction of mitogen‐activated protein kinase phosphatase‐1 (mkp‐1). The effects of the proteasome inhibitors on NE‐stimulated Aanat induction appear to be mediated by accumulation of a protein repressor.