Nurr1 expression is regulated by voltage-dependent calcium channels and calcineurin in cultured hippocampal neurons

Abstract

Nurr1 is an orphan nuclear transcription factor expressed in the brain. While Nurr1 is assumed to be an immediate early gene, it is not fully understood how Nurr1 expression is regulated in an activity-dependent manner in the central nervous system. Here, we investigated the molecular mechanisms underlying the regulation of Nurr1 expression in cultured hippocampal and cortical neurons. We found that upregulation of neural activity by high KCl and bicuculline enhances Nurr1 levels, while blockade of its activity by tetrodotoxin reduces Nurr1 levels. The induction of Nurr1 expression was mediated by voltage-dependent calcium channels (VDCCs), as shown by cadmium and VDCC-specific inhibitors. Furthermore, calcineurin, but not calcium/calmodulin-dependent protein kinase (CaMK) was critical for the induction. Thus, Nurr1 expression is regulated by VDCC and calcineurin in a cell-autonomous, neural activity-dependent manner.

Keywords: 6-Cyano-7-nitroquinoxaline-2,3-dione; CNQX; CaMK; Calcineurin; DL-2-Amino-5-phosphonopentanoic acid; DL-APV; Hippocampal neurons; Nurr1 (Nr4a2); TTX; Transcription; VDCC; Voltage-dependent calcium channel; calcium/calmodulin-dependent protein kinase; tetrodotoxin; voltage-dependent calcium channel.