Transcriptional Regulation of the Human 5-HT1A Receptor Gene by Lithium: Role of Deaf1 and GSK3β

Serotonin 1A (5-HT1A) autoreceptors located on serotonin neurons inhibit their activity, and their upregulation has been implicated in depression, suicide and resistance to antidepressant treatment. Conversely, post-synaptic 5-HT1A heteroreceptors are important for antidepressant response. The transcription factor deformed epidermal autoregulatory factor 1 (Deaf1) acts as a presynaptic repressor and postsynaptic enhancer of 5-HT1A transcription, but the mechanism is unclear. Because Deaf1 interacts with and is phosphorylated by glycogen synthase kinase 3 beta (GSK3 beta)-a constitutively active protein kinase that is inhibited by the mood stabilizer lithium at therapeutic concentrations-we investigated the role of GSK3 beta in Deaf1 regulation of human 5-HT1A transcription. In 5-HT1A promoter-reporter assays, human HEK293 kidney and 5-HT1A-expressing SKN-SH neuroblastoma cells, transfection of Deaf1 reduced 5-HT1A promoter activity by similar to 45%. To identify potential GSK3 beta site(s) on Deaf1, point mutations of known and predicted phosphorylation sites on Deaf1 were tested. Deaf1 repressor function was not affected by any of the mutants tested except the Y300F mutant, which augmented Deaf1 repression. Both lithium and the selective GSK3 inhibitors CHIR-99021 and AR-014418 attenuated and reversed Deaf1 repression compared to vector. This inhibition was at concentrations that maximally inhibit GSK3 beta activity as detected by the GSK3 beta-sensitive TCF/LEF reporter construct. Our results support the hypothesis that GSK3 beta regulates the activity of Deaf1 to repress 5-HT1A transcription and provide a potential mechanism for actions of GSK3 inhibitors on behavior.

Automated summary

Serotonin 1A receptors play a crucial role in depression and response to antidepressant treatment. The transcription factor Deaf1 is involved in regulating the activity of these receptors, with GSK3 beta playing a role in this regulation. This study provides insights into the mechanism behind the effects of GSK3 beta inhibitors on behavior.