GSK4716 enhances 5-HT1AR expression by glucocorticoid receptor signaling in hippocampal HT22 cells

ABSTRACT¹

¹ 5-HT, Serotonin, 5-hydroxytryptamine; 5-HT1AR, Serotonin receptor 1A; BSA, Bovine serum albumin; ERRγ, Estrogen-related receptor gamma; PBS, Phosphate-buffered saline; GR, Glucocorticoid receptor; NF, Nuclear factor; NR, Nuclear receptors; SEM, Standard error of the mean

Objectives

The serotonin (5-hydroxytryptamine, 5-HT) receptor 1A (5-HT1AR) is closely associated with serotonergic neurotransmission in the brain, being the most prevalent and widely distributed receptor of its kind. The purpose of this study is to investigate the regulation mechanism of 5-HT1AR by GSK4716.

Methods

To investigate the mechanism of GSK4716-mediated 5-HT1AR regulation, we used hippocampus-derived HT22 cells expressing 5-HT1AR. The expression level of 5-HT1AR and associated proteins, were detected by reporter gene assay and western blotting.

Results

GSK4716, an estrogen-related receptor gamma agonist increased 5-HT1AR expression by interacting with the GR, a repressor of 5-HT1AR transcription. Dexamethasone, a GR agonist, decreased the GSK4716-induced increase in 5-HT1AR, which was associated with an alteration in nuclear GR. Furthermore, GR antagonist RU486 reversed the effects induced by dexamethasone, including the elevation of nuclear GR levels and the reduction of 5-HT1AR transcription and expression.

Conclusion

The results could provide insight into the potential applications of small molecules, such as GSK4716, in the regulation of 5-HT1AR expression, which plays a role in serotonergic neurotransmission.

GRAPHICAL ABSTRACT

KEYWORDS:

• 5-HT1AR
• estrogen-related receptor gamma
• glucocorticoid receptor
• GSK4716
• serotonergic neurotransmission

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions statement

JL and HJC conceived and supervised the study; JP and JL performed experiments; JL and WL analysed data; JP and JL wrote the manuscript; JL and HJC made manuscript revisions.

Notes

¹ 5-HT, Serotonin, 5-hydroxytryptamine; 5-HT1AR, Serotonin receptor 1A; BSA, Bovine serum albumin; ERRγ, Estrogen-related receptor gamma; PBS, Phosphate-buffered saline; GR, Glucocorticoid receptor; NF, Nuclear factor; NR, Nuclear receptors; SEM, Standard error of the mean

Additional information

Funding

This study was supported by Woosuk University.