Identification of a Potential Molecular Link Between the Glucocorticoid and Serotonergic Signaling Systems

Glucocorticoid receptor (GR) and serotonin (5-hydroxytryptamine (5-HT)) signaling systems play a pivotal role in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis, but the molecular nature of interactions between these two systems remain largely unidentified. We used computational and experimental approaches to evaluate if DNA-protein interactions would provide a molecular link for the interaction between 5-HT and GR systems. Bioinformatic analysis identified nine binding sites in various serotonin receptors (HTR1D, HTR1F, HTR2A, HTR3A, and HTR6) for transcription factors in the GR family. Electrophoretic mobility shift assays (EMSA) using HeLa nuclear extract and purified full-length GR verified most of the predicted DNA-protein interactions. Six binding sites verified by EMSA results were evolutionarily conserved in multiple species. Multiple lines of evidence from computational and experimental analyses in this study support the potential of a molecular link between 5-HT and GR signaling systems. This finding provides new approaches to studies directed at mechanisms for glucocorticoid negative feedback regulation of the HPA axis involving 5-HT and interventional studies directed to neuropsychiatric diseases.