Abstract
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.
References
aan het Rot M, Mathew SJ, Charney DS (2009) Neurobiological mechanisms in major depressive disorder. CMAJ 180:305–313
Bao AM, Meynen G, Swaab DF (2008) The stress system in depression and neurodegeneration: focus on the human hypothalamus. Brain Res Rev 57:531–553
Berger M, Gray JA, Roth BL (2009) The expanded biology of serotonin. Ann Rev Med 60:355–366
Bhatnagar S, Vining C (2004) Pituitary-adrenal activity in acute and chronically stressed male and female mice lacking the 5-HT-3A receptor. Stress 7:251–256
Cartharius K, Frech K, Grote K (2005) MatInspector and beyond: promoter analysis based on transcription factor binding sites. Bioinformatics 21:2933–2942
Cleare AJ, Bearn J, Allain T (1995) Contrasting neuroendocrine responses in depression and chronic fatigue syndrome. J Affect Disord 34:283–289
Gold PW, Chrousos GP (1999) The endocrinology of melancholic and atypical depression: relation to neurocircuitry and somatic consequences. Proc Assoc Am Physicians 111:22–34
Hanley NR, Van de Kar LD (2003) Serotonin and the neuroendocrine regulation of the hypothalamic–pituitary-adrenal axis in health and disease. Vitam Horm 66:189–255
Heisler LK, Pronchuk N, Nonogaki K (2007) Serotonin activates the hypothalamic-pituitary-adrenal axis via serotonin 2C receptor stimulation. J Neurosci 27:6956–6964
Ichikawa M, Okamura-Oho Y, Okunishi R (2005) Expression analysis of genes responsible for serotonin signaling in the brain. Neurobiol Dis 19:378–385
Lanfumey L, Mongeau R, Cohen-Salmon C, Hamon M (2008) Corticosteroid-serotonin interactions in the neurobiological mechanisms of stress-related disorders. Neurosci Biobehav Rev 32:1174–1184
Lopez-Figueroa AL, Norton CS, Lopez-Figueroa MO (2004) Serotonin 5-HT1A, 5-HT1B, and 5-HT2A receptor mRNA expression in subjects with major depression, bipolar disorder, and schizophrenia. Biol Psychiatry 55:225–233
Lowry CA (2002) Functional subsets of serotonergic neurones: implications for control of the hypothalamic-pituitary-adrenal axis. J Neuroendocrinol 14:911–923
Makino S, Hashimoto K, Gold PW (2002) Multiple feedback mechanisms activating corticotropin-releasing hormone system in the brain during stress. Pharmacol Biochem Behav 73:147–158
Mikkelsen JD, Hay-Schmidt A, Kiss A (2004) Serotonergic stimulation of the rat hypothalamo-pituitary-adrenal axis: interaction between 5-HT1A and 5-HT2A receptors. Ann N Y Acad Sci 1018:65–70
Nelson CC, Hendy SC, Shukin RJ (1999) Determinants of DNA sequence specificity of the androgen, progesterone, and glucocorticoid receptors: evidence for differential steroid receptor response elements. Mol Endocrinol 13:2090–2107
Newton R (2000) Molecular mechanisms of glucocorticoid action: what is important? Thorax 55:603–613
Ohmori O, Shinkai T, Hori H, Nakamura J (2002) Genetic association analysis of 5-HT(6) receptor gene polymorphism (267C/T) with tardive dyskinesia. Psychiatry Res 110:97–102
Olff M, Guzelcan Y, de Vries GJ, Assies J, Gersons BP (2006) HPA- and HPT-axis alterations in chronic posttraumatic stress disorder. Psychoneuroendocrinology 31:1220–1230
Ou XM, Storring JM, Kushwaha N, Albert PR (2001) Heterodimerization of mineralocorticoid and glucocorticoid receptors at a novel negative response element of the 5-HT1A receptor gene. J Biol Chem 276:14299–14307
Shiraki T, Kondo S, Katayama S (2003) Cap analysis gene expression for high-throughput analysis of transcriptional starting point and identification of promoter usage. Proc Natl Acad Sci USA 100:15776–15781
Smith AK, Dimulescu I, Falkenberg VR (2008) Genetic evaluation of the serotonergic system in chronic fatigue syndrome. Psychoneuroendocrinology 33:188–197
Tanriverdi F, Karaca Z, Unluhizarci K, Kelestimur F (2007) The hypothalamo-pituitary-adrenal axis in chronic fatigue syndrome and fibromyalgia syndrome. Stress 10:13–25
Acknowledgements
Support for V. R. Falkenberg was provided by the research participation program at the Centers for Disease Control and Prevention (CDC), National Center for Zoonotic Vector-Borne Enteric Diseases, Division of Viral and Rickettsial Diseases, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the CDC.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Falkenberg, V.R., Rajeevan, M.S. Identification of a Potential Molecular Link Between the Glucocorticoid and Serotonergic Signaling Systems. J Mol Neurosci 41, 322–327 (2010). https://doi.org/10.1007/s12031-009-9320-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12031-009-9320-6