Corticosteroid receptor

Hesen, W. Joels, M. (1996). Modulation of 5-HTia responsiveness in CAi pyramidal neurons by in vivo activation of corticosteroid receptors. J. Neuroendocrinol. 8, 433-8. 

Corticosteroid receptors regulate transcription in the nervous system 464... 

The mechanisms of corticosteroid receptor regulation of transcription have been elucidated 464... 

FIGURE 26-5 Immunohistochemical localization of type I corticosteroid receptor (mineralocorticoid receptor) in the rat hippocampus. (A) Mineralocorticoid immunoreactivity is concentrated in pyramidal cell fields of the cornu ammonis (CA2). (B) High-power photomicrograph shows that steroid-bound mineralocorticoid receptors are primarily localized to neuronal cell nuclei. (Courtesy of Dr James P. Herman, Department of Anatomy and Neurobiology, University of Kentucky.)... 

The mechanisms of corticosteroid receptor regulation of transcription have been elucidated. Both type I and type II corticosteroid receptors are members of a superfamily of ligand-activated transcription factors defined by protein sequence similarity. Included in this superfamily are various other steroid receptors, such as the estrogen receptor, as well as members of the retinoic acid receptor... 

Ligand-bound corticosteroid receptors have been shown to interact to form heterodimers with other transcription factors, such as the jun protein. Such interactions are responsible for transactivation of the ds-regulatory sites known as AP-1 sites and for the glucocorticoid-mediated suppression of transcription, such as that seen in the pro-opiomelanocortin gene. A number of such specific protein interactions have been reported these interactions and their locations relative to other transcription factors transform a ubiquitous steroid hormone signal into a tissue-specific, graded cellular response. 

Koehl, M. et al., Prenatal stress alters circadian activity of hypothalamo-pituitary-adrenal axis and hippocampal corticosteroid receptors in adult rats of both genders, J. Neurobiol., 40, 302, 1999. 

DeRijk R, de Kloet ER. (2005) Corticosteroid receptor genetic polymorphisms and stress responsivity. Endocrine. 28, 263-270. 

HT3), dopamine, and corticosteroid receptors, the targets of existing therapies for... 

Abnormality in the regulatory feedback mechanism may explain the overactivity of the HPA axis seen in depressed patients, since a lack of dexam-ethasone suppression of cortisol secretion is observed (Carroll et al., 1981). In addition, despite a hypercortisolaemia, depressive patients generally do not demonstrate Cushingoid features, possibly because of a reduction in the function of corticosteroid receptors. It has therefore been hypothesised that the primary abnormality in depression may thus be an impairment of corticosteroid receptor function (Barden et al., 1995). 

Holsboer F (2000) The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology 23 477-501... 

GC exert their regulatory effects on the HPA system via two types of corticosteroid receptors the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR) (Reul and De Kloet 1985). GRs occur everywhere in the brain but are most abundant in hypothalamic CRH neurons and pituitary corticotropes. MRs, in contrast, are highly expressed in the hippocampus and, at lower expression levels, in hypothalamic sites involved in the regulation of salt appetite and autonomic outflow. The MR binds GC with a tenfold higher affinity than does the GR (Reul and De Kloet 1985). These findings on corticosteroid receptor diversity led to the working hypothesis that the tonic influences of corticosterone... 

De Kloet ER, Vreugdenhil E, Oitzl MS, Joels M (1998) Brain corticosteroid receptor balance in health and disease. Endocr Rev 19 269-301... 

Holsboer F (1999) The rationale for corticotropin-releasing hormone receptor (CRH-R) antagonists to treat depression and anxiety. J Psychiatr Res 33 181-214 Holsboer F (2000) The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology 23 477-501... 

Muller MB, Holsboer F, Keck ME (2002) Genetic modification of corticosteroid receptor signaling novel insights into pathophysiology and treatment strategies of human affective disorders. Neimopeptides 36 117-131... 

De Beilis MD, Baum AS, Birmaher B, Keshavan MS, Eccard CH, Boring AM, Jenkins FJ, Ryan ND (1999) A.E. Bennett Research Award. Developmental traumatology. Part 1 Biological stress systems [see comments]. Biol Psychiatry 45 1259-1270 de Kloet ER, Joels M, Oitzl M, Sutanto W (1991) Implication of brain corticosteroid receptor diversity for the adaptation syndrome concept. Methods Achiev Exp Pathol 14 104-132 Delahanty DL, Raimonde AJ, Spoonster E (2000) Initial posttraumatic urinary cortisol levels predict subsequent PTSD symptoms in motor vehicle accident victims. Biol Psychiatry 48 940-947... 

Holsboer F (2001) Stress, hypercortisolism and corticosteroid receptors in depression implications for therapy. J Affect Disord 62 77-91 Ito K, Yoshida K, Sato K, et al (2002) A variable number of tandem repeats in the serotonin transporter gene does not affect the antidepressant response to fluvoxamine. Psychiatry... 

Maccari, S., Piazza, P.V., Deminiere, J.M., Lemaire, V., Mormede, P., Simon, H., Angelucci, L., and Le Moal, M. (1991) Life events-induced decrease of type I corticosteroid receptors is associated with reduced corticosterone feedback and enhanced vulnerability to amphetamine self-administration. Brain Res 547 7-12. 

Whereas it is conceivable that a CRH/vasopressin hyperdrive contributes to behavioral, emotional, and hormonal symptoms of mood disorders, the question remains which mechanisms mediate this hyperactivity of CRH and vasopressin-secreting neurons. The gene expression of both neuropeptides is suppressed by ligand-activated glucocorticoid receptors. The efficiency of this negative feedback action of circulating corticosteroids depends on the number of corticosteroid receptors, their affinity, and the degree of interaction with other factors (e.g., heat shock protein) involved in the transcription machinery. 

In summary, these clinical and preclinical findings support the view that mood disorders can be seen as stress system disorders, in which impairment of GR and MR action plays a causal role. The impairments may be genetically determined or acquired through a variety of early stressors, or both. It is possible that antidepressants exert their clinical efficacy through reinstatement of complete corticosteroid receptor function. Of course, other important actions of these drugs also need careful consideration. 

In my admittedly biased view, the most coherent approach is that of a profoundly disturbed stress system that under specific conditions paves the way to development of mood disorders. These stress-system alterations can be genetic or acquired through trauma in early life or even in utero. Consistent with this neuroendocrine hypothesis are findings that centrally released neuropeptides that drive the HPA system also have behavioral effects that are similar to affective symptoms. This view is further supported by the documented ability of various antidepressants to enhance corticosteroid receptor synthesis and efficacy. Moreover, the stress system, particularly the corticosteroids and their receptors, interferes with all of the neurotransmitter receptor systems, including intracellular signaling, that have been considered in the context of mood disorders. New drugs targeted directly to various elements of the stress system will constitute a major step forward. 

Andreatini R, Leite JR Evidence against the involvement of ACTH/CRF release or corticosteroid receptors in the anxiolytic effect of corticosterone. Braz J Med Biol Res 27(5) 1237-1241, 1994... 

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