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Review
. 2009 Oct:1179:153-66.
doi: 10.1111/j.1749-6632.2009.04988.x.

Glucocorticoid signaling in the cell. Expanding clinical implications to complex human behavioral and somatic disorders

George P Chrousos  1 , Tomoshige Kino
Affiliations
Review

Glucocorticoid signaling in the cell. Expanding clinical implications to complex human behavioral and somatic disorders

George P Chrousos et al. Ann N Y Acad Sci. 2009 Oct.

Abstract

Glucocorticoids contribute to the maintenance of basal and stress-related homeostasis in all higher organisms, and influence a large proportion of the expressed human genome, and their effects spare almost no organs or tissues. Glucocorticoids regulate many functions of the central nervous system, such as arousal, cognition, mood, sleep, the activity and direction of intermediary metabolism, the maintenance of a proper cardiovascular tone, the activity and quality of the immune and inflammatory reaction, including the manifestations of the sickness syndrome, and growth and reproduction. The numerous actions of glucocorticoids are mediated by a set of at least 16 glucocorticoid receptor (GR) isoforms forming homo- or hetero-dimers. The GRs consist of multifunctional domain proteins operating as ligand-dependent transcription factors that interact with many other cell signaling systems, including large and small G proteins. The presence of multiple GR monomers and homo- or hetero-dimers expressed in a cell-specific fashion at different quantities with quantitatively and qualitatively different transcriptional activities suggest that the glucocorticoid signaling system is highly stochastic. Glucocorticoids are heavily involved in human pathophysiology and influence life expectancy. Common behavioral and/or somatic complex disorders, such as anxiety, depression, insomnia, chronic pain and fatigue syndromes, obesity, the metabolic syndrome, essential hypertension, diabetes type 2, atherosclerosis with its cardiovascular sequelae, and osteoporosis, as well as autoimmune inflammatory and allergic disorders, all appear to have a glucocorticoid-regulated component.

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Figures

Figure 1
Figure 1
A: Feedback-regulated compensatory changes in the activity of the HPA axis and their effects in peripheral tissues, such as the liver, fat and blood vessels. Note that glucocorticoid sensitivity in the HPA axis and the peripheral tissues can be independently regulated and the former determines the serum free cortisol levels, thus combination of their directions influence net peripheral action of this hormone. ACTH: Adrenocorticotropic hormone; AVP: Arginine vasopressin; CRH: Corticotropin-releasing hormone; DOC: Deoxycorticosterone; B: Corticosterone. Modified from references , & . B: Known GR mutations that cause familial/sporadic glucocorticoid resistance syndrome. Localization of GR mutations that cause familial/sporadic glucocorticoid resistance syndrome are shown in the human GR gene (top) and in the human GR protein (bottom). From references & . C: Alteration of net glucocorticoid effects in target tissues by activity of the central HPA axis and peripheral tissue sensitivity to glucocorticoids. Net glucocorticoid action in peripheral tissues, such as the CNS, liver, fat and vasculature, are determined by two components, the central HPA axis and sensitivity of peripheral tissue to glucocorticoids. From reference .
Figure 1
Figure 1
A: Feedback-regulated compensatory changes in the activity of the HPA axis and their effects in peripheral tissues, such as the liver, fat and blood vessels. Note that glucocorticoid sensitivity in the HPA axis and the peripheral tissues can be independently regulated and the former determines the serum free cortisol levels, thus combination of their directions influence net peripheral action of this hormone. ACTH: Adrenocorticotropic hormone; AVP: Arginine vasopressin; CRH: Corticotropin-releasing hormone; DOC: Deoxycorticosterone; B: Corticosterone. Modified from references , & . B: Known GR mutations that cause familial/sporadic glucocorticoid resistance syndrome. Localization of GR mutations that cause familial/sporadic glucocorticoid resistance syndrome are shown in the human GR gene (top) and in the human GR protein (bottom). From references & . C: Alteration of net glucocorticoid effects in target tissues by activity of the central HPA axis and peripheral tissue sensitivity to glucocorticoids. Net glucocorticoid action in peripheral tissues, such as the CNS, liver, fat and vasculature, are determined by two components, the central HPA axis and sensitivity of peripheral tissue to glucocorticoids. From reference .
Figure 1
Figure 1
A: Feedback-regulated compensatory changes in the activity of the HPA axis and their effects in peripheral tissues, such as the liver, fat and blood vessels. Note that glucocorticoid sensitivity in the HPA axis and the peripheral tissues can be independently regulated and the former determines the serum free cortisol levels, thus combination of their directions influence net peripheral action of this hormone. ACTH: Adrenocorticotropic hormone; AVP: Arginine vasopressin; CRH: Corticotropin-releasing hormone; DOC: Deoxycorticosterone; B: Corticosterone. Modified from references , & . B: Known GR mutations that cause familial/sporadic glucocorticoid resistance syndrome. Localization of GR mutations that cause familial/sporadic glucocorticoid resistance syndrome are shown in the human GR gene (top) and in the human GR protein (bottom). From references & . C: Alteration of net glucocorticoid effects in target tissues by activity of the central HPA axis and peripheral tissue sensitivity to glucocorticoids. Net glucocorticoid action in peripheral tissues, such as the CNS, liver, fat and vasculature, are determined by two components, the central HPA axis and sensitivity of peripheral tissue to glucocorticoids. From reference .
Figure 2
Figure 2. Regulation of tissue GR activity by distinct signaling pathways
Transcriptional activity of GR in glucocorticoid target tissues is regulated by numerous signaling pathways through distinct mechanisms. From references , , –, , , & .
Figure 3
Figure 3. Regulation of GR transcriptional activity through phosphorylation
A: Human GR has three major phosphorylation sites at serines 203, 211 and 226 and two minor phosphorylation sites at serines 113 and 141. The former sites are phosphorylated by several kinases indicated. From references & –. B: Schematic regulation of GR-induced transcriptional activity by CDK5. CDK5 regulates GR-induced transcriptional activity by changing attraction of transcriptional cofactors to responsive promoters in the central nervous system, possibly through molecules that specifically interact with phosphorylated or nonphosphorylated ligand-bound GR. The direction and size of the effect depends also on the presence of other gene promoter-, tissue- or brain region-specific transcriptional cofactors. Modified from references & .
Figure 3
Figure 3. Regulation of GR transcriptional activity through phosphorylation
A: Human GR has three major phosphorylation sites at serines 203, 211 and 226 and two minor phosphorylation sites at serines 113 and 141. The former sites are phosphorylated by several kinases indicated. From references & –. B: Schematic regulation of GR-induced transcriptional activity by CDK5. CDK5 regulates GR-induced transcriptional activity by changing attraction of transcriptional cofactors to responsive promoters in the central nervous system, possibly through molecules that specifically interact with phosphorylated or nonphosphorylated ligand-bound GR. The direction and size of the effect depends also on the presence of other gene promoter-, tissue- or brain region-specific transcriptional cofactors. Modified from references & .
Figure 4
Figure 4. Endogenous/exogenous inputs to the stress system and their effects on the metabolic and cardiovascular systems and bone
ABP: Arterial blood pressure; APR: Acute phase reactants; AVP: Arginine vasopressin; CRH: Corticotropin-releasing hormone; E2: Estradiol; EDS: Excessive daytime sleepiness; GH: Growth hormone; HDL: High-density lipoprotein; HPA Axis: Hypothalamic-pituitary-adrenal axis; IGF-1: Insulin-like growth factor-1; IL-6: Interleukin-6; LC: Locus caeruleus; LDL: Low-density lipoprotein; LH: Luteinizing hormone; NE: Norepinephrine; T: Testosterone; T3: Triiodothyronine; TG: Triglyceride; TSH: Thyroid-stimulating hormone. From reference .
Figure 5
Figure 5
Central regulation of the stress system in normal (left panel) and chronically stressed and stress hyperresponsive individuals (right panel). The stress system (PVN CRH/AVP and LC/NE) activates the amygdala and the MCLS and receives activating signals from the amygdala and suppressive signals from the MCLS and the hippocampus. Chronic stress has behavioral and somatic consequences summarized in the bottom of right panel. MCLS= Mesocorticolimbic (Reward) System; PVN= Paraventricular nucleus; CRH= Corticotropin-releasing hormone; AVP= Arginine vasopressin. Modified from reference .
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References

    1. Chrousos GP. Glucocorticoid therapy. In: Flig P, Frohman L, editors. Endocrinology and Metabolism. McGraw-Hill; New York, NY: 2001. pp. 609–632.
    1. Franchimont D, et al. Glucocorticoids and inflammation revisited: The state of the art [abstract]. NIH Clinical Staff Conference. Neuroimmunomodulation. 2003;10:247–260. - PubMed
    1. Galon J, et al. Gene profiling reveals unknown enhancing and suppressive actions of glucocorticoids on immune cells. FASEB J. 2002;16:61–71. - PubMed
    1. Chrousos GP. Stressors, stress, and neuroendocrine integration of the adaptive response. The 1997 Hans Selye Memorial Lecture. Ann N Y Acad Sci. 1998;851:311–335. - PubMed
    1. Wust S, et al. Common polymorphisms in the glucocorticoid receptor gene are associated with adrenocortical responses to psychosocial stress. J Clin Endocrinol Metab. 2004;89:565–573. - PubMed

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