Intracellular glucocorticoid signaling: a formerly simple system turns stochastic
- PMID: 16204701
- DOI: 10.1126/stke.3042005pe48
Intracellular glucocorticoid signaling: a formerly simple system turns stochastic
Abstract
Glucocorticoids contribute fundamentally to the maintenance of basal and stress-related homeostasis in all higher organisms. The major roles of these steroids in physiology are amply matched by their remarkable contributions to pathology. Glucocorticoids influence about 20% of the expressed human genome, and their effects spare almost no organs or tissues. For many years we thought that the numerous actions of glucocorticoids were mediated by a single receptor molecule: the classic glucocorticoid receptor (GR) isoform alpha, a complex, multifunctional domain protein, operating as a ligand-dependent transcription factor. The GR gene, however, encodes two 3' splicing variants, GRalpha and GRbeta, from alternative use of two distinct terminal exons (9alpha and 9beta), and each variant mRNA is translated from at least eight initiation sites into multiple GRalpha and possibly GRbeta isoforms, amounting to a minimum of 16 GR monomers and 256 different homo- or heterodimers. The translational GRalpha isoforms may be produced variably in target tissues, have varying intrinsic transcriptional activities, and influence different complements of glucocorticoid-responsive genes. It is likely that expression and functional differences might also be present between the putative GRbeta translational isoforms. The presence of multiple GR monomers and dimers in different quantities with quantitatively and qualitatively different transcriptional activities suggests that the glucocorticoid signaling system is highly stochastic.
Similar articles
-
The origin and functions of multiple human glucocorticoid receptor isoforms.Ann N Y Acad Sci. 2004 Jun;1024:102-23. doi: 10.1196/annals.1321.008. Ann N Y Acad Sci. 2004. PMID: 15265776 Review.
-
Glucocorticoid action networks and complex psychiatric and/or somatic disorders.Stress. 2007 Jun;10(2):213-9. doi: 10.1080/10253890701292119. Stress. 2007. PMID: 17514590 Review.
-
The human glucocorticoid receptor: one gene, multiple proteins and diverse responses.Steroids. 2005 May-Jun;70(5-7):407-17. doi: 10.1016/j.steroids.2005.02.006. Steroids. 2005. PMID: 15862824 Review.
-
Cortisol resistance in conditions such as asthma and the involvement of 11beta-HSD-2: a hypothesis.Horm Metab Res. 2006 Jun;38(6):368-76. doi: 10.1055/s-2006-944530. Horm Metab Res. 2006. PMID: 16823718 Review.
-
Tissue mRNA expression of the glucocorticoid receptor and its splice variants in fatal critical illness.Clin Endocrinol (Oxf). 2009 Jul;71(1):145-53. doi: 10.1111/j.1365-2265.2008.03443.x. Epub 2008 Oct 13. Clin Endocrinol (Oxf). 2009. PMID: 19178514 Clinical Trial.
Cited by
-
Developmental Neuroendocrinology of Early-Life Stress: Impact on Child Development and Behavior.Curr Neuropharmacol. 2024;22(3):461-474. doi: 10.2174/1570159X21666230810162344. Curr Neuropharmacol. 2024. PMID: 37563814 Free PMC article. Review.
-
Glucocorticoid receptors regulate central amygdala GABAergic synapses in Marchigian-Sardinian alcohol-preferring rats.Neurobiol Stress. 2023 Jun 4;25:100547. doi: 10.1016/j.ynstr.2023.100547. eCollection 2023 Jul. Neurobiol Stress. 2023. PMID: 37547774 Free PMC article.
-
Applications of artificial intelligence-machine learning for detection of stress: a critical overview.Mol Psychiatry. 2024 Jun;29(6):1882-1894. doi: 10.1038/s41380-023-02047-6. Epub 2023 Apr 5. Mol Psychiatry. 2024. PMID: 37020048 Review.
-
Pregnancy Is Associated with Impaired Transcription of Human Endogenous Retroviruses and of TRIM28 and SETDB1, Particularly in Mothers Affected by Multiple Sclerosis.Viruses. 2023 Mar 9;15(3):710. doi: 10.3390/v15030710. Viruses. 2023. PMID: 36992419 Free PMC article.
-
Context-Dependent Role of Glucocorticoid Receptor Alpha and Beta in Breast Cancer Cell Behaviour.Cells. 2023 Mar 1;12(5):784. doi: 10.3390/cells12050784. Cells. 2023. PMID: 36899920 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Other Literature Sources
Medical