The Glucocorticoid Receptor: Isoforms, Functions, and Contribution to Glucocorticoid Sensitivity

Overview

Journal Endocr Rev

Publisher Oxford University Press

Specialty Endocrinology

Date 2024 Mar 29

PMID 38551091

Authors

Jack Lockett

Warrick J Inder

Vicki L Clifton

Affiliations

Soon will be listed here.

Abstract

Glucocorticoids exert pleiotropic effects on all tissues to regulate cellular and metabolic homeostasis. Synthetic forms are used therapeutically in a wide range of conditions for their anti-inflammatory benefits, at the cost of dose and duration-dependent side effects. Significant variability occurs between tissues, disease states, and individuals with regard to both the beneficial and deleterious effects. The glucocorticoid receptor (GR) is the site of action for these hormones and a vast body of work has been conducted understanding its function. Traditionally, it was thought that the anti-inflammatory benefits of glucocorticoids were mediated by transrepression of pro-inflammatory transcription factors, while the adverse metabolic effects resulted from direct transactivation. This canonical understanding of the GR function has been brought into question over the past 2 decades with advances in the resolution of scientific techniques, and the discovery of multiple isoforms of the receptor present in most tissues. Here we review the structure and function of the GR, the nature of the receptor isoforms, and the contribution of the receptor to glucocorticoid sensitivity, or resistance in health and disease.

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References

Morris D, Kola B, Borboli N, Kaltsas G, Gueorguiev M, McNicol A . Identification of adrenocorticotropin receptor messenger ribonucleic acid in the human pituitary and its loss of expression in pituitary adenomas. J Clin Endocrinol Metab. 2003; 88(12):6080-7. DOI: 10.1210/jc.2002-022048. View

Cain D, Cidlowski J . Specificity and sensitivity of glucocorticoid signaling in health and disease. Best Pract Res Clin Endocrinol Metab. 2015; 29(4):545-56. PMC: 4549805. DOI: 10.1016/j.beem.2015.04.007. View

Lu N, Cidlowski J . Translational regulatory mechanisms generate N-terminal glucocorticoid receptor isoforms with unique transcriptional target genes. Mol Cell. 2005; 18(3):331-42. DOI: 10.1016/j.molcel.2005.03.025. View

Nicolaides N, Kino T, Roberts M, Katsantoni E, Sertedaki A, Moutsatsou P . The Role of S-Palmitoylation of the Human Glucocorticoid Receptor (hGR) in Mediating the Nongenomic Glucocorticoid Actions. J Mol Biochem. 2017; 6(1):3-12. PMC: 5538142. View

Marik P, Pastores S, Annane D, Meduri G, Sprung C, Arlt W . Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine. Crit Care Med. 2008; 36(6):1937-49. DOI: 10.1097/CCM.0b013e31817603ba. View

Kino T, Liou S, Charmandari E, Chrousos G . Glucocorticoid receptor mutants demonstrate increased motility inside the nucleus of living cells: time of fluorescence recovery after photobleaching (FRAP) is an integrated measure of receptor function. Mol Med. 2005; 10(7-12):80-8. PMC: 1431369. DOI: 10.2119/2005-00026.Kino. View

Rogerson F, Brennan F, Fuller P . Mineralocorticoid receptor binding, structure and function. Mol Cell Endocrinol. 2004; 217(1-2):203-12. DOI: 10.1016/j.mce.2003.10.021. View

Heuser I, Gotthardt U, Schweiger U, Schmider J, Lammers C, Dettling M . Age-associated changes of pituitary-adrenocortical hormone regulation in humans: importance of gender. Neurobiol Aging. 1994; 15(2):227-31. DOI: 10.1016/0197-4580(94)90117-1. View

Han H, Park J, Park S, Lee K, Bae S, Kim H . A Prospective Multicenter Study Evaluating Secondary Adrenal Suppression After Antiemetic Dexamethasone Therapy in Cancer Patients Receiving Chemotherapy: A Korean South West Oncology Group Study. Oncologist. 2015; 20(12):1432-9. PMC: 4679085. DOI: 10.1634/theoncologist.2015-0211. View

10.

Wang Q, Blackford Jr J, Song L, Huang Y, Cho S, Simons Jr S . Equilibrium interactions of corepressors and coactivators with agonist and antagonist complexes of glucocorticoid receptors. Mol Endocrinol. 2004; 18(6):1376-95. DOI: 10.1210/me.2003-0421. View

11.

Tsujimura S, Saito K, Nawata M, Nakayamada S, Tanaka Y . Overcoming drug resistance induced by P-glycoprotein on lymphocytes in patients with refractory rheumatoid arthritis. Ann Rheum Dis. 2007; 67(3):380-8. DOI: 10.1136/ard.2007.070821. View

12.

Escoter-Torres L, Greulich F, Quagliarini F, Wierer M, Uhlenhaut N . Anti-inflammatory functions of the glucocorticoid receptor require DNA binding. Nucleic Acids Res. 2020; 48(15):8393-8407. PMC: 7470971. DOI: 10.1093/nar/gkaa565. View

13.

Friedmann B, Kindermann W . Energy metabolism and regulatory hormones in women and men during endurance exercise. Eur J Appl Physiol Occup Physiol. 1989; 59(1-2):1-9. DOI: 10.1007/BF02396572. View

14.

Saif Z, Hodyl N, Stark M, Fuller P, Cole T, Lu N . Expression of eight glucocorticoid receptor isoforms in the human preterm placenta vary with fetal sex and birthweight. Placenta. 2015; 36(7):723-30. PMC: 4830346. DOI: 10.1016/j.placenta.2015.05.001. View

15.

Moore W, Bleecker E, Curran-Everett D, Erzurum S, Ameredes B, Bacharier L . Characterization of the severe asthma phenotype by the National Heart, Lung, and Blood Institute's Severe Asthma Research Program. J Allergy Clin Immunol. 2007; 119(2):405-13. PMC: 2837934. DOI: 10.1016/j.jaci.2006.11.639. View

16.

Zhu J, Gong J, Goodman Jr O, Cartegni L, Nanus D, Shen R . Bombesin attenuates pre-mRNA splicing of glucocorticoid receptor by regulating the expression of serine-arginine protein p30c (SRp30c) in prostate cancer cells. Biochim Biophys Acta. 2007; 1773(7):1087-94. PMC: 1939980. DOI: 10.1016/j.bbamcr.2007.04.016. View

17.

Barnes P, Greening A, Crompton G . Glucocorticoid resistance in asthma. Am J Respir Crit Care Med. 1995; 152(6 Pt 2):S125-40. DOI: 10.1164/ajrccm/152.6_Pt_2.S125. View

18.

Lonard D, OMalley B . Nuclear receptor coregulators: judges, juries, and executioners of cellular regulation. Mol Cell. 2007; 27(5):691-700. DOI: 10.1016/j.molcel.2007.08.012. View

19.

Vaughan G, Becker R, Allen J, Goodwin Jr C, PRUITT Jr B, MASON Jr A . Cortisol and corticotrophin in burned patients. J Trauma. 1982; 22(4):263-73. DOI: 10.1097/00005373-198204000-00001. View

20.

Sun K, Myatt L . Enhancement of glucocorticoid-induced 11beta-hydroxysteroid dehydrogenase type 1 expression by proinflammatory cytokines in cultured human amnion fibroblasts. Endocrinology. 2003; 144(12):5568-77. DOI: 10.1210/en.2003-0780. View