Write short notes on steroid receptors. Illustrate your answer with reference to the glucocorticoid receptor
Nathaniel Knox Cartwright, Petros Carvounis in Short Answer Questions for the MRCOphth Part 1, 2018
The glucocorticoid receptor is a typical steroid receptor: – there is only a single class of glucocorticoid receptor and it is found in nearly all cells– like all steroid receptors it is intracellular– glucocorticoids must diffuse across the plasma membrane before combining with and activating the receptor– heat shock protein (hsp)-90 is associated with the glucocorticoid receptor and acts as a molecular chaperone, maintaining the unactivated receptor in its optimum configuration and preventing the unbound receptor from migrating to the nucleus– following cortisol binding, hsp-90 detaches from the receptor and the receptor–ligand complex migrates to the nucleus– in the nucleus the receptor–ligand complex binds to DNA at promoter regions of steroid-responsive target genes, inducing or suppressing their transcription– there are between 10 and 100 steroid-responsive genes in each cell: this explains the wide range of action of steroids.
Gonadotropins and Sex Hormones
Istvan Berczi in Pituitary Function and Immunity, 2019
Several investigators observed that the response of human peripheral blood lymphocytes to mitogens (PHA, Con A, PPD) and in the mixed lymphocyte culture is inhibited by estradiol and DES. 145–149 However, physiological concentrations of estradiol were found to enhance the PWM stimulated immunoglobulin secretion of human lymphocytes. Additional experiments revealed that this enhancing effect was due to the inhibition of suppressor T lymphocytes by estradiol.150 Others found that the suppressive effect of sex steroids on mitogen responses and on the mixed lymphocyte reaction was either very weak or nonexistent, and it has been postulated that sex hormones exert their inhibitory effects by suboptimal binding to glucocorticoid receptors in lymphocytes. The relative immunosuppressive potency of a given hormone is related to its affinity for the glucocorticoid receptor.151,152
Regulation of the α2-Macroglobulin Gene
Andrzej Mackiewicz, Irving Kushner, Heinz Baumann in Acute Phase Proteins, 2020
Experimental attempts to answer these questions are hampered by the fact that in contrast to the in vivo situation, in most liver- or hepatoma-derived cell culture systems, the permissive effect of glucocorticoids for acute phase protein synthesis is not observed. After transfection of the hepatoma cell lines Hep G2, Hep 3B, and FAO with a2-M promoter/luciferase60 or α2-M promoter/CAT constructs,68 IL-6 induced the reporter gene expression even in the absence of glucocorticoids, and dexamethasone enhanced this induction only less than twofold. An 18-bp fragment of the α2-M promoter containing the APRE core motif was shown to confer this glucocorticoid effect.60 Since no direct interaction of the glucocorticoid receptor with this sequence or with factors binding to it was observed, this effect might be mediated by the activation of an intermediate gene.60 Whether the small effect of glucocorticoids on the α2-M promoter observed in hepatoma cell lines reflects the glucocorticoid requirement in vivo, however, or whether another mechanism is involved remains to be elucidated.
Clinical profile of the functionally selective glucocorticoid receptor agonist BI 653048 in healthy male subjects
Published in Expert Opinion on Investigational Drugs, 2019
Christian Harcken, Paul Scholl, Gerald Nabozny, David Thomson, Daniel Bianchi
GCs mediate their effects through the glucocorticoid receptor (GR), a member of the nuclear receptor family of intracellular receptors that are primarily located in the cytoplasm as monomers. Upon ligand binding, activated GRs translocate to the nucleus to regulate specific genes. GR dimers can regulate gene activation (transactivation), whereas GR monomers regulate gene repression (transrepression) by interacting with pro-inflammatory transcription factors (e.g. nuclear factor-κB and activator protein-1). While it has been proposed that transrepression is solely responsible for the desired anti-inflammatory effects of GCs, and that transactivation is responsible for most of the GC-mediated side effects [1998,7], recent data suggest that the functional consequences of the different GR interactions are more nuanced [5,8,9]. This initial hypothesis has prompted research into the discovery of a glucocorticoid receptor ligand (GRL) that is functionally selective between transrepression and transactivation. These compounds are known as dissociated GCs or selective glucocorticoid receptor agonists (SEGRAs); two examples of SEGRAs that have entered clinical trials include mapracorat and fosdagrocorat [10,11], though clinical development has been discontinued for both [12].
Glucocorticoid sensitivity and inflammatory status of peripheral blood mononuclear cells in patients with coronary artery disease
Published in Annals of Medicine, 2018
Simon Jönsson, Anna K. Lundberg, Rosanna W. S. Chung, Lena Jonasson
A crucial question is why inflammation is sustained in CAD patients. One potential explanation is hypothalamus–pituitary–adrenal (HPA) axis dysfunction. The HPA axis and its end-product glucocorticoids, predominantly cortisol, are essential in resolving the inflammatory process and maintaining homeostasis [10,11]. This occurs mainly through the binding of glucocorticoids to glucocorticoid receptor (GR)-α in the cytosol. GR-α is known to be the predominant and functionally active receptor while an alternative splice variant of the GR gene, the GR-β isoform, is considered a negative regulator of GR-α-mediated effects [12]. After translocation to the nucleus, the glucocorticoid/GR-α complex exerts its anti-inflammatory effects by DNA binding and interaction with transcription factors, such as NF-κB. A number of in vitro studies have also consistently shown that glucocorticoids suppress the inflammation-induced synthesis and release of MMP-9 and TIMP-1 in various cell types, including human PBMCs [13–15].
Investigation on glucocorticoid receptors within platelets from adult patients with immune thrombocytopenia
Published in Hematology, 2020
Kam Chau Yung, Cheng Wei Xu, Ze Wen Zhang, Wen Jun Yu, Qian Li, Xian Ru Xu, Ya Fei Han, Xin Jia Wang, Jun Yin
The glucocorticoid receptor (GR) belonging to the nuclear transcription factor, is expressed in virtually all cells of the human body, which is widely found in the cytoplasm of various cells of the body. The amount of expression varies from different tissues [2]. All GRs are encoded by the nuclear receptor subfamily 3 group C member 1 (NR3C1) gene, which is located on the short arm of chromosome 5, consisting of 9 core exons (exons 1–9). Exon 1 is variable and encodes the 5′-untranslated region of the gene, controlled by alternative promotor usage. Seven in the middle (exons 2–8) are common to all GR isoforms. But the exon 9 by alternative splicing includes two isoforms (exons 9α and 9β) which generate either a GRα- or GRβ-encoding transcript [3]. There are 777 amino acids in GRα, while 742 amino acids in GRβ. These two isoforms share identical amino acids 1–727. There are extra 50 amino acids since amino acids 728 in GRα, whereas only 15 additional amino acids in GRβ. GRα contains three major functional domains, including N-terminal domain (NTD, first 421 amino acids), DNA-binding domain (DBD, the next 65 amino acids) and hormone-binding domain (HBD, the last 251 amino acids). There is the hinge region (amino acids 486–526) between DBD and HBD, which provides flexibility for the structure of GR. Because of the sequence of amino acids, GRβ has a shortened ligand-binding domain (LBD) which cannot bind glucocorticoids [4].
Related Knowledge Centers
- Cortisol
- Gene Expression
- Glucocorticoid
- Nuclear Receptor
- Metabolism
- Immune System
- Receptor
- Gene
- Developmental Biology
- Pleiotropy