Abstract
Background Glucocorticoids are commonly used in the clinical setting for their potent anti-inflammatory effects; however, significant variations in response to treatment have been demonstrated. Although the underlying mechanisms have yet to be fully understood, this variable response may be a result of alterations in human glucocorticoid receptor (hGR) expression and function. In addition to hGRα, the biologically active isoform, a screening of current databases and publications revealed five alternative splice isoforms and hundreds of variants that have been reported to date. Many of these changes in the hGR-coding gene, NR3C1, have been linked to pathophysiology. However, many studies focus on evaluating hGR expression in vitro or detecting previously reported variants.ResultsIn this study, blood from healthy volunteers, burn and asthma patients, as well as from peripheral blood mononuclear cells isolated from leukoreduced donor whole blood, were screened for NR3C1 isoforms. We identified more than 1500 variants, including an additional 21 unique splice isoforms which contain 15 new cryptic exons. A dynamic database, named the Universal hGR (UhGR), was created to annotate and visualize the variants.ConclusionThis identification of naturally occurring and stress-induced hGR isoforms, as well as the establishment of an hGR-specific database, may reveal new patterns or suggest areas of interest that will lead to the improved understanding of the human stress response system.
Highlights
Glucocorticoids are commonly used in the clinical setting for their potent anti-inflammatory effects; significant variations in response to treatment have been demonstrated
Alternative splice isoforms To survey for published splice variants, PubMed and several NR3C1 Locus-specific database (LSDB) were searched, and five alternative splice variants identified (Fig. 2a). hGRβ arises from alternatively spliced exon 9, resulting in a 742 amino acid protein, of which the first 727 match the 777 amino acids in hGRα [12]
First identified in 1999, hGRγ reportedly comprises 3.8–8.7% of normal Glucocorticoid receptor (GR) expression and has three base pairs (+GTA) retained between exons 3 and 4, introducing an extra arginine in the DNA-binding domain (DBD) that reduces the transcriptional activation of hGRα by half [14]. human glucocorticoid receptor (hGR)-P and hGR-A were both discovered in 1993 in a glucocorticoid-resistant human multiple myeloma cell line [15]. hGR-P retains a portion of intron G, which contains an early stop codon that results in a 676 amino acid protein, of which amino acids 1–674 match hGRα, and is missing a portion of the ligand-binding domain (LBD). hGR-A lacks exons 5 through 7, generating a 592 amino acid protein that has a truncated hinge region and LBD
Summary
Glucocorticoids are commonly used in the clinical setting for their potent anti-inflammatory effects; significant variations in response to treatment have been demonstrated. During a post-injury systemic inflammatory response, the glucocorticoid pathway is essential to mounting the anti-inflammatory response needed to return the body to homeostasis [5]; there can be wide variations in individual responses to seemingly identical physiologic stressors. These variations may be influenced, in part, by an individual’s regulation hGR is a ligand-inducible and ubiquitously expressed nuclear hormone receptor that is part of the hypothalamic-pituitary-adrenal (HPA) axis, where it is involved in attenuating the stress response. The glucocorticoid/hGR complex undergoes conformational changes and translocates to the nucleus where it binds to glucocorticoid response elements (GREs) and interacts with co-regulators that assist with hGR’s transcriptional activities [7]
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