Interindividual Glucocorticoid Sensitivity in Young Healthy Subjects: The Role of Glucocorticoid Receptor α and β Isoforms Ratio

Colli, Leandro M.; Amaral, Fernando Colbari do; Torres, Natália; Castro, Margaret de

doi:10.1055/s-2007-980191

Cited by 20 publications

(17 citation statements)

References 39 publications

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“…The existence of an isoform of the glucocorticoid receptor, termed GRβ, arising from alternative splicing of the terminal exon has been well documented in human cell lines and tissue [3, 17, 18]. The two isoforms are identical through amino acid 727, but the beta isoform contains an additional 15 amino acids and the alpha isoform 50 amino acids which share little homology.…”

Section: Discussionmentioning

confidence: 99%

Evidence for a glucocorticoid receptor beta splice variant in the rat and its physiological regulation in liver

et al. 2013

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Glucocorticoids are important regulators of metabolism and immune function. Synthetic glucocorticoids are extensively used for immunosuppression/anti-inflammatory therapy. Since the glucocorticoid receptor (GR) is central to most hormone effects; its in vivo regulation will influence hormone/drug action. An alternative splice variant, GRβ, is present in humans and may function as a dominant negative regulator of GR transcriptional activity. Recently, a similar splice variant was reported in mouse, although the mechanism of alternative splicing differs from that in humans. We present evidence that a splice variant of GR with an alternative C-terminus also occurs in the rat by a mechanism of intron inclusion. A highly quantitative qRT-PCR assay for the simultaneous measurement of both splice variants in a single sample was developed in order to accurately measure their regulation. We used this assay to assess the tissue specific expression of both mRNAs, and demonstrate that GRα is predominant in all tissues. In addition, the regulation of both GRα and GRβ mRNA by various physiological factors in rat liver was assessed. GRα showed a robust circadian rhythm, which was entrained with the circadian oscillation of the endogenous hormone. Time series experiments showed that both corticosteroids and LPS but not insulin dosing resulted in the transient down-regulation of GRα mRNA. LPS treatment also resulted in down-regulation of GRβ expression. A modest up-regulation in GRβ expression was observed only in animals having chronically elevated plasma insulin concentrations. However the expression of GRβ was significantly lower than that of GRα in all cases.

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Section: Discussionmentioning

confidence: 99%

Evidence for a glucocorticoid receptor beta splice variant in the rat and its physiological regulation in liver

et al. 2013

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“… 62 GRα mediates glucocorticoid action, while GRβ and GR‐P have been shown to mediate GRα activity and are unable to bind ligands. Generally, GRβ is expressed at very low levels compared to GRα; however, its expression is increased in tissues in inflammatory diseases, and it seems to be associated with decreased sensitivity to glucocorticoids 72 …”

Section: Glucocorticoids: Release Availability and Receptor Actionmentioning

confidence: 99%

Glucocorticoid Dysregulations and Their Clinical Correlates

Marques

Silverman

Sternberg

2009

Annals of the New York Academy of Sciences

140

103

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Clinicians have long known that a substantial proportion of patients treated with high-dose glucocorticoids experience a variety of serious side effects, including metabolic syndrome, bone loss, and mood shifts, such as depressive symptomatology, manic or hypomanic symptoms, and even suicide. The reason for individual variability in expression or severity of these side effects is not clear. However, recent emerging literature is beginning to shed light on possible mechanisms of these effects. As an introduction to this volume, this chapter will review the basic biology of glucocorticoid release and molecular mechanisms of glucocorticoid receptor function, and will discuss how dysregulation of glucocorticoid action at all levels could contribute to such side effects. At the molecular level, glucocorticoid receptor polymorphisms may be associated either with receptor hypofunction or hyperfunction and could thus contribute to differential individual sensitivity to the effects of glucocorticoid treatment. Numerous factors regulate hypothalamic-pituitary-adrenal (HPA) axis responsiveness, which could also contribute to individual differences in glucocorticoid side effects. One of these is sex hormone status and the influence of estrogen and progesterone on HPA axis function and mood. Another is immune system activity, in which immune molecules, such as interleukins and cytokines, activate the HPA axis and alter brain function, including memory, cognition, and mood. The effects of cytokines in inducing sickness behaviors, which overlap with depressive symptomatology, could also contribute to individual differences in such symptomatology. Taken together, this knowledge will have important relevance for identifying at-risk patients to avoid or minimize such side effects when they are treated with glucocorticoids. A framework for assessment of patients is proposed that incorporates functional, physiological, and molecular biomarkers to identify subgroups of patients at risk for depressive symptomatology associated with glucocorticoid treatment, and for prevention of side effects, which in many cases can be life-threatening.

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“…GRb has dominant-negative effects on hormone-induced GRa action (6,7), and an intrinsic transcriptional activity has been recently proposed (8). The GRa/GRb ratio, however, does not seem to be responsible for interindividual variability of glucocorticoid sensitivity in normal subjects (9). Additionally, each isoform is subject to several posttranslational modifications, including phosphorylation, ubiquitinationm and sumoylation, which have been shown to modulate the receptor protein stability and/ or function (10).…”

Section: Introductionmentioning

confidence: 99%

NR3C1 polymorphisms in Brazilians of Caucasian, African, and Asian ancestry: glucocorticoid sensitivity and genotype association

Souza

Martins

Silva-Junior

et al. 2014

Arq Bras Endocrinol Metab

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Objective: The Brazilian population has heterogeneous ethnicity. No previous study evaluated NR3C1 polymorphisms in a Brazilian healthy population. Materials and methods: We assessed NR3C1 polymorphisms in Brazilians of Caucasian, African and Asian ancestry (n = 380). In a subgroup (n = 40), we compared the genotypes to glucocorticoid (GC) sensitivity, which was previously evaluated by plasma (PF) and salivary (SF) cortisol after dexamethasone (DEX) suppression tests, GC receptor binding affinity (K d ), and DEX-50% inhibition (IC 50 ) of concanavalin-A-stimulated mononuclear cell proliferation. p.N363S (rs6195), p.ER22/23EK (rs6189-6190), and BclI (rs41423247) allelic discrimination was performed by Real-Time PCR (Polymerase Chain Reaction). Exons 3 to 9 and exon/intron boundaries were amplified by PCR and sequenced. Results: Genotypic frequencies (%) were: rs6195 (n = 380; AA:96.6/AG:3.14/GG:0.26), rs6189-6190 (n = 264; GG:99.6/ GA:0.4), rs41423247 (n = 264; CC:57.9/CG:34.1/GG:8.0), rs6188 (n = 155; GG:69.6/GT:25.7/TT:4.7), rs258751 (n = 150; CC:88.0/CT:10.7/TT:1.3), rs6196 (n = 176; TT:77.2/TC:20.4/CC:2.4), rs67300719 (n = 137; CC:99.3/CT:0.7), and rs72542757 (n = 137; CC:99.3/CG:0.7). The rs67300719 and rs72542757 were found only in Asian descendants, in whom p.N363S and p.ER22/23EK were absent. The p.ER22/23EK was observed exclusively in Caucasian descendants. Hardy-Weinberg equilibrium was observed, except in the Asian for rs6188 and rs258751, and in the African for p.N363S. The K d , IC 50 , baseline and after DEX PF or SF did not differ between genotype groups. However, the mean DEX dose that suppressed PF or SF differed among the BclI genotypes (P = 0.03). DEX dose was higher in GG-(0.7 ± 0.2 mg) compared to GC-(0.47 ± 0.2 mg) and CC-carriers (0.47 ± 0.1 mg). Conclusion: The genotypic frequencies of NR3C1 polymorphisms in Brazilians are similar to worldwide populations. Additionally, the BclI polymorphism was associated with altered pituitary-adrenal axis GC sensitivity. Arq Bras Endocrinol Metab. 2014;58(1):53-61 Keywords NR3C1 genotypes; allelic frequencies; glucocorticoid sensitivity RESUMO Objetivo: Este estudo avalia polimorfismos (SNPs) do NR3C1 na população brasileira, que possui origem étnica heterogênea. Materiais e métodos: SNPs do NR3C1 foram avaliados em brasileiros de ancestralidade caucasiana, africana ou japonesa (n = 380). Em um subgrupo (n = 40), os genótipos foram comparados à sensibilidade aos glicocorticoides (GC), previamente avaliada por cortisol plasmático (PF) e salivar (SF) após supressão com dexametasona (DEX), ensaio de afinidade do receptor ao GC (K d ) e inibição por DEX de 50% da proliferação de mononucleares estimulada por concanavalina-A (IC 50 ). Discriminação alélica de p.N363S (rs6195), p.ER22/23EK (rs6189-6190) e BclI (rs41423247) foi realizada por PCR em tempo real. Éxons 3 a 9 e transições éxon/íntron foram amplificados e sequenciados. Resultados: Frequências genotípicas (%) foram: rs6195 (n = 380; AA:96,6/AG:3,14/GG:0,26), rs6189-6190 (n = 264; GG:99,6/GA:0...

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Interindividual Glucocorticoid Sensitivity in Young Healthy Subjects: The Role of Glucocorticoid Receptor α and β Isoforms Ratio

Cited by 20 publications

References 39 publications

Evidence for a glucocorticoid receptor beta splice variant in the rat and its physiological regulation in liver

Evidence for a glucocorticoid receptor beta splice variant in the rat and its physiological regulation in liver

Glucocorticoid Dysregulations and Their Clinical Correlates

NR3C1 polymorphisms in Brazilians of Caucasian, African, and Asian ancestry: glucocorticoid sensitivity and genotype association

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