Genetic variation of the glucocorticoid receptor from a steroid-resistant primate

Brandon, David D.; Markwick, Alison; Flores, Maria Vega; Dixon, Kathy H.; Albertson, Barry D.; Loriaux, D. Lynn

doi:10.1677/jme.0.0070089

Cited by 45 publications

(26 citation statements)

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“…Indeed, the human GRg (Arg 453 ) is half maximally activated compared to wild-type with a similar EC 50 in an in vitro co-transfection assay with GR arg 453 and pMMTV-luciferase reporter plasmid in COS7 (African green monkey kidney) cells (Ray et al 1996, Wang & Fondell 2001. Alternative splicing comparable to that in human GRg is also seen in the cotton-top marmoset (Saguinus oedipus) and thus is of wider occurrence (Brandon et al 1991).…”

Section: Non-fish Vertebratesmentioning

confidence: 99%

“…However, there is considerable individual variation in sensitivity to GCs (Hearing et al 1999), which may affect the outcome of GC treatment. Mutations and splice variation in the GR gene and subsequent polymorphisms in the protein of humans and other vertebrates may explain the individual variation in sensitivity, rather than alteration in the consensus sequence of the GR-binding site in the DNA of target genes (Brandon et al 1991, Keightley & Fuller 1994, Lamberts et al 1996, DeRijk et al 2002, van Rossum et al 2002, Bray & Cotton 2003, Stevens et al 2004b.…”

Section: Introductionmentioning

confidence: 99%

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Evolution of glucocorticoid receptors with different glucocorticoid sensitivity

Stolte¹,

Kemenade²,

Savelkoul³

et al. 2006

Journal of Endocrinology

148

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Glucocorticoids (GCs) are commonly used to treat a variety of immune diseases. However, the efficacy of treatment is greatly influenced by an individual variation in sensitivity to GCs, which is caused by differences in the glucocorticoid receptor (GR). The variable receptor profile results from variations in the GR gene, or alternative splicing of the gene coded. We investigated the evolution of the GR gene by comparing genomic GR sequences of vertebrates. Exon length and amino acid sequence are conserved among all classes of vertebrates studied, which indicates strong evolutionary pressure on conservation of this gene. Interestingly, teleostean fishes have two different GR proteins. One of the duplicate fish GR genes has a nine-amino-acid insert in the DNA binding region that results from alternative splicing. The duplicate GR genes and products of alternative splicing in teleostean fishes are differentially expressed in vivo and show different transactivation capacity in vitro. The presence of two GR genes appears to be a result of divergence of receptors rather than of ligands. Teleostean fishes express different, evolutionarily related, functional GR proteins within a single organism. Hereby, teleostean fishes present a model that facilitates investigation of the molecular basis of cortisol resistance and different regulatory functions of cortisol.

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Section: Non-fish Vertebratesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Evolution of glucocorticoid receptors with different glucocorticoid sensitivity

Stolte¹,

Kemenade²,

Savelkoul³

et al. 2006

Journal of Endocrinology

148

View full text Add to dashboard Cite

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“…Corticosteroid / glucocorticoid resistance (tolerance of, or insensitivity to, high circulating levels of hormone) has been well-documented in mammalian species, both as a pathological abnormality in human patients (Arai and Chrousos, 1995) and as a non-pathologic characteristic of certain primate and rodent species (Brandon et al, 1991;Taymans et al, 1997). Target-tissue sensitivity to steroid hormones may be modulated in a number of ways.…”

mentioning

confidence: 99%

“…Target-tissue sensitivity to steroid hormones may be modulated in a number of ways. These mechanisms include alterations in the abundance of receptors within target-tissues (Iida et al, 1985), modification of the affinity of the receptor for the ligand (Brandon et al, 1991), or changes in the processing of the activated receptor after formation of the receptor-ligand complex (Rhouma et al, 1997). In addition, levels of cortisol-binding globulins in the plasma may be important in regulating target-tissue availability of cortisol (Alexander and Irvine, 1998).…”

mentioning

confidence: 99%

High Blood Cortisol Levels and Low Cortisol Receptor Affinity: Is the Chub, Leuciscus cephalus, a Cortisol-Resistant Teleost?

Pottinger

Carrick

Appleby

et al. 2000

General and Comparative Endocrinology

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The NERC and CEH trademarks and logos ('the Trademarks') are registered trademarks of NERC in the UK and other countries, and may not be used without the prior written consent of the Trademark owner. ABSTRACTIn contrast to the relatively minor intra-and inter-species differences in blood cortisol levels reported for salmonid species, there is a more pronounced distinction between cortisol levels among the Salmonidae and Cyprinidae, with both basal and stressinduced cortisol levels markedly higher in the latter. This study shows that in the chub, Leuciscus cephalus, a widely distributed European cyprinid, mean blood cortisol levels during stress (1500 ng ml -1 ) exceeded those reported for most other species of fish and even in unstressed chub, cortisol levels (50 -100 ng ml -1 ) were within the range known to cause immunosuppression, growth retardation and reproductive dysfunction in salmonid fish. The chub appears to be atypical only with respect to plasma cortisol levels; the levels of plasma glucose and plasma lactate in unstressed and stressed chub are similar to those reported for other species. Plasma levels of 11-ketotestosterone in males and 17-estradiol in females are lower than reported for salmonids but similar to other cyprinid species and display clear stressinduced reduction. Comparative analysis of the binding characteristics of the trout and chub gill cortisol receptor revealed that the total number of binding sites in gill tissue for each species was similar (Bmax; ~50 -100 fmol mg -1 protein). However, the affinity of the binding site for cortisol displayed an 8-fold difference between the species (rainbow trout: Kd ~ 6 nM; chub: Kd ~ 50 nM). Therefore, the potentially adverse effects of high circulating levels of cortisol found both at rest and under conditions of stress in chub may be offset by the lower affinity of the cortisol receptor, rather than the abundance of target-tissue receptor sites. This strategy is similar to that reported for some glucocorticoid-resistant rodent species and New World primates.3

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“…However, if GR function is impaired, then higher than normal concentrations of corticosterone are required to maintain homeostasis. Thus in rodents and primates, naturally occurring or genetically engineered differences in receptor function are associated with abnormal patterns of hormone secretion (Mantero et al 1983, Brandon et al 1991, Hurley et al 1991, Cole et al 1993, Stewart et al 1993, Keightley & Fuller 1994. We compared both ligand specificity and thermolability of GR, as well as binding capacity, in hepatic cytosol of MNS and MHS.…”

Section: Discussionmentioning

confidence: 99%

Glucocorticoid receptor polymorphism in genetic hypertension

Kenyon

Panarelli

Zagato

et al. 1998

Journal of Molecular Endocrinology

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The Milan hypertensive strain of rat (MHS) displays abnormalities in both renal function and adrenocortical activity. While the pressor role of the former has been studied in detail, the role of the latter has not yet been clearly evaluated. In the present study, glucocorticoid receptor (GR) binding characteristics in liver cytosol from adult MHS and Milan normotensive controls (MNS) have been investigated. Dexamethasone, aldosterone and corticosterone were bound with lower affinity to cytosol of MHS rats compared with that of MNS rats. This pattern of binding could explain the raised plasma corticosterone concentrations and adrenocortical hypertrophy previously noted in MHS.The coding sequence of MHS and MNS GR genes have been determined. The MHS gene differed in four respects from that of MNS: three silent point mutations and a polymorphic microsatellite region in exon 2. The latter polymorphism has been used in cosegregation studies of F 2 hybrids of MHS MNS. The MHS GR genotype was associated with hypercalciuria and lower blood pressure in female rats and lower body weight in male rats. Although the effect on blood pressure is small, it is consistent with the affinity data. MHS GR genotype cosegregated with lower blood pressure in F 2 rats and displayed a lower affinity in binding studies.In conclusion, GR polymorphism may be responsible for differences of adrenocortical function between MHS and MNS. This may lead to a reduction in the blood pressure difference between the two strains.

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Genetic variation of the glucocorticoid receptor from a steroid-resistant primate

Cited by 45 publications

References 0 publications

Evolution of glucocorticoid receptors with different glucocorticoid sensitivity

Evolution of glucocorticoid receptors with different glucocorticoid sensitivity

High Blood Cortisol Levels and Low Cortisol Receptor Affinity: Is the Chub, Leuciscus cephalus, a Cortisol-Resistant Teleost?

Glucocorticoid receptor polymorphism in genetic hypertension

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