Accumulation of Cytoplasmic Glucocorticoid Receptor Is Related to Elevation of FKBP5 in Lymphocytes of Depressed Patients

Lukić, Iva; Mitić, Miloš; Soldatović, Ivan; Jovičić, Milica; Maric, Nadja P.; Radulovic, Jelena; Adžić, Miroslav

doi:10.1007/s12031-014-0451-z

Cited by 21 publications

(11 citation statements)

References 41 publications

(65 reference statements)

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“…Our findings of differential activity and stress‐related behavior as function of Fkbp genotype may indicate an association between Fkbp5 genotype and stress‐related behavior in the absence of pathology. Interestingly, both our data from female rats and those from human studies suggest that modifications in the 3’ untranslated region (RS8161939 in our study and rs3800373 in humans (Lukic et al, ) contribute to these effects, indicating a potential role for regulation of FKBP5 mRNA in these effects, perhaps through processes involved in alternative splicing events. Functional genomic studies of the effects of these variations are needed to test this hypothesis.…”

Section: Discussionsupporting

confidence: 59%

Both maternal care received and genotype influence stress‐related phenotype in female rats

Pan

Lawson

Dudin

et al. 2018

Developmental Psychobiology

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Rat dams differ naturally in the level of maternal care they provide to their offspring within the same litter. We explored possible mechanisms of differential maternal care focused on genetic variation. We examined single nucleotide polymorphisms in the glucocorticoid receptor, FK506-binding protein, and serotonin transporter genes in two separate cohorts, and the relationship between differential maternal care received, genotype, and offspring phenotype. Allelic variation in all three genes was significantly associated with levels of maternal care received by offspring and behavioral and endocrine stress responses in adulthood. Differences in pup behavior were also associated with allelic variation in these genes. Together, these results indicate that the dam/pup interaction is dynamic and implicate the genotype of the offspring in influencing the level of maternal care received. They further suggest that some genotypes may have a dampening effect on the impact of maternal care on stress-related phenotypes in adulthood.

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Section: Discussionsupporting

confidence: 59%

Both maternal care received and genotype influence stress‐related phenotype in female rats

Pan

Lawson

Dudin

et al. 2018

Developmental Psychobiology

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“…As previously mentioned, FKBP5 plays a dual role in GC signaling, first as a negative regulator of GR’s nuclear translocation, and second as a transcriptional readout of GR’s activity. An increase in baseline FKBP5 can thus be interpreted as decreased nuclear translocation of GR (Lukic et al 2015), and the downstream consequences of such reduction in GR translocation would be lower Dex-induced transcription of FKBP5, consistent with the notion of impaired GC signaling.…”

Section: Discussionmentioning

confidence: 55%

HIV and symptoms of depression are independently associated with impaired glucocorticoid signaling

Bekhbat

Mehta

Kelly

et al. 2018

Psychoneuroendocrinology

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Chronic inflammation caused by HIV infection may lead to deficient glucocorticoid (GC) signaling predisposing people living with HIV to depression and other psychiatric disorders linked to GC resistance. We hypothesized that comorbid HIV and depressive symptoms in women would synergistically associate with deficits in GC signaling. This cross-sectional study used samples obtained from the Women's Interagency HIV Study (WIHS). The Centers for Epidemiological Studies (CES-D) was used to define depression in four groups of women from the Women's Interagency HIV Study (WIHS): 1) HIV-negative, non-depressed (n = 37); 2) HIV-negative, depressed (n = 34); 3) HIV-positive, non-depressed (n = 38); and 4) HIV-positive, depressed (n = 38). To assess changes in GC signaling from peripheral blood mononuclear cells (PBMCs), we examined baseline and dexamethasone (Dex)-stimulated changes in the expression of the GC receptor (GR, gene: Nr3c1) and its negative regulator Fkbp5 via quantitative RT-PCR. GR sensitivity was evaluated in vitro by assessing the Dex inhibition of lipopolysaccharide (LPS)-stimulated IL-6 and TNF-α levels. Depressive symptoms and HIV serostatus were independently associated with elevated baseline expression of Fkbp5 and Nr3c1. Depressive symptoms, but not HIV status, was independently associated with reduced LPS-induced release of IL-6. Counter to predictions, there was no interactive association of depressive symptoms and HIV on any outcome. Comorbid depressive symptoms with HIV infection were associated with a gene expression and cytokine profile similar to that of healthy control women, a finding that may indicate further disruptions in disease adaptation.

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“…This study gives a novel insight to potential sex differences in FKBP51 expression, which may be a leading factor for GR resistance. It is hypothesized that depressed patients have increased basal levels of FKBP51 (Lukic et al, 2015; Tatro et al, 2009) and has become an important target for physiological stress regulation and potential new drug target therapies for patients with major depressive disorder (Binder et al, 2004; Kirchheiner et al, 2008; Stamm et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Sex differences in hypothalamic–pituitary–adrenal axis regulation after chronic unpredictable stress

2020

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Introduction: Exposure to stress, mediated through the hypothalamic-pituitary-adrenal (HPA) axis, elicits sex differences in endocrine, neurological, and behavioral responses. However, the sex-specific factors that confer resilience or vulnerability to stress and stress-associated psychiatric disorders remain largely unknown. The evident sex differences in stress-related disease prevalence suggest the underlying differences in the neurobiological underpinnings of HPA axis regulation. Method:Here, we used a chronic unpredictable stress (CUS) model to investigate the behavioral and biochemical responses of the HPA axis in C57BL/6 mice. Animals were tested in the open field and forced swim test to examine anxiety-like and depressivelike behaviors. Plasma corticosterone levels were measured after behavior and CUS, and glucocorticoid receptor (GR) expression and cytosolic and nuclear fractions of binding protein FKBP51 expression were taken to measure function and regulation of the stress response. Results:Our results indicate increased depressive-like behavior in males and females which correlated with increased corticosterone levels following CUS. However, females displayed more anxiety-like behaviors with and without CUS. Interestingly, we found trends toward dysregulation of GR protein expression in CUS females, and an increase in the GR inhibitory protein, FKBP51, in the cytosol of CUS males but not females. Conclusion:These results suggest biochemical alterations to the HPA axis regulation which may elicit a glucocorticoid resistance in females after chronic stress and may contribute to the sex-biased vulnerability to stress-related psychiatric disorders. K E Y W O R D Schronic stress, FKBP51, glucocorticoid receptor, HPA axis, sex differences

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Accumulation of Cytoplasmic Glucocorticoid Receptor Is Related to Elevation of FKBP5 in Lymphocytes of Depressed Patients

Cited by 21 publications

References 41 publications

Both maternal care received and genotype influence stress‐related phenotype in female rats

Both maternal care received and genotype influence stress‐related phenotype in female rats

HIV and symptoms of depression are independently associated with impaired glucocorticoid signaling

Sex differences in hypothalamic–pituitary–adrenal axis regulation after chronic unpredictable stress

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