Glucocorticoid receptor alpha translational isoforms as mediators of early adversities and negative emotional states

Abstract

Childhood trauma (CT) increases the risk for psychopathology through disturbed acquisition and extinction of fear. The effects of CT are mediated by abnormalities of the hypothalamic-pituitary-adrenal axis and glucocorticoid receptor (GR). Since, the alterations in GRα translational isoforms have been documented in psychiatric disorders we sought to: 1) explore whether multiple GRα isoforms in the human peripheral blood mononuclear cells of two independent cohorts (whole cell n = 40; and nuclear extracts n = 43, adult subjects) mediate the effect of CT on negative affectivity (NA) measured by Depression, Anxiety and Stress Scales (DASS), and 2) examine their role/function during fear extinction in the animal model. In multiple regression analysis, CT, nuclear 40-kDa GRα, their interactions and FKBP5 explained 22%−35% of variance in DASS scores. Structural equation modeling showed that CT had a significant direct effect on 40-kDa and DASS in both cohorts, and on the nuclear 25-kDa GRα. The association between 40-kDa and total DASS was significantly mediated by nuclear FKBP5, whereas on DASS anxiety, over FKBP5 in both cohorts and nuclear full length GRα. Nuclear 40-kDa GRα and its interaction with CT had a significant direct effect on DASS anxiety. In mice, the successful extinction learning was followed by nuclear translocation of 40-kDa GRα and induction of BDNF exon IV expression. Our data revealed that the association between CT and adult NA in non-clinical subjects is mediated by the GRα translational isoforms, in particular 40-kDa GRα, and emphasized its role in fear extinction and neural plasticity.

Sex‐specific contribution of glucocorticoid receptor alpha isoforms to anxiety and depressive‐like behavior in mice

“…We used GR P20 antibody for their detection, which epitope maps at C‐terminus of GRα isoforms. With this antibody, we detected five IR bands at approximately 95, 67, 50, 40, and 25 kDa (Figure S2), identified by other authors as well (Adzic et al, 2019; Sinclair, Tsai, et al, 2011; Sinclair, Webster, et al, 2011).…”

“…Although the role of these isoforms has already been studied in schizophrenia and bipolar disorder (Sinclair et al, , 2012, their role in MDD has yet to be elucidated. Our previous study emphasized the role of different GRα translational isoforms in lymphocytes as mediating factors between childhood trauma and negative emotional states in adulthood (Adzic et al, 2019). In the present study, we wanted to investigate further the role of these isoforms in pathophysiology of depression by studying the effects of adolescent CUS on depressive behavior in adult male and female mice.…”

Identification of multiple isoforms of glucocorticoid receptor in nasal polyps of patients with chronic rhinosinusitis

“…Recently, several translational isoforms of GR have been reported to exist in different species, various tissues and several cell lines [ 11 , 13 , 34 , 35 ]. According to the previous study of Nick, when the human GRα was expressed in COS-1 cells, which lack endogenous GR, multiple proteins of 94, 91, 82–84, and 53–56 kDa were detected by using different selective anti-peptide GR antibodies [ 13 ].…”

“…Glucocorticosteroid (GC), is recommended as the first-line medicine for the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) [ 7 ]. As the biological effects of GC are mediated primarily through activation of intracellular glucocorticoid receptors (GR), recent evidence suggests that altered GR isoform expression may be associated with different GC sensitivity and disease severity [ 8 – 11 ].…”

“…GR could generate at least 5 characterized splice variants (GRα, GRβ, GRγ, GRA, and GRP) through alternative splicing. Via alternative initiation of translation from one single species of mRNA, GRα could further generate eight translational isoforms (A, B, C1, C2, C3, D1, D2, and D3) [ 11 , 13 – 17 ]. Moreover, different GR isoforms generated by alternative splicing and translation initiation have different functions [ 12 , 13 , 18 – 20 ].…”