Abstract
The hypothalamus-pituitary-adrenal (HPA) axis directly controls the stress response. Dysregulation of this neuroendocrine system is a common feature among psychiatric disorders. Steroid hormone receptors, like glucocorticoid receptor (GR), function as transcription factors of a diverse set of genes upon activation. This activity is regulated by molecular chaperone heterocomplexes. Much is known about the structure and function of these GR/heterocomplexes. There is strong evidence suggesting altered regulation of steroid receptor hormones by chaperones, particularly the 51 kDa FK506-binding protein (FKBP51), may work with environmental factors to increase susceptibility to various psychiatric illnesses including post-traumatic stress disorder (PTSD), major depressive disorder (MDD), and anxiety. This review highlights the regulation of steroid receptor dynamics by the 90kDa heat shock protein (Hsp90)/cochaperone heterocomplexes with an in depth look at how the structural regulation and imbalances in cochaperones can cause functional effects on GR activity. Links between the stress response and circadian systems and the development of novel chaperone-targeting therapeutics are also discussed.
Highlights
The HPA, or hypothalamic-pituitary-adrenal, axis is a critical neuroendocrine system controlling numerous processes including autonomic functions, the immune response, metabolic activity, and, importantly, the stress response [1,2,3,4]
The paraventricular nucleus of the hypothalamus releases corticotropin releasing hormone (CRH), which activates the anterior lobe of the pituitary gland causing the release of adrenocorticotropic hormone (ACTH)
There has been substantial research investigating the role of glucocorticoid receptor (GR) in regulating the stress response, recent work has advanced our understanding of both the structural and functional regulation of GR by Hsp90 heterocomplexes
Summary
The HPA, or hypothalamic-pituitary-adrenal, axis is a critical neuroendocrine system controlling numerous processes including autonomic functions (e.g., digestion), the immune response, metabolic activity, and, importantly, the stress response [1,2,3,4]. When stressors are encountered, including both physical insult and psychological stress, the HPA axis is activated [5,6,7]. Circulating CORT inhibits the release of CRH and ACTH through a negative feedback loop ending the HPA activated stress response (Figure 1) [8,9,10]. SScchheemmaattiicc ooff gglluuccooccoorrttiiccooiidd rreecceeppttoorr ((GGRR)) ttrraannssaaccttiivvaattiioonniinn rreessppoonnssee ttoo ccoorrttiissooll ((CCOORRTT)). TAhet cthenetceernotefrtohfisthciosmcopmlepx,letxh,eth9e09k0DkaDahehaetasthsohcokckpprorotetienin(H(Hsspp9900))ccoollllaabboorraatetess wwiitthh ccoocchhaappeerroonneess,, iinncclluuddiinngg ttwwoo FFKK550066--bbiinnddiinngg pprrootteeiinnss,, FFKKBBPP5511 aanndd FFKKBBPP5522,, ccyycclloopphhiilliinn 4400 ((CCyyPP4400)),, aanndd pprrootteeiinn pphhoosspphhaattaassee 55 ((PPPP55)) ttoo ccoonnttrrooll GGRR ttrraannssaaccttiivvaattiioonn,, aaffffeeccttiinngg bbootthh sseennssiittiivviittyy ttoo CCOORRTT aanndd nnuucclleeaarr ttrraannssllooccaattiioonn [[3300,,3311]]. NNoottaabbllyy,, FFKKBBPP5511 aaffffeeccttss GGRR ttrraannssaaccttiivvaattiioonn iinn aa ddiissssiimmiillaarr mmaannnneerr ttoo tthhee ootthheerr ccoocchhaappeerroonneess. FFKKBBPP5522,, as well as CyP40 and PP5, have been shown to promote GR activity, which may be a combination of. This review discusses chaperone involvement in GR physiology and the impact of chaperone imbalances that may lower resilience against psychiatric disorders
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