1. Bag‐1 mediates glucocorticoid receptor trafficking to mitochondria after corticosterone stimulation: Potential role in regulating affective resilience
- Author
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Shaolei Luo, Bruce S. McEwen, Yangyang Hou, Peixiong Yuan, Yue Jia, Husseini K. Manji, Lei Feng, Yaping Zhang, Richard G. Hunter, Haoran Li, Chunjie Xiao, Hongkun Bao, Gang Wang, and Jing Du
- Subjects
Male ,0301 basic medicine ,medicine.medical_specialty ,Anhedonia ,Primary Cell Culture ,Chromosomal translocation ,Stimulation ,Mitochondrion ,Biology ,Biochemistry ,Rats, Sprague-Dawley ,Pathogenesis ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Receptors, Glucocorticoid ,0302 clinical medicine ,Glucocorticoid receptor ,Pregnancy ,Corticosterone ,Internal medicine ,medicine ,Animals ,Swimming ,Neurons ,Dose-Response Relationship, Drug ,Depression ,Resilience, Psychological ,Stimulation, Chemical ,Mitochondria ,Rats ,DNA-Binding Proteins ,Affect ,Protein Transport ,030104 developmental biology ,Endocrinology ,chemistry ,Female ,030217 neurology & neurosurgery ,Glucocorticoid ,Transcription Factors ,medicine.drug ,Behavioural despair test - Abstract
Molecular abnormalities within the Glucocorticoid Receptor (GR) stress signaling pathway involved in dysfunction of mitochondria and confer vulnerability to stress related psychiatric disorders. Bcl-2 associated athanogene (Bag-1) is a target for the actions of mood stabilizers. Bag-1 interacts with GR, thereby regulating glucocorticoid function. In this study, we investigate the potential role of Bag-1 in regulating GR translocation into mitochondria. Corticosterone (CORT) treatment significantly enhanced Bag-1/GR complex formation and GR mitochondrial translocation in cultured rat cortical neurons after treatment for 30 minutes and 24 hours. By contrast, after stimulation with CORT for 3 days, localization of the Bag-1/GR complex and mitochondrial GR were reduced. Similar results were obtained in mice, in which administrated CORT in drinking water for 21 days significantly impaired the GR levels in the mitochondria, while Bag-1 overexpression rescued this reduction. Furthermore, chronic CORT exposure led to anhedonia-like and depression-like behaviors in the sucrose-consumption test and forced swimming test, and these behaviors were rescued by Bag-1 overexpression. These results suggest that Bag-1 mediates GR trafficking to mitochondria and regulates affective resilience in response to a CORT increase and provide potential insight into the mechanisms by which Bag-1 and GR could contribute to the physiology and pathogenesis of psychiatric disorders in response to the change of stress hormone.
- Published
- 2020