Mechanisms of brain glucocorticoid resistance in stress-induced psychopathologies

Exposure to stress activates the hypothalamic–pituitary–adrenal axis and leads to increased levels of glucocorticoid (GC) hormones. Prolonged elevation of GC levels causes neuronal dysfunction, decreases the density of synapses, and impairs neuronal plasticity. Decreased sensitivity to glucocorticoi...

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Bibliographic Details
Published in:Biochemistry (Moscow) 2017-03, Vol.82 (3), p.351-365
Main Authors: Merkulov, V. M., Merkulova, T. I., Bondar, N. P.
Format: Article
Language:English
Subjects:
Animals
Antidepressants
Biochemistry
Biomedical and Life Sciences
Biomedicine
Bioorganic Chemistry
Biosynthesis
Epigenetics
Glucocorticoids
Glucocorticoids - metabolism
Health aspects
Hormones
Humans
Life Sciences
Mental Disorders - genetics
Mental Disorders - metabolism
Mental Disorders - physiopathology
Microbiology
Physiological aspects
Polymorphism, Genetic
Protein Isoforms - genetics
Protein Isoforms - metabolism
Proteins
Psychopathology
Receptors, Glucocorticoid - genetics
Receptors, Glucocorticoid - metabolism
Review
Signal Transduction
Stress (Psychology)
Stress response
Stress, Psychological - genetics
Stress, Psychological - metabolism
Stress, Psychological - physiopathology
Tacrolimus Binding Proteins - genetics
Tacrolimus Binding Proteins - metabolism
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Summary:Exposure to stress activates the hypothalamic–pituitary–adrenal axis and leads to increased levels of glucocorticoid (GC) hormones. Prolonged elevation of GC levels causes neuronal dysfunction, decreases the density of synapses, and impairs neuronal plasticity. Decreased sensitivity to glucocorticoids (glucocorticoid resistance) that develops as a result of chronic stress is one of the characteristic features of stress-induced psychopathologies. In this article, we reviewed the published data on proposed molecular mechanisms that contribute to the development of glucocorticoid resistance in brain, including changes in the expression of the glucocorticoid receptor (GR) gene, biosynthesis of GR isoforms, and GR posttranslational modifications. We also present data on alterations in the expression of the FKBP5 gene encoding the main component of cell ultra-short negative feedback loop of GC signaling regulation. Recent discoveries on stressand GRinduced changes in epigenetic modification patterns as well as normalizing action of antidepressants are discussed. GR and FKBP5 gene polymorphisms associated with stress-induced psychopathologies are described, and their role in glucocorticoid resistance is discussed.
ISSN:0006-2979
1608-3040
DOI:10.1134/S0006297917030142