Corticosteroid receptor polymorphisms: Determinants of vulnerability and resilience

被引:127
作者
DeRijk, Roel H. [1 ]
de Kloet, E. Ron [1 ]
机构
[1] Leiden Univ, Med Ctr, Div Med Pharmacol, Leiden Amsterdam Ctr Drug Res, NL-2300 RA Leiden, Netherlands
关键词
vulnerability; genetic variant; glucocorticoid receptor; meniralocorticoid receptor; stress;
D O I
10.1016/j.ejphar.2007.11.072
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Why some individuals thrive and others break down under similar adverse conditions, is a central question in the neuroendocrinology of stress related psychopathology. The brain mineralocorticoid (MR) and glucocorticoid receptors (GR) operate in balance to coordinate behavioural, autonomic and neuroendocrine response patterns involved in homeostasis and health. Genetic variants of both the MR and GR have been functionally characterized. The four GR-gene single nuelcotide polymorphisms (SNPs) (ER22/23EK (allele frequency: 3%), N363S (4%), Bcll (37%), A3669G (15%)) and the two MR-gene SNPs (-2 G/C (50%), MR-1180V (11%)) showed in vitro changes in transactivational capacity, or affect stability of the mRNA (GR exon 9 beta A3669G). All of these MR-and GR-SNPs change the regulation of the hypothalamus-pituitary-adrenal (HPA) axis at different levels including basal level (-2 G/C), dexamethasone induced negative feedback (ER22/23EK, N363S, BclI, 9 beta A3669G) or following a psychosocial stress test (Trier Social Stress Test (TSST); all of the MR-and GR-SNPs). Importantly, the MR-1180V increased autonomic output and enhanced cortisol secretion during the TSST. Recently, several of these MR-and GR-variants have been found associated with psychopathology (depression, bipolar disorder). These data provide evidence that dysregulation of MR and GR are causative in the pathogenesis of depression and that these MR-and GR-gene variants are part of the genetic make up that determines individual stress-responsivity and coping style, affecting vulnerability to disease. (C) 2008 Elsevier B.V. All rights reserved.
引用
收藏
页码:303 / 311
页数:9
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