Corticosteroid receptor-gene variants: modulators of the stress-response and implications for mental health.
The stress-response, including autonomic and hypothalamic-pituitary-adrenal (HPA) axis reactivity, is essential for maintaining homeostasis during a challenge. Brain mineralocorticoid receptors and glucocorticoid receptors operate in balance to coordinate the stress-response. Genetic variants in both the human mineralocorticoid and glucocorticoid receptor-genes have been functionally characterized. In vitro effects of these genetic variants on transactivation and mRNA stability have been described. In vivo, two mineralocorticoid receptor-gene SNPs (-2 G/C (allele frequency: 50%), MR I180V (11%)) and four glucocorticoid receptor-gene SNPs (ER22/23EK (3%), N363S (4%), BclI (37%), A3669G (15%)) are associated with changes in hypothalamic-pituitary-adrenal (HPA) axis reactivity. Importantly, the two mineralocorticoid receptor-gene variants (but none of the glucocorticoid receptor-gene variants) also associate with changes in autonomic output as measured as increased heart beat following a psychosocial stress (TSST). Moreover, several of these mineralocorticorticoid receptor- and glucocorticoid receptor variants have been found associated with stress-related disorders, including depression. These data indicate that dysregulation of mineralocorticoid- and glucocorticoid receptor are causative in the pathogenesis of depression. Moreover, these mineralocorticoid- and glucocorticoid receptor-gene variants constitute part of the genetic make up that determines individual stress-responsiveness inducing vulnerability to disease. Furthermore, mineralocorticoid- and glucocorticoid receptors are drug targets, thereby aiming at the underlying mechanisms of stress-related disorders.
Derijk
Roel H
RH
Department of Psychiatry, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands. r.h.de.rijk@LACDR.Leidenuniv.nl
van Leeuwen
Nienke
N
Klok
Melanie D
MD
Zitman
Frans G
FG
D000818:Animals; D014644:Genetic Variation; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000502:physiology; D001523:Mental Disorders / Q000235:genetics / Q000523:psychology; D008603:Mental Health; D020641:Polymorphism, Single Nucleotide; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics*; D013315:Stress, Psychological / Q000235:genetics* / Q000523:psychology*
D018161:Receptors, Mineralocorticoid; D011987:Receptors, Steroid