Corticosteroid receptor-gene variants: modulators of the stress-response and implications for mental health

Publication Type:

Journal Article

Source:

Eur J Pharmacol, Volume 585, Number 2-3, p.492-501 (2008)

ISBN:

0014-2999 (Print)0014-29

DOI Name (links to online publication)

10.1016/j.ejphar.2008.03.012

Keywords:

Animals; Genetic Variation; Humans; Hypothalamo-Hypophyseal System/physiology; Mental Disorders/genetics/psychology; *Mental Health; Polymorphism; Single Nucleotide; Receptors; Mineralocorticoid/metabolism; Receptors; Steroid/*genetics; Stress; Psychologi

Abstract:

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.

18/01/2013