Signaling Pathways in Brain Involved in Predisposition and Pathogenesis of Stress-Related Disease: Genetic and Kinetic Factors Affecting the MR/GR Balance

: Optimal regulation of the stress response is a prerequisite for adaptation, homeostasis, and health. There are two modes of operation in the stress response. First, an immediate response mode mediated by corticotrophin‐releasing hormone‐1 (CRH‐1) receptors that organizes the behavioral, sympatheti...

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Bibliographic Details
Published in:Annals of the New York Academy of Sciences 2004-12, Vol.1032 (1), p.14-34
Main Authors: de KLOET, E RONALD, DERIJK, ROEL
Format: Article
Language:English
Subjects:
Animals
behavior
brain
Brain - physiopathology
corticosteroids
Homeostasis - physiology
Humans
Hypothalamo-Hypophyseal System - physiology
Kinetics
Neurosecretory Systems - physiology
receptors
Receptors, Glucocorticoid - genetics
Receptors, Glucocorticoid - metabolism
Receptors, Mineralocorticoid - genetics
Receptors, Mineralocorticoid - metabolism
Signal Transduction - genetics
Signal Transduction - physiology
single nucleotide polymorphisms (SNPs)
stress
Stress, Psychological - genetics
Stress, Psychological - physiopathology
vulnerability genes
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Summary:: Optimal regulation of the stress response is a prerequisite for adaptation, homeostasis, and health. There are two modes of operation in the stress response. First, an immediate response mode mediated by corticotrophin‐releasing hormone‐1 (CRH‐1) receptors that organizes the behavioral, sympathetic, and hypothalamic‐pituitary‐adrenal (HPA) response to a stressor. Second, a slower mode, which facilitates behavioral adaptation, promotes recovery, and reestablishes homeostasis. Corticosteroid hormones are implicated in both stress system modes. On the one hand, cortisol and corticosterone determine the threshold or sensitivity of the fast responding mode, whereas the very same hormones in high concentrations facilitate termination of the stress response. In the brain, these actions exerted by the corticosteroid hormones are mediated by two distinct nuclear receptor types, that is, mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs). Whereas MRs maintain neuronal homeostasis and limit the disturbance by stress, GRs help to recover after the challenge and to store the experience for coping with future encounters. Imbalance in MR/GR‐mediated actions compromises homeostatic processes in these neurons, which is thought to underlie maladaptive behavior and HPA dysregulation that may lead to aberrant metabolism, impaired immune function, and altered cardiovascular control. The balance in MR/GR‐mediated actions depends on bioavailability of corticosteroids, access to the receptors, the stoichiometry of co‐regulators, and other proteins as well as genetic factors, among which single nucleotide polymorphisms (SNPs) of the GRs are extensively documented. Stress can bias the receptor signaling pathways, changing “good” corticosteroid actions into “bad” ones.
ISSN:0077-8923
1749-6632
DOI:10.1196/annals.1314.003