ReviewThe role of FKBP5, a co-chaperone of the glucocorticoid receptor in the pathogenesis and therapy of affective and anxiety disorders
Introduction
Susceptibility to affective and anxiety disorders is determined by a combined effect of genes and environment, with heritability estimates for these disorders ranging from 30% to 80% complemented by a major impact of negative life events or childhood maltreatment (Kendler, 1995). One important, but not the only system mediating long-term effects of stress and thus negative life events on the development of psychiatric disorders is the stress hormone system. This review article only focuses on this, but not other systems mediating the stress response. Stress activates the central corticotropin releasing hormone (CRH) system within minutes. In addition to its well documented role as a hypothalamic hypophysiotropic factor that stimulates pituitary ACTH synthesis and secretion and thereby controls the activity of the HPA-axis (Vale et al., 1981), CRH neurons also innervate the locus coeruleus, thus activating the other major stress response axis, the central nervous system (CNS) noradrenergic and sympathetic nervous systems (Valentino et al., 1983). The CRH system also locally regulates adrenal steroidogenesis and catecholamine synthesis and release from the adrenal gland (Tsatsanis et al., 2007), again, dually influencing the HPA-axis and norepinephrine and epinephrine secretion. In addition, activation of CRH neurotransmission in limbic brain regions has been associated with the behavioral effects relevant for an adequate stress response, such as increased arousal, decreased libido and food intake (Holsboer, 1999, Nemeroff, 1996). Via this system, stress thus orchestrates behavioral effects, a noradrenergic/sympathetic stress response as well as increased release of ACTH and the glucocorticoid cortisol. Glucocorticoids promote the physiologic stress response by preparing the end organs for a fight and flight response but they are also critical for terminating the response via a negative feedback on several levels of the axis via the activation of the glucocorticoid receptor (GR).
Section snippets
Glucocorticoid receptor function in mood and anxiety disorders
The proper negative feedback via the glucocorticoid receptor thus appears to be critical for a healthy stress response and prolonged or excessive activation of this system have been implicated in the pathogenesis of mood and anxiety disorders (Holsboer, 2000, Pariante and Miller, 2001). In fact, an impaired signaling via corticosteroid-activated GR, leading to an impaired negative feedback regulation and thus to partial glucocorticoid resistance appears to be one of the most robust biological
Molecular regulators of GR function, focus on FKBP5
The GR is a ligand-activated transcription factor that translocates from the cytosol to the nucleus after ligand binding. This activation and translocation process, and subsequent GR action on gene transcription, is regulated by a large molecular complex (Pratt et al., 2006, Pratt and Toft, 1997). This multiprotein machinery centers around the molecular chaperones (molecules that allow the proper folding for peptides and proteins) of heatshock protein 70 (hsp70) and heatshock protein 90
FKBP5 polymorphisms
Fig. 2 represents the genetic structure of FKBP5 in two different ethnicities. In humans, common single nucleotide polymorphisms (SNPs) in FKBP5 (see Fig. 2) have been associated with increased FKBP5 protein expression as well as variation in the correlation between plasma cortisol levels and peripheral blood FKBP5 mRNA expression (Binder et al., 2004) suggesting that the alleles of these polymorphisms are associated with a differential induction of FKBP5 by GR activation (see Fig. 3). By
FKBP5 and risk for stress-related psychiatric disorders
Given the fact that these polymorphisms are associated with higher FKBP5 levels leading to GR resistance and impaired negative feedback, one could speculate that FKBP5 alleles associated with a slower return to baseline of stress-induced cortisol levels also increase the risk for stress-related psychiatric disorders. Currently, there is evidence for the impact of FKBP5 in both mood and anxiety disorders.
Conclusions
The above presented data would thus suggest that an overshooting induction of FKBP5 following cortisol release in response to a stressor would lead to an impaired negative feedback of cortisol release and thus prolonged elevations of cortisol following a stressor. This maladaptive prolonged stress response may render individuals more vulnerable to psychiatric disease, as shown for unipolar and bipolar depression as well as PTSD. Because FKBP5 expression is responsive to cortisol, genetic or
Role of the funding source
Dr. Binder is funded by the Max-Planck Society as well as NIMH and received a Doris Duke Charitable Foundation Clinical Scientist Award. Funding from these agencies had no further role in the conception and writing of the report and in the decision to submit the paper for publication.
Conflict of interest
None declared.
Acknowledgements and financial disclosures
In the past, Dr. Binder has received grant support from Pfizer Pharmaceuticals, GSK and NARSAD. Currently, Dr. Binder receives grant support from NIMH and the Doris Duke charitable foundation. Dr. Binder is co-inventor on the following patent applications: “FKBP5: a novel target for antidepressant therapy”, International publication number: WO 2005/054500 and “Polymorphisms in ABCB1 associated with a lack of clinical response to medicaments”, International application number: PCT/EP2005/005194.
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