FK506 Binding Protein 5 Shapes Stress Responsiveness: Modulation of Neuroendocrine Reactivity and Coping Behavior

Touma, Chadi; Gassen, Nils C.; Herrmann, Leonie; Cheung‐Flynn, Joyce; Büll, Dominik; Ionescu, Irina; Heinzmann, Jan-Michael; Knapman, Alana; Siebertz, Anna; Depping, Anna-Mareike; Hartmann, Jakob; Hausch, Felix; Schmidt, Mathias; Holsboer, Florian; Ising, Marcus; Cox, Marc B.; Schmidt, Ulrike; Rein, Theo

doi:10.1016/j.biopsych.2011.07.023

Cited by 231 publications

(212 citation statements)

References 62 publications

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“…Additionally, the level of FKBP51 induction in the hippocampus is significantly correlated to the neuroendocrine and behavioral phenotype in a complex manner. In FKBP51 KO mice, Touma et al (2011) reported an increased active stress coping in the FST, which was only present after a strong stressor. In line with these findings, FKBP51 correlates with stress sensitivity in mice KV Wagner et al we here show that higher FKBP51 levels in response to a challenge, in this case CSDS, were correlated to a reduction in active stress coping.…”

Section: Discussionmentioning

confidence: 97%

“…FKBP51 mRNA was upregulated in stress-related brain regions such as the hippocampus in response to acute stressors or a glucocorticoid challenge . Additionally, FKBP51 knockout mice were reported to show increased active stress coping behavior in the forced swim test (Touma et al, 2011) and a resilient phenotype in response to CSDS (Hartmann et al, 2012), suggesting a prominent role of FKBP51 in stress coping behavior.…”

Section: Introductionmentioning

confidence: 99%

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Differences in FKBP51 Regulation Following Chronic Social Defeat Stress Correlate with Individual Stress Sensitivity: Influence of Paroxetine Treatment

Wagner

Marinescu

Hartmann

et al. 2012

Neuropsychopharmacol

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Various clinical studies have identified FK506-binding protein 51 (FKBP51) as a target gene involved in the development of psychiatric disorders such as depression. Furthermore, FKBP51 has been shown to affect glucocorticoid receptor signaling by sensitivity modulation and it is implicated in stress reactivity as well as in molecular mechanisms of stress vulnerability and resilience. We investigated the physiological, behavioral, and neuroendocrine parameters in an established chronic stress model both directly after stress and after a recovery period of 3 weeks and also studied the efficacy of paroxetine in this model. We then examined FKBP51 mRNA levels in the dorsal and ventral part of the hippocampus and correlated the expression to behavioral and endocrine parameters. We show robust chronic stress effects in physiological, behavioral, and neuroendocrine parameters, which were only slightly affected by paroxetine treatment. On the contrary, paroxetine led to a disruption of the neuroendocrine system. FKBP51 expression was significantly increased directly after the stress period and correlated with behavioral and neuroendocrine parameters. Taken together, we were able to further elucidate the role of FKBP51 in the mechanisms of stress resilience and vulnerability, especially with respect to behavioral and neuroendocrine parameters. These findings strongly support the concept of FKBP51 as a marker for glucocorticoid receptor sensitivity and its involvement in the development of psychiatric disorders.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Differences in FKBP51 Regulation Following Chronic Social Defeat Stress Correlate with Individual Stress Sensitivity: Influence of Paroxetine Treatment

Wagner

Marinescu

Hartmann

et al. 2012

Neuropsychopharmacol

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“…FKBP51 is well recognized for its ability to regulate GR sensitivity and HPA axis functioning (Touma et al 2011. Most notably, FKBP51 acts as a negative regulator of GR by reducing nuclear translocation of the GR complex and ligand-binding sensitivity (Davies et al 2002, Wochnik et al 2005, Binder 2009).…”

Section: Introductionmentioning

confidence: 99%

Interplay between diet-induced obesity and chronic stress in mice: potential role of FKBP51

Balsevich

Uribe

Wagner

et al. 2014

Journal of Endocrinology

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While it is known that stress promotes obesity, the effects of stress within an obesogenic context are not so clear and molecular targets at the interface remain elusive. The FK506-binding protein 51 (FKBP51, gene: Fkbp5) has been identified as a target gene implicated in the development of stress-related psychiatric disorders and is a possible candidate for involvement in stress and metabolic regulation. The aims of the current study are to investigate the interaction between chronic stress and an obesogenic context and to additionally examine whether FKBP51 is involved in this interaction. For this purpose, male C57BL/6 mice were exposed to a high-fat diet for 8 weeks before being challenged with chronic social defeat stress. Herein, we demonstrate that chronic stress induces hypophagia and weight loss, ultimately improving features arising from an obesogenic context, including glucose tolerance and levels of insulin and leptin. We show that Fkbp5 expression is responsive to diet and stress in the hypothalamus and hippocampus respectively. Furthermore, under basal conditions, higher levels of hypothalamic Fkbp5 expression were related to increased body weight gain. Our data indicate that Fkbp5 may represent a novel target in metabolic regulation.

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“…FKBP51 knock-out (FKBP51 − / − ) MEFs kindly provided by Dr. MB Cox (University of Texas, El Paso, USA) were grown in DMEM supplemented with 10% FBS and 100 units/ml streptomycin, and have been described before. 6 HEK293T cells were transfected with Lipofectamine 2000 (Life Technologies/ Thermo Fisher Scientific, Carlsbad, CA, USA) following the manufacturer's instruction, and were electroporated for in vitro hormone binding, as previously described. 46 FKBP51 − / − MEFs were electroporated as previously described.…”

Section: Discussionmentioning

confidence: 99%

“…5 Therefore, FKBP51 is critical for GR in vivo function and a key mediator during stress. 6 Ligand binding to the GR induces an exchange between FKBP51 and the closely related TPR protein FKBP52, 7 which in turn enhances GR activity. 8 Abnormal FKBP51 function has been implicated in a wide variety of diseases, in particular stress-related disorders associated with impaired GR signaling.…”

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confidence: 99%

The activity of the glucocorticoid receptor is regulated by SUMO conjugation to FKBP51

et al. 2016

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FK506-binding protein 51 (FKBP51) regulates the activity of the glucocorticoid receptor (GR), and is therefore a key mediator of the biological actions of glucocorticoids. However, the understanding of the molecular mechanisms that govern its activity remains limited. Here, we uncover a novel regulatory switch for GR activity by the post-translational modification of FKBP51 with small ubiquitin-like modifier (SUMO). The major SUMO-attachment site, lysine 422, is required for FKBP51-mediated inhibition of GR activity in hippocampal neuronal cells. Importantly, impairment of SUMO conjugation to FKBP51 impacts on GR-dependent neuronal signaling and differentiation. We demonstrate that SUMO conjugation to FKBP51 is enhanced by the E3 ligase PIAS4 and by environmental stresses such as heat shock, which impact on GR-dependent transcription. SUMO conjugation to FKBP51 regulates GR hormone-binding affinity and nuclear translocation by promoting FKBP51 interaction within the GR complex. SUMOylation-deficient FKBP51 fails to interact with Hsp90 and GR thus facilitating the recruitment of the closely related protein, FKBP52, which enhances GR transcriptional activity. Moreover, we show that the modification of FKBP51 with SUMO modulates its binding to Hsp90. Our data establish SUMO conjugation as a novel regulatory mechanism in the Hsp90 cochaperone activity of FKBP51 with a functional impact on GR signaling in a neuronal context.

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FK506 Binding Protein 5 Shapes Stress Responsiveness: Modulation of Neuroendocrine Reactivity and Coping Behavior

Cited by 231 publications

References 62 publications

Differences in FKBP51 Regulation Following Chronic Social Defeat Stress Correlate with Individual Stress Sensitivity: Influence of Paroxetine Treatment

Differences in FKBP51 Regulation Following Chronic Social Defeat Stress Correlate with Individual Stress Sensitivity: Influence of Paroxetine Treatment

Interplay between diet-induced obesity and chronic stress in mice: potential role of FKBP51

The activity of the glucocorticoid receptor is regulated by SUMO conjugation to FKBP51

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