Fkbp5, also known as FK506 binding protein 51, encodes a molecular chaperone and scaffolding protein. It has a significant role in regulating hormone signaling, especially in modulating glucocorticoid receptor interaction involved in the adaptive stress response [4]. FKBP5 intracellular concentration affects the binding affinity of the glucocorticoid receptor to glucocorticoids, and its expression can be regulated by the mineralocorticoid receptor [3,4].

In a cardiomyocyte-specific FKBP5 knockdown mouse model, downregulation of FKBP5 promoted atrial arrhythmogenesis. It enhanced the transcription of Slc8a1 (encoding NCX1) via hypoxia-inducible factor 1α, mimicking the cellular phenotype of chronic atrial fibrillation patients [1]. In Fkbp5 knockout mice, there was no significant alteration in circadian rhythms, but they showed protection against stress-mediated disruptions in rhythmicity in a sex-dependent manner. Also, protein changes in the brain were observed in a region-and sex-dependent manner, with elevated levels of proteins associated with neuronal-cell adhesion and synaptic integrity in aged knockout mice [5]. In Fkbp5ko mice used to study multiple sclerosis, the progress of myelin loss and regeneration was slower compared to wild-type mice, indicating a role of FKBP5 in regulating mitophagy through PPAR-γ [2].

In conclusion, Fkbp5 is crucial in hormone-related signaling and stress response. Mouse models, such as the cardiomyocyte-specific knockdown, knockout, and ko models, have revealed its role in atrial arrhythmogenesis, demyelinating diseases, and stress-related disruptions in circadian rhythms, providing insights into related disease mechanisms [1,2,5].

References:

1. Wang, Xiaolei, Song, Jia, Yuan, Yue, Dobrev, Dobromir, Li, Na. 2023. Downregulation of FKBP5 Promotes Atrial Arrhythmogenesis. In Circulation research, 133, e1-e16. doi:10.1161/CIRCRESAHA.122.322213. https://pubmed.ncbi.nlm.nih.gov/37154033/

2. Sun, Xingzong, Qian, Menghan, Li, Hongliang, Dai, Lili, Bao, Hongkun. 2023. FKBP5 activates mitophagy by ablating PPAR-γ to shape a benign remyelination environment. In Cell death & disease, 14, 736. doi:10.1038/s41419-023-06260-7. https://pubmed.ncbi.nlm.nih.gov/37952053/

3. Hartmann, Jakob, Bajaj, Thomas, Klengel, Claudia, Schmidt, Mathias V, Ressler, Kerry J. . Mineralocorticoid receptors dampen glucocorticoid receptor sensitivity to stress via regulation of FKBP5. In Cell reports, 35, 109185. doi:10.1016/j.celrep.2021.109185. https://pubmed.ncbi.nlm.nih.gov/34077736/

4. Mendonça, Mariana S, Mangiavacchi, Paula M, Rios, Álvaro F L. 2021. Regulatory functions of FKBP5 intronic regions associated with psychiatric disorders. In Journal of psychiatric research, 143, 1-8. doi:10.1016/j.jpsychires.2021.08.014. https://pubmed.ncbi.nlm.nih.gov/34433110/

5. Gebru, Niat T, Guergues, Jennifer, Verdina, Laura A, Gulick, Danielle, Blair, Laura J. 2024. Fkbp5 gene deletion: Circadian rhythm profile and brain proteomics in aged mice. In Aging cell, 23, e14314. doi:10.1111/acel.14314. https://pubmed.ncbi.nlm.nih.gov/39225086/