FKBP5, also known as FKBP51, encodes a co-chaperone protein. It is involved in modulating glucocorticoid receptor interaction, thus playing a crucial role in the adaptive stress response. The intracellular concentration of FKBP5 affects the binding affinity of the glucocorticoid receptor to glucocorticoids. The gene contains glucocorticoid response elements in its introns which regulate its expression [2].

In a cardiomyocyte-specific FKBP5 knockdown mouse model, downregulation of FKBP5 promoted atrial arrhythmogenesis. This was associated with action potential alternans, spontaneous Ca2+ waves, and increased NCX1 protein levels and activity. FKBP5-deficiency enhanced Slc8a1 (encoding NCX1) transcription via hypoxia-inducible factor 1α, as FKBP5 negatively modulates hypoxia-inducible factor 1α protein levels by interacting with heat-shock protein 90 [1]. In Fkbp5 knockout mice, there was no significant change in circadian rhythms detected by wheel-running activity, but it offered protection against stress-mediated disruptions in rhythmicity in a sex-dependent manner. Also, protein changes were observed in a brain region-and sex-dependent manner, with elevated levels of proteins associated with neuronal-cell adhesion and synaptic integrity in aged Fkbp5 KOs [3].

In conclusion, FKBP5 is essential for regulating the adaptive stress response by modulating glucocorticoid receptor interaction. The use of FKBP5 knockout or knockdown mouse models has revealed its role in atrial arrhythmogenesis and its impact on circadian rhythm and brain proteomics. These findings contribute to our understanding of related disease mechanisms, such as those in atrial fibrillation and potentially stress-related neuropsychiatric disorders [1,3].

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. 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/

3. 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/