Abstract
Stress activates the nuclear translocation of glucocorticoid receptors (GR) to trigger gene expression. Abnormal GR levels can alter the stress responses in animals and therapeutic effects of antidepressants. Here, we reported that stress-mediated nuclear translocation of GR reduced Ahi1 in the stressed cells and mouse brains. Ahi1 interacts with GR to stabilize each other in the cytoplasm. Importantly, Ahi1 deficiency promotes the degradation of GR in the cytoplasm and reduced the nuclear translocation of GR in response to stress. Genetic depletion of Ahi1 in mice caused hyposensitivity to antidepressants under the stress condition. These findings suggest that AHI1 is an important regulator of GR level and may serve as a therapeutic target for stress-related disorders.
Highlights
Stress activates the hypothalamic–pituitary–adrenal (HPA) axis to release glucocorticoid hormones from the adrenal cortex, which cross the blood–brain barrier and target mineralocorticoid receptors and glucocorticoid receptors (GR) in the brain
To delineate the mechanism behind these phenomena, our studies show that Ahi[1] interacts with GR to regulate its translocation from the cytoplasm to the nuclei, thereby modifying GR-mediated stress response
We recently found that Huntingtin-associated protein 1 (Hap1), an Ahi1-interacting protein that stabilizes Ahi[118,19,32], could diminish the effect of dexamethasone acetate (Dex) on the GR level in the hypothalamus[33]
Summary
Stress activates the hypothalamic–pituitary–adrenal (HPA) axis to release glucocorticoid hormones from the adrenal cortex, which cross the blood–brain barrier and target mineralocorticoid receptors and glucocorticoid receptors (GR) in the brain. GR is translocated from the cytoplasm to the nuclei to trigger stress response signaling pathways[1,2,3]. Impaired GR signaling is considered an important contributor to stressrelated disorders, such as major depressive disorders (MDD)[4,5], and targeting impaired GR functions is a therapeutic mechanism of different antidepressants[6,7]. How the GR signaling pathway is involved in stress-related disorders and their treatments remains to be fully investigated. The Abelson helper integration site 1 (AHI1) gene plays a pivotal role in brain development, and the mutations of AHI1 cause Joubert syndrome, a neurodevelopmental disorder[8]. Ahi[1] deficiency in mice is associated with depressive-like behaviors[11,15] and a stressresilient phenotype[16,17]. We still lack direct knowledge of the mechanisms for an association between
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