The Role of Endoplasmic Reticulum Stress and Unfolded Protein Response in Glucocorticoid Production

An optimal glucocorticoid stress response is essential because it allows animals to adjust their phenotype to constantly changing environments. Considerable progress has been made regarding our understanding of how various cellular mechanisms of glucocorticoid action modulate animals' stress response phenotype. However, a potentially overlooked mediator of glucocorticoid production and individual's stress response phenotype is the endoplasmic reticulum (ER) and its unfolded protein response (UPR), given that all steroid hormones are synthesised within the mitochondria and the ER. We hypothesise that UPR regulates glucocorticoid synthesis, and ER stress induction would inhibit glucocorticoid production in the adrenal cortex. We conducted in vivo and in vitro studies using outbred deer mice Peromyscus maniculatus and Y-1 adrenal cell lines respectively to investigate the effects of ER stress and UPR on adrenocorticotropic hormone induced glucocorticoid production. Specifically, we tested if induction and alleviation of ER stress using tunicamycin and tauroursodeoxycholic acid, respectively, would affect corticosterone production in deer mice and Y-1 cells and the protein expression of a steroidogenic enzyme in Y-1 cells. We showed that ER stress and UPR modulate glucocorticoid production at both the cell and whole-organism levels, but this is achieved independent of alteration in protein level of 21-Hydroxylase.