Mineralocorticoid Receptors Play an Important Role in Stress Regulation

Everyone has experienced stress at least once in their life. A students taking an exam, a soldier at war, a candidate for a job interview or a project manager for a public presentation. Butterflies in the stomach, an urge to go to the bathroom or restlessness, the symptoms of stress are numerous and specific to each person. They are usually temporary, but in some cases stress can become chronic and lead to mood and anxiety disorders or post-traumatic stress disorder.

Neuro-Hormonal Response to Stress. Image courtesy of Campos-Rodríguez R

From a biological point of view, the brain’s responses to stress remain poorly studied and understood. The hypothalamic-pituitary-adrenal (HPA) axis is the link between the nervous system and the endocrine system, which releases hormones. Its main function is to regulate the body’s response to stress. As a result of a cascade of reactions between the hypothalamus, the pituitary and finally the adrenal glands, the amount of cortisol, the stress hormone, increases. This triggers a series of changes in the body that enable it to cope with stress. Dysregulation of the HPA axis has been implicated in certain psychiatric pathologies.

A group of American and German researchers have carefully dissected the metabolic reactions that occur in the hippocampus during stress. This area of the brain is particularly sensitive because it contains a large number of receptors for glucocorticoids, the family of hormones to which cortisol belongs. They identified three key proteins that work together to produce a normal or altered response to stress. They published the results of this complex study in Cell Reports.

Deciphering the mechanisms of stress

The stress response in the HPA axis is the result of a balance between glucocorticoid receptors (GR) and mineralocorticoid receptors (MR). Both receptors are located in the cell nucleus and cortisol is able to bind to these receptors and activate them. The third protein involved is FKBP5, which acts as a switch for the GRs: when present, the protein inhibits their activation. When the body is under stress, cortisol decreases the expression of the gene encoding FKBP5, reducing GR activity and the stress response. This is known as the “negative feedback” mechanism.
But scientists have observed in mice and human tissues that mineralocorticoids also have an effect on FKBP5. When MRs are expressed in large amounts, FKBP5 is also produced in large amounts and fulfills its function as a GR inhibitor. Thus, the stress response is lower. Conversely, fewer MRs means less FKBP5 and thus less GR inhibition, the stress response is enhanced.

A starting point for research into future treatments.

Why are these observations interesting? Some stress-related psychiatric diseases are caused by the dysregulation of these stress response mechanisms. By understanding them in as much detail as possible, scientists can identify new therapeutic targets in the hope of treating diseases such as post-traumatic stress disorder or depression. In addition, our data highlight the important but under-recognized role of MR signaling in stress-related psychiatric disorders,” said Kerry J. Ressler, a scientist involved in this study. The results of this study will open new avenues for future research.