Molecular mechanism of antidepressants action has been discovered


March 18, 2022

Scientists from the Max Planck Institute of Psychiatry in collaboration with a research group from the Biomedicine Research Institute of Buenos Aires (IBioBA) conducted studies to evaluate the effects of antidepressants and found a molecular mechanism that contributes to explain the basis of their functioning and could be the starting point for the development of personalized drugs. The results were published in the journal Molecular Psychiatry of the Nature group.

Animals do not suffer post-traumatic stress: once the zebra manages to flee from the lion, for example, it is calm in a pasture and goes back to doing what it was doing before feeling danger in the presence of its predator. Dysregulation of the system occurs in the human brain. What produces stress at the molecular level is complex, it is a chain of signals that are activated and put our organism on alert: glucocorticoids are able to act in all the cells of our body thanks to the glucocorticoid receptor (GR), which binds to them and migrates to the cell nucleus, where it fulfills its biological function of regulating genes, which execute the 'alert' signal (which translates as the response to stress).

The GR, in turn, has a negative regulator: the protein FKBP51, which is responsible for inhibiting (or not allowing) its migration to the nucleus. "We studied FKBP51 in particular because it is known that high levels of this protein are associated with stress-related diseases; and these diseases, in turn, are related to glucocorticoid receptor resistance. It is as if there is a stimulus and the GR cannot respond correctly", explains postdoctoral fellow Ludmila Budziñski, first author of the paper together with PhD student Clara Sokn.

In addition to this, FKBP51 is a target of SUMOylation (a modification that occurs after the protein is synthesized), "that is to say that the SUMO peptide binds to it and this is necessary for it to exert its inhibitory effect", clarifies Ana Liberman, head of the research project. In turn, in order to be SUMOylated, FKBP51 needs the SUMOylation enzymatic machinery, particularly PIAS4. This enzyme is what allows FKBP51 to be specifically and effectively SUMOylated.


The work describes that tricyclic antidepressants inhibit FKBP51 SUMOylation, and that this inhibition caused by the decreased interaction of FKBP51 with PIAS4, directly impacts on the negative regulatory functions of FKBP51 on GR (which is deregulated in stress-related diseases). Thus, the action of antidepressants as repressors of FKBP51 SUMOylation acts as a molecular switch that helps to restore glucocorticoid receptor sensitivity.


In sum, this publication provides a potential new avenue of intervention of antidepressants that contributes to explain how they favor the restoration of homeostasis -or balance- of the system, which is affected in stress-associated psychiatric diseases. Considering the growing need to find new strategies for the treatment of this type of diseases, especially in the current pandemic situation, "the study of the molecular mechanism involved in the modulation of FKBP51 activity by SUMO conjugation and the identification of possible inhibitors of its SUMOylation is of utmost importance", says Liberman. Having a deeper understanding of the action of these drugs could contribute in the future to the development of new antidepressant drugs with new mechanisms of action and fewer side effects; "especially in patients where the expression or activity of FKBP51 is increased, so, without a doubt, these findings contribute to understanding the importance of personalized medicine", concludes Liberman.

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