A Brand New Response to Stress Response

You can have too much of a good thing, and the evolutionary advantage humans have been given with our “fight or flight” response to stress can come at a heavy price. Cortisol, the signature hormone that induces our stress response, has many different functions that serve to protect our health. But its functionality is a tightrope walk that depends on a fine balance between ensuring a necessary, high-energy response to various daily stresses we encounter, and triggering the onset of metabolic disorders like increased blood pressure or high blood sugar, and mood disorders like anxiety or depression.

This dichotomy is a baffling riddle that requires a unique research response. Carolyn Cummins, scientist and associate professor in the Department of Pharmaceutical Sciences at the Leslie Dan Faculty of Pharmacy is investigating how the genetic response to stress hormones might contribute to disease.

The Cummins’ lab most recent study, published in Nucleic Acids Research, has uncovered two previously unknown functions for the ARGLU1 protein that carries implications for the treatment of neuronal disease. First is that ARGLU1 is a co-activator of the glucocorticoid receptor (GR) to which the stress hormone cortisol binds, thereby enabling the cortisol to induce that heightened stress response with which we’re all familiar.

Second is that ARGLU1 plays a role in alternative splicing, the mechanism by which one gene can be broken up and combined in a number of variations. The resulting diversity of proteins produced from one gene is literally greater than the sum of its parts, and has played an important role in helping organisms adapt to their changing environments.

Uncovering new ways stress hormones can induce changes in the brain

The finding that the stress hormone uses the ARGLU1 gene in both transcription and alternative splicing patterns is unique because it suggests that, in addition to transcriptional regulation, there is a whole new unexplored layer of control by which stress hormones can induce changes in the brain. The results of this study are particularly interesting given the known psychological effects of stress and the importance of alternative splicing for neurogenesis.

Alternative splicing and the technological tools to study it on a genome-wide scale have only recently been available. While much progress has been made in understanding the interplay between nuclear receptors and their co-activators in the initiation of gene expression (transcription), the post-transcriptional role of co-regulators in the process of alternative splicing is still poorly understood.

The discovery that ARGLU1 is linked to post-transcriptional signaling is a step forward.

The researchers also demonstrated that loss of ARGLU1 causes significant developmental defects in pre-clinical models. While both changes in transcription and splicing are likely playing a role, additional studies with proteins that selectively rescue one or the other function need to be performed to determine their relative importance.

Researchers in the Cummins lab are now exploring how ARGLU1 will impact the stress hormone signaling cascade with respect to development of metabolic disease.