A distinctive approach to comprehending regulatory signalling mechanisms underlying the hypothalamic‒pituitary‒adrenal (HPA) axis

Signalling pathways are sequences of events that manage information flow within an organism in response to both external and internal stimuli. The hypothalamic–pituitary–adrenal (HPA) axis is the main stress-responding neuroendocrine subsystem. It is characterized by a vast array of signalling pathways, networks and feedback loops occurring at various temporal and spatial scales. Comprehending the complexities of signalling mechanisms, as well as the involvement of signalling actors, is vital for elucidating their implications in stress-related disorders and overall health. Herein, we elaborate on the regulatory signalling mechanisms of the human HPA axis, determined by integrating published experimental findings with insights from reaction network modelling, deterministic mass-action chemical kinetics and stoichiometric network analysis (SNA). A simplification of the complex interplay between signalling pathways governed by the hypothalamic corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) was of particular interest. Our findings highlight the importance of multiple parallel signalling pathways in maintaining homeostasis and generating optimal adaptive responses to stress. Their potential to support an organism’s self-protective capacity is also indicated. The proposed interdisciplinary approach, which provides distinctive insights, can be useful in designing and interpreting the corresponding real experiments.