About this Research Topic
By stimulating adrenal corticosteroid synthesis, the adrenocorticotropic hormone (ACTH) plays a pivotal role in homeostasis and stress response. In this Research Topic, we will discuss the various mechanisms involved in ACTH action, from ACTH binding to its receptor to steroid secretion, as well as the pathological consequences of the disruption of specific components of the pathways. A particular attention will be given to how various kinases, phosphatases and cytoskeleton-associated proteins interact to ensure homeostasis and/or meet physiological demands.
The Research Topic will include:
- Growth-promoting activities of ACTH;
- Acute and chronic regulation of steroid secretion by ACTH, including effect of ACTH on circadian rythms of secretion.
- Properties of ACTH binding to its receptor to signaling pathways, including the importance of melanocortin-2 receptor accessory protein (MRAP) in MC2R expression and function.
- Intracellular cascades of signaling: Although cAMP is the main second messenger involved in ACTH action, several types of intracellular kinases, phosphatases and phosphodiesterases, are also involved.
- Effects of ACTH on electrical properties of adrenocortical cells: The importance of ionic activity in ACTH action began to emerge as a result of the selective disruption of ion channels genes in transgenic mice. In some instances, these knockout mouse models mimic human disease.
- Involvement of the cytoskeleton and extracellular matrix in ACTH effects: Rapid redistribution of microfilaments and microtubules at the membrane level upon ACTH stimulation activates several membrane-associated cytoskeletal proteins, which in turn regulate several intracellular cascades of events, leading to fine tuning of the mechanisms regulating steroid secretion. Others proteins affecting cell morphology and function include ephrins and their receptors, thrombospondins and gap junctions, which facilitate direct intercellular exchange between adjacent cells, thus facilitating propagation of signaling between neighboring cells.
- Interactive regulation of adrenal steroid secretion: Although ACTH and Ang II are the main regulators of adrenal function, all adrenal steroids can also be regulated by a complex interaction between several systemic and paracrine factors. ACTH interacts with several of these factors.
- Role of the HPA axis in the development of metabolic disorders: In particular, chronic stress and sleep disturbance are both associated with hyperactivity of the adrenal gland, resulting in increased glucocorticoid secretion inducing food intake and weight gain which in turn leads to insulin and leptin resistance.
Many of the aspects addressed in this Research Topic still represent a challenge for future studies, their outcome aimed at providing evidence that the adrenal cortex, through the steroid hormones it secretes, occupies a central position in many metabolic functions where homeostasis is disrupted. Furthermore, due to the importance of fetal and neonatal imprinting, there is increasing evidence that several metabolic dysfunctions found in the adult result from fetal and neonatal programming. An in-depth investigation of the mechanisms underlying these pathways would be invaluable in developing new therapeutic tools and strategies.
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