Corticosteroid receptor dynamics : analysis by advanced fluorescence microscopy

In this thesis I aimed to explore further finesses in the cellular dynamics of the two corticosteroid receptors, the MR and the GR, in both their membrane-associated and their nuclear subpopulations. Amongst others I quantified the dynamics of the receptors at the membrane (only MR) and at the chromatinKNAWUBL - phd migration 201

Rapid non-genomic effects of corticosteroids and their role in the central stress response

In response to a stressful encounter, the brain activates a comprehensive stress system that engages the organism in an adaptive response to the threatening situation. This stress system acts on multiple peripheral tissues and feeds back to the brain; one of its key players is the family of corticosteroid hormones. Corticosteroids affect brain functioning through both delayed, genomic and rapid, non-genomic mechanisms. The latter mode of action has long been known, but it is only in recent years that the physiological basis in the brain is beginning to be unravelled. We now know that corticosteroids exert rapid, non-genomic effects on the excitability and activation of neurons in (amongst others) the hypothalamus, hippocampus, amygdala and prefrontal cortex. In addition, corticosteroids affect cognition, adaptive behaviour and neuroendocrine output within minutes. Knowledge on the identity of the receptors and secondary pathways mediating the non-genomic effects of corticosteroids on a cellular level is accumulating. Interestingly, in many cases, an essential role for the 'classical' mineralocorticoid and glucocorticoid receptors in a novel membrane-associated mechanism is found. Here, we systematically review the recent literature on non-genomic actions of corticosteroids on neuronal activity and functioning in selected limbic brain targets. Further, we discuss the relevance of these permissive effects for cognition and neuroendocrine control, and the integration of this novel mode of action into the complex balanced pattern of stress effects in the brain. Journal of Endocrinology (2011) 209, 153-167Diabetes mellitus: pathophysiological changes and therap

Mineralocorticoid and glucocorticoid receptors at the neuronal membrane, regulators of nongenomic corticosteroid signalling

The balance between corticosteroid actions induced via activation of the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR) determines the brain's response to stress. While both receptors are best known for their delayed genomic role, it has become increasingly evident that they can also associate with the plasma membrane and act as mediators of rapid, nongenomic signalling. Nongenomic corticosteroid actions in the brain are required for the coordination of a rapid adaptive response to stress; membrane-associated MRs and GRs play a major role herein. However, many questions regarding the underlying mechanism are still unresolved. How do MR and GR translocate to the membrane and what are their downstream signalling partners? In this review we discuss these issues based on insights obtained from related receptors, most notably the estrogen receptor alpha. (C) 2011 Elsevier Ireland Ltd. All rights reserved.Diabetes mellitus: pathophysiological changes and therap

Staff Council Minutes - June 20, 2017

Diabetes mellitus: pathophysiological changes and therap

Tyrosine hydroxylase in the brain and its regulation by glucocorticoids

Early life stress events can produce long-lasting changes in neurochemistry and behaviors related to monoamine systems, with increased risks of cardiovascular, metabolic, neuroendocrine, psychiatric disorders, generalized anxiety and depression in adulthood. Tyrosine hydroxylase (TH), the key enzyme for catecholamine synthesis, also plays an important role in the activity of the noradrenergic system and may be a target for glucocorticoids during the perinatal programming of physiological functions and behavior. Administration of hydrocortisone or dexamethasone to female rats on day 20 of pregnancy and to 3-day-old neonatal pups significantly increased TH mRNA levels (real-time PCR) and enzyme activity as well as protein levels determined by ICH in the locus coeruleus. Moreover, our treatment led to increase in TH mRNA levels in 25- and 70-day-old animals, as well as an increase in enzyme activity in the brainstem and cerebral cortex of adult rats. The long-term changes in TH expression are limited by the perinatal period of development. Administration of hormones on day 8 of life was not accompanied by changes in TH mRNA levels or enzyme activity. Glucocorticoids use several mechanisms to bring about transactivation or transrepression of genes. The main mechanism includes direct binding of the hormone-activated GRs to glucocorticoid responsive elements (GREs) in the promoter region of genes. However, despite optimistic claims made the classical GRE was not found in the TH gene promoter. Protein – protein interactions between hormone-activated GR and other transcription factors, for example, AP-1, provide an additional mechanism for the effects of glucocorticoids on gene expression. An important feature of this mechanism is its dependence on the composition of proteins formed by AP-1. Hormone-activated GRs are able to enhance gene expression when AP-1 consists of the Jun / Jun homodimer, but do not do that when AP-1 appears as the Jun / Fos heterodimer. Furthermore, as has been shown recently, the GRE / AP-1 composite site is the major site of interaction of glucocorticoids with  the TH gene in the pheochromocytoma cell line. Ontogenetic variation in the expression of Fos and Jun family proteins, which affects their ratio, can be one of the reasons for the TH gene regulation by glucocorticoids at near-term fetuses and neonates. However, to date this hypothesis has been supported only by in vitro data, and the existence of this mechanism in in vivo conditions needs to be explored in further studies