Chapter 3.1 Corticosteroid receptors and HPA-axis regulation

Abstract

: The activity of the hypothalamic–pituitary–adrenal (HPA) axis has three modes of operation: (1) pulsatility with intervals of approximately 60 min; (2) circadian variation with peak activity prior to the onset of the active period; and (3) a profound activation in response to physical and psychological stressors. End products of the HPA axis are cortisol and corticosterone, which co-ordinate, in concert with the other components of the HPA axis, the body and brain responses to the stressor and thereby facilitate adaptive processes. The actions of the corticosteroids are mediated by receptors of which the mineralocorticoid (MR) and glucocorticoid (GR) receptors acting as gene transcription factors are best investigated. This chapter addresses the following aspects of corticosteroid action on HPA-axis activity: First, MR binds cortisol and corticosterone with a ten-fold higher affinity than GR. This differential affinity has led to the concept that via MR homeostasis and HPA activity is maintained, while GR-mediated signalling facilitates their recovery from stress and promotes adaptive processes in preparation for future events. Second, the MR- and GR-mediated effects target the core of the HPA axis as well as its afferents. This provides an enormous diversity to corticosteroid action. Third, corticosteroid feedback varies as a function of the phase in HPA pulsatility, the nature and intensity of the stressor and depends on genetic determinants expressed as receptor variants and polymorphisms. Fourth, during development HPA activity is low and stable due to enhanced corticosteroid feedback and adrenal hyporesponsiveness. Early life experience at that time can program HPA reactivity and corticosteroid feedback for life. Fifth, the molecular mechanism of corticosteroid action proceeds along two fundamentally different pathways. MR and GR bind to specific DNA motifs (glucocorticoid response elements – GREs) in regulatory regions like promoters and exert direct control over the transcription machinery for which recruitment of co-regulators is often indispensable. This mode of operation mostly leads to transactivation or occasionally to repression of transcription. The other mode involves interaction of the receptor with transcription factors (i.e. NFκB and AP-1) to prevent them from transcription regulation and is selective for GR. The outcome is mostly transrepression of gene transcription aimed to dampen stress-induced processes. The chapter is concluded with the thesis that imbalance in MR- and GR-mediated actions may lead to neuroendocrine dysregulation and behavioural impairments, which after passing a certain threshold enhances the vulnerability to stress-related disorders for which the individual is genetically pre-disposed.