Glucocorticoid signaling and stress-related limbic susceptibility pathway: About receptors, transcription machinery and microRNA

Background. Stress is essential for health, but if coping with stress fails, the action of the stress hormones cortisol and corticosterone (CORT) becomes dysregulated, precipitating a condition favorable for increased susceptibility to psychopathology. We focus on the question how the action of CORT can change from protective to harmful. Approach. CORT targets the limbic brain, where it affects cognitive processes and emotional arousal. The magnitude and duration of the CORT feedback signal depends on bio-availability of the hormone, the activity of the CORT receptor machinery and the stress-induced drive. If CORT action becomes dysregulated, we postulate that this is linked to compromised receptor regulation in the limbic brain's susceptibility pathway. Results. CORT action on gene transcription is mediated by high affinity mineralocorticoid (MR) and 10 fold lower affinity glucocorticoid (GR) receptors that also can mediate fast non-genomic actions. MR and GR operate a feedback loop that involves access and binding to the receptors, activation and shuttling of the CORT receptor complexes, which require interaction with coregulators and transcription factors for transcriptional outcome. CORT modulates the expression of gene transcripts encoding specific chaperones, motor proteins and transcription factors as well as its own receptors. The emerging evidence of microRNAs operating translational control points to further fine-tuning in receptor signaling. Conclusion. Imbalance in MR:GR-mediated actions caused by receptor variants and epigenetic modulations have been proposed as risk factor in stress-related disease. We here provide key regulatory steps in the activation, transport and regulation of CORT receptors that may sensitize susceptibility pathways underlying psychopathology.