Glucocorticoids
202308261722
Molecules
Receptors
Glucocorticoid receptors belong to the nuclear receptor superfamily of transcription factors. They are activated by glucocorticoids released from the Adrenal Cortex during HPA axis activation.
Mineralocorticoid receptor
- High affinity for glucocorticoids
- Heavily localized in limbic system & Hippocampus
- Tonic influences of GCs predominantly via hippocampal MR
- Associated with memory retrieval and encoding. Blocking MRs in rats changes their swimming pattern in the Morris Water Maze task, indicative of lack of retrieval of correct information.
Glucocorticoid receptor
- Low affinity for glucocorticoids
- Distributed widely throughout primitive brain, including Hippocampus, amygdala, PFC.
- Mediate feedback actions of GCs at Pituitary Gland 1, hypothalamus, Hippocampus, and amygdala.
- Inhibitive activity → negative feedback on the HPA axis.
- Sensitivity is regulated by FKBP5, which encodes the FK506 binding protein 51. FK5BP51 expression is induced by GR activation, and when the protein binds to GR it reduces the receptor’s affinity for GC.
- Mediates the damaging effects of chronic stress.
- Associated with memory consolidation
Signaling
- Ligand occupied GRs mediate transcription of thousands of genes by direct binding to DNA response elements and/or by physical association with other transcription factors.
- Cortisol can cross cell membranes due to its lipophilic nature and bind to cytosolic intracellular receptors.
- GR signaling occurs via two mechanisms:
- Direct interaction with glucocorticoid response elements (GRE) in DNA promoter region
- Interaction with other transcription factors including c-jun, AP1, NF-B, TFIID complex, STAT5, CREB
Modulation of BDNF expression & signaling
Glucocorticoids are essential in activation of the PLC-y pathway in BDNF signaling. Complex of GR with TrkB, BDNF’s receptor, is essential. Disruption of glucocorticoid signaling due to chronic stress desensitizes GRs and reduces ability to complex with TrkB, impairing BDNF signaling through the PLC-y pathway.