Figure 3

Schematic representation of corticosteroid-triggered multiple tentative rapidly influencing neuronal function. Corticosteroids are represented by red triangles. Nuclear GR (nGR) interact with caveolins [cf. [81]]; the interaction probably depends on posttranslational modifications of nGR to yield so-called membrane corticosteroid receptors (mCR). Alternatively, CS-initiated intracellular signaling cascades may result from corticosteroid binding to proteins embedded in the plasma membrane, e.g. G-protein-coupled receptors (GPCR) [75] which, upon activation, activate protein kinase A (PKA) and protein kinase C (PKC) in turn. Other evidence points to membrane-bound corticosteroid binding proteins that interact with members of the src family of kinases (SFK) to activate the mitogen-activated protein kinase (MAPK) pathway and/or modulate the activity of other membrane-associated proteins, e.g. NMDA receptors and other ion channels with potential steroid binding sites [76, 85, 86, 222]. Under basal conditions, nGR are tethered in the cytoplasm in the form of a protein complex that includes the chaperone heat shock protein 90 (hsp90) which itself may directly interact with Src kinases and the MAPK kinase, MEK [cf. [83]]. Additionally, direct interactions between the nGR and Ras which may be functionally relevant have been described [84]. Finally, MAPK-mediated phsophorylation of nGR may influence the transcriptional activity of nGR [32]. Thus, corticosteroid actions at the plasma membrane can converge and prime or potentiate hormonal actions on gene transcription.