Cooperativity and complementarity: synergies in non-classical and classical glucocorticoid signaling.

Glucocorticoids (GCs) are an ubiquitous class of steroid hormones that exert a wide array of physiological effects. Traditionally, GC action has been considered to primarily involve transcriptional effects following the binding of hormone to the glucocorticoid receptor (GR) and subsequent activation or repression of target genes. However, a number of findings suggest that cellular responses following GC exposure may be mediated by transcription-independent, or “non-classical,” mechanisms. We have added to this growing body of work by recently uncovering a novel GC signaling pathway that operates through plasma membrane GRs to limit gap junction intercellular signaling and limit the proliferation of neural progenitor cells (NPCs). In this review, we highlight our current state of knowledge of non-classical GR signaling, in particular as it applies to neuronal function. Using NPCs as a cellular model, we speculate on the components of this non-classical pathway and the mechanisms whereby a number of cytoplasmic and nuclear signaling events may be integrated.