Nuclear translocation of the unliganded glucocorticoid receptor is influenced by membrane fluidity, but not A2AR agonism.

Epidemiological evidence suggests that chronic consumption of caffeine, a non-selective antagonist of adenosine A2AR receptors (A2AR), can be neuroprotective in a number of age-related neurodegenerative disorders including Alzheimer's disease. A growing body of work shows that this neuroprotection may act via a synergistic interaction with the glucocorticoid receptor (GR) and its associated genetic response elements. Therefore, we hypothesized that A2AR signaling may directly stimulate glucocorticoid receptor translocation via downstream signaling elements within the cell. Surprisingly, we found no effect of A2AR agonism on GR translocation in the absence of steroid. As expected, membrane-bound dexamethasone was capable of stimulating full GR translocation, albeit at a slower rate. This non-liganded translocation was unaffected by A2AR ligands, providing strong evidence that GR translocation occurs independently of activation of A2ARs. To identify other potential mechanisms of translocation, membrane fluidity was increased significantly by benzyl alcohol, which also induced full nuclear translocation of the GR, but unlike the membrane-bound dexamethasone, benzyl alcohol did result in transcriptional upregulation of GR-dependent genes. Taken together, our data shows that the unliganded GR is sensitive to changes in membrane state and can be transcriptionally active.