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 A_2AR receptors (A_2AR), 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 A_2AR signaling may directly stimulate glucocorticoid receptor translocation via downstream signaling elements within the cell. Surprisingly, we found no effect of A_2AR 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 A_2AR ligands, providing strong evidence that GR translocation occurs independently of activation of A_2ARs. 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.