Discovery of a functional glucocorticoid receptor beta-isoform in zebrafish

In humans, two glucocorticoid receptor (GR) splice variants exist: GRα and GRβ, which are identical between amino acids 1–727 and then diverge. Whereas GRα (the canonical GR) acts as a ligand-activated transcription factor, GRβ does not bind traditional glucocorticoid agonists, lacks GRα’s transactivational activity, and acts as a dominant-negative inhibitor of GRα. It has been suggested that this receptor isoform is involved in the induction of glucocorticoid resistance in asthma patients. Unfortunately, a GR β-isoform has been detected in only humans, and therefore, an animal model for studies on this isoform is lacking. In the present study, we demonstrate that in zebrafish a GR isoform exists that diverges from the canonical zebrafish GR at the same position as human GRβ from human GRα. The zebrafish GR β-isoform acts as a dominant-negative inhibitor in reporter assays, and the extent of inhibition and the effective GRα/GRβ ratio is similar to studies performed with the human GR isoforms. In addition,...