Role of the alternatively spliced glucocorticoid receptor isoform GRβ in steroid responsiveness and glaucoma

Abstract

Glucocorticoid (GC)-induced ocular hypertension (OHT) is a serious side effect of GC therapy in susceptible individuals. This OHT is due to increased aqueous humor (AH) outflow resistance in the trabecular meshwork (TM) caused by GC-mediated changes in TM structure and function. GCs may also play a role in the development of primary open-angle glaucoma (POAG). Elevated cortisol levels in the AH or enhanced GC sensitivity may be one of the reasons for elevated intraocular pressure in POAG patients. The GC OHT responder population is at greater risk of developing POAG compared with non-responders. We recently have gained insight into the molecular mechanisms responsible for this differential GC responsiveness, which is attributed to differences in GC receptor isoform expression in the TM. This article summarizes current knowledge on alternative GC receptor splicing to generate GC receptor alpha (GRα) and GRβ and their roles in the regulation of GC responsiveness in normal and glaucoma TM.

FIG. 1.

Nuclear import and export of glucocorticoid receptor alpha (GRα) and GRβ and proteosomal degradation regulate glucocorticoid (GC) activities. Both GRα and GRβ proteins reside within the cytoplasm. Upon binding glucocorticoids (GC), GRα becomes activated (GRα*) and is translocated into the nucleus through the nuclear pore complex. GRα* then dimerizes and binds to glucocorticoid response elements (GRE) on GC-regulated genes to increase or decrease gene transcription. GRβ is translocated into the nucleus in a ligand-independent manner where it then acts as a dominant negative regulator by blocking GRα* activity. The levels of both GRα and GRβ can also be regulated by degradation of these proteins in the proteasome complex.

FIG. 2.

Alternative splicing of the human GR. The GR gene (NR3C1) contains terminal exons 9α and 9β that are alternatively spliced from the primary hnRNA transcript to generate GRα and/or GRβ mRNAs. SRps 20, 30, and 40 in the spliceosome complex are involved in this differential splicing. Exogeneous compounds [bombesin or thailanstatins (TSTs)] also regulate this alternative splicing. The GRα and GRβ mRNAs are translated to form the ligand (GC) binding GRα isoform and the dominant negative regulator isoform GRβ.