Glucororticoid Receptor Alternative Splicing: Key Players and Role in TM and Glaucoma

Elevated intraocular pressure (IOP) is the primary risk factor in glaucoma, a leading cause of irreversible blindness. Various morphological and biochemical changes in the trabecular meshwork (TM) appear to be responsible for blocking aqueous humor outflow, thereby elevating IOP. Glucocorticoids (GCs) are known to induce ocular hypertension and other biochemical changes associated with glaucoma. Interestingly, there are differences in steroid responsiveness among the population, with 40% people known as responders who significantly elevate IOP upon GC treatment and others being classified as nonresponders. The steroid-responders are at higher risk of developing primary open angle glaucoma (POAG) as compared to the steroid nonresponders. At the same time, almost all POAG patients are moderate to high steroid responders. GC responsiveness is regulated by the relative ratios of the GC activated transcription factor GC receptor alpha (GRα) and the alternatively spliced dominant negative regulator isoform of this receptor (GRβ). Glaucomatous TM cell strains have a higher GRα/GRβ ratio compared to normal TM cells making them more sensitive to GCs. Regulation of the GRα/GRβ splicing is not very well documented. The role of splicing factors that regulate spliceosome assembly seems to be one of the key factors regulating the process of alternative splicing. We have shown that the relative levels of the different serine-arginine (SR) proteins (SRps) in the TM regulate the differential expression of the two alternatively spliced isoforms of GR, GRα and GRβ and that expression of these SR proteins regulates GC responsiveness in TM cells. In addition, we evaluated a special class of compounds (thailanstatins or TSTs) and found them to modulate this splicing process to enhance GRβ levels in TM cells. These splicing modulators increased GRβ/GRα in TM, decreased GC response and provide potential glaucoma therapeutic agents.