The Human Glucocorticoid Receptor Beta: From Molecular Mechanisms to Clinical Implications

Glucocorticoids play a fundamental role in a plethora of cellular processes and physiologic functions through binding on a ubiquitously expressed receptor, the glucocorticoid receptor (GR), which functions as a ligand-activated transcription factor influencing the transcription rate of numerous genes in a positive or negative fashion. For many years, we believed that the pleiotropic actions of glucocorticoids were mediated by a single GR protein expressed by the NR3C1 gene. Nowadays, we know that the NR3C1 gene encodes 2 main receptor isoforms, the GRα and the GRβ, through alternative splicing of the last exons. Furthermore, the alternative initiation of GR mRNA translation generates 8 distinct GRα and possibly 8 different GRβ receptor isoforms. The tremendous progress of cellular, molecular, and structural biology in association with the data explosion provided by bioinformatics have enabled a deeper understanding of the role of GRβ in cellular homeostasis. In this review article, I will provide an update on the cellular properties and functions of hGRβ and summarize the current knowledge about the evolving role of the beta isoform of glucocorticoid receptor in endocrine physiology, pathophysiology, and beyond.