GPR158, an orphan member of G protein-coupled receptor Family C: glucocorticoid-stimulated expression and novel nuclear role

2013-02-05 21:38:24

PLoS One; 2013 Feb; 8(2):e57843

Nitin Patel, Tatsuo Itakura, Jose M. Gonzalez Jr, Stephen G. Schwartz, and M. Elizabeth Fini


The G-protein-coupled receptors (GPCRs) comprise a large superfamily of cell-surface proteins characterized by the presence of a seven transmembrane (7TM) domain. Activated by a broad range of ligands, GPCRs are implicated in many important physiological and disease processes, making them therapeutic targets for a large percentage of current pharmaceuticals. Sequencing of the human genome revealed about 800 previously unknown ‘orphan’ receptors of the GPCR superfamily. The current challenge is to functionally characterize and de-orphanize these receptors, by identification of their endogenous agonists. GPCRs have been classified into seven families based on phylogenetic analysis of the 7TM domain. Human GPCR Family C contains 22 receptor subtypes, including eight metabotropic glutamate receptors (mGlu), and two gamma-aminobutyric acid (GABA) type B receptors (GABBR1 and GABBR2), both with important functions in the central nervous system. Seven of the Family C receptors are orphans, with roles in health and disease largely unknown.

The GPCR Family C orphan GPR158 came to our attention through a small pharmacogenomic study we conducted on risk for glucocorticoid (GC)-induced ocular hypertension (OH). We found very little information on this gene. Phylogenetically, GPR158 is most closely related to the GABA receptors. Bioinformatics websites such as GeneCards and the Human Protein Atlas (HPA) revealed that GPR158 is expressed at highest levels in the brain, but also in a variety of other cell types. Recently it was shown that the closely related orphan GPR179 is required for depolarizing bipolar cell function in the retina, and is mutated in autosomal-recessive complete congenital stationary night blindness. Most recently, both GPR179 and GPR158 were shown to recruit regulator of G protein signaling (RGS) complexes and thus regulate activity of other GPCRs.

In the study reported here, we characterize GPR158 using cells derived from the trabecular meshwork (TBM) tissue of the eye's aqueous outflow pathways, the function of which is affected by GCs. We find an unusual nuclear localization for GPR158, demonstrate mechanisms for nuclear trafficking, and show that this has functional consequences. Like treatment with GC, overexpression of GPR158 enhances cell proliferation as well as the barrier function of a TBM cell monolayer. Regulated paracellular permeability of the TBM barrier controls aqueous outflow facility in vivo. Since GCs stimulate GPR158 expression, the results are consistent with a role for elevation of GPR158 expression in GC-induced OH, which can lead to primary open angle glaucoma (POAG).

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