The dark and bright sides of retinal G protein-coupled receptor (RGR) in vision and disease

The visual chromophore 11-cis-retinal (11cRAL) is essential to vertebrate phototransduction and therefore, must be regenerated so vision can be sustained. 11cRAL regeneration mediated by the classical visual cycle is insufficient under photopic conditions. Expressed in the retinal pigment epithelium (RPE) and Müller glia, the retinal G protein-coupled receptor (RGR) can act as an alternative visual cycle photoisomerase, photogenerating 11cRAL in bright light conditions. While named a G protein-coupled receptor, RGR has no known coupled G protein. In the photoisomerase process, RGR bound all-trans-retinal (atRAL) is converted to 11cRAL. Here, we review how this core reaction integrates into RPE and Müller cell visual cycles. Significantly, mutations in human RGR are associated with inherited retinal degeneration and age-related macular degeneration, ocular diseases impairing vision. In this article, we comprehensively review 30 years of research into this membrane-bound protein, to comprehend RGR's i) biological role in vision, ii) association with ocular disease, iii) and surprising role in non-ocular function and disease. We discuss studies with opposing views on the proposed role of RGR as mediating a non-canonical visual cycle which photogenerates 11cRAL. We highlight knowledge gaps that current RGR research is addressing.