RGR, or retinal G-protein-coupled receptor, serves as a retinal photoisomerase in the visual system of vertebrates. It is involved in isomerizing all-trans-retinal to 11-cis-retinal, thereby maintaining the photosensitivity of visual rhodopsins and playing a crucial role in visual chromophore regeneration. It functions in both the retinal pigment epithelium (RPE) and Müller cells, contributing to the visual cycle [3,6].

In mouse models, cell-specific gene reactivation of RGR in either RPE or Müller cells revealed that both contribute to scotopic and photopic functions. RGR-mediated 11-cis-retinal formation is rapidly hydrolyzed, supporting rapid visual pigment regeneration [1]. In addition, in models of retina-choriocapillaris atrophy, abnormal RGR proteins, such as the exon-skipping splice variant RGR-d, led to choriocapillaris and RPE atrophy, suggesting a link to age-related macular degeneration (AMD) [2,5]. In glioma, low RGR expression was associated with worse overall survival, and its molecular function may be related to negatively regulating tumorigenesis through interaction with CDHR1 [4].

In summary, RGR is essential for visual chromophore regeneration and the visual cycle. Mouse models have been instrumental in uncovering its role in maintaining photoreceptor light responses and its association with ocular diseases like AMD. In non-ocular diseases such as glioma, RGR also appears to play a role in tumorigenesis, highlighting its broad-reaching biological importance in both normal and disease conditions.

References:

1. Tworak, Aleksander, Kolesnikov, Alexander V, Hong, John D, Kefalov, Vladimir J, Palczewski, Krzysztof. 2023. Rapid RGR-dependent visual pigment recycling is mediated by the RPE and specialized Müller glia. In Cell reports, 42, 112982. doi:10.1016/j.celrep.2023.112982. https://pubmed.ncbi.nlm.nih.gov/37585292/

2. Bao, Xuan, Zhang, Zhaoxia, Guo, Yanjiang, Zhao, Mingwei, Fong, Henry K W. 2021. Human RGR Gene and Associated Features of Age-Related Macular Degeneration in Models of Retina-Choriocapillaris Atrophy. In The American journal of pathology, 191, 1454-1473. doi:10.1016/j.ajpath.2021.05.003. https://pubmed.ncbi.nlm.nih.gov/34022179/

3. Morimoto, Naoya, Nagata, Takashi, Inoue, Keiichi. 2023. Reversible Photoreaction of a Retinal Photoisomerase, Retinal G-Protein-Coupled Receptor RGR. In Biochemistry, 62, 1429-1432. doi:10.1021/acs.biochem.3c00084. https://pubmed.ncbi.nlm.nih.gov/37057907/

4. Feng, Jianglong, Zhang, Wei, Zeng, Wen, Yang, Wenxiu, Lu, Hongguang. . A pan-cancer analysis of RGR opsin expression and its downregulation associated with poor prognosis in glioma. In Neoplasma, 70, 683-696. doi:10.4149/neo_2023_230617N317. https://pubmed.ncbi.nlm.nih.gov/38053380/

5. Ren, Chi, Cui, Haoran, Bao, Xuan, Fong, Henry K W, Zhao, Mingwei. . Proteopathy Linked to Exon-Skipping Isoform of RGR-Opsin Contributes to the Pathogenesis of Age-Related Macular Degeneration. In Investigative ophthalmology & visual science, 64, 41. doi:10.1167/iovs.64.13.41. https://pubmed.ncbi.nlm.nih.gov/37883094/

6. Ruddin, Grace, McCann, Tess, Fehilly, John D, Kearney, Jodie, Kennedy, Breandán N. 2025. The dark and bright sides of retinal G protein-coupled receptor (RGR) in vision and disease. In Progress in retinal and eye research, 106, 101339. doi:10.1016/j.preteyeres.2025.101339. https://pubmed.ncbi.nlm.nih.gov/39961453/