The orphan G-protein coupled receptor GPR179 is a new player in night vision

• Applicant: Professor Dr. Ralf Enz
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2016 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 317150427

Our visual perception is remarkable stable, despite the high variability of detected light intensities by the retina, ranging form daylight (photopic) to night (scotopic) vision. This stability is mainly ensured by distinct signal pathways for scotopic and photopic vision, and by the expression of specific proteins therein. Here, we will elucidate proteins and molecular mechanisms that contribute to scotopic vision of the mammalian retina and that are altered in congenital stationary night blindness (CSNB). Scotopic vision starts with rod photoreceptors that transmitt their signals onto the highly specialized G-protein coupled metabotropic glutamate receptor type 6 (mGluR6) expressed in the dendritic tips of ON-bipolar cells. Upon activation, mGluR6 closes the non-selective cation channel TRPM1 via G-protein signalling involving Gao and RGS7. Surprisingly, despite the above described knowledge, identity, function and regulation of proteins involved in scotopic are still enigmatic. This has been demonstrated recently with the identification of a new player for this pathway: The orphan G-protein coupled receptor GPR179. GPR179 interacts and perfectly co-localizes with mGluR6, TRPM1 and RGS7. Indeed, mutations in all these proteins are associated with CSNB. Interestingly, while mGluR6 contains the shortest C-terminus of all mGluRs (32 amino acids = 3.6% of the entire receptor), the GPR179 C-terminus is extremely long (1738 amino acids = 73%), potentially offering a huge variety of binding sites for regulatory proteins. Preliminary analysis showed that the long GPR179 C-terminus does not contain conserved domains or stable room structures. Rather, this C-terminus is unstructured and contains over 80 short linear sequence motifs, pointing towards a variety of interactions with proteins that regulate GPR179. Based on the described data we hypothesize that GPR179 is the central component of a synaptically localized signal complex that organizes proteins in scotopic vision, both in space and time. While localization and physiological functions of GPR179 were elucidated in recent years, data characterizing the interaction between GPR179, mGluR6 and TRPM1 are largely missing. Also, the identity of additional GPR179 binding proteins that regulate this orphan receptor are unknown. Here, we will analyse molecular mechanisms of the reported binding between GPR179, mGluR6, TRPM1 and RGS7, thereby providing molecular tools and mechanistic knowledge for successive functional studies. In parallel, we will identify and characterize new GPR179 interactors potentially involved in scotopic vision. Finally, we will investigate functional consequences of the analysed protein interactions. Our studies will elucidate composition and functions of GPR179 associated signal complexes, thereby describe new molecular mechanisms relevant for CSNB.

• DFG Programme: Research Grants