A new link between GABA receptors and two proteins in night vision: GPR179 and LRRTM4

• Applicant: Professor Dr. Ralf Enz
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 559303950

Light intensities detected by the retina are highly variable between day and night, nevertheless our visual perception remains remarkable stable. This stability is mainly ensured by distinct signal pathways for daylight and night vision, and by the expression of specific proteins therein. Here, we will analyze proteins for night vision (scotopic vision) that are malfunctioning in congenital stationary night blindness. Night vision starts with rod photoreceptors that transmit their signals onto the G-protein coupled metabotropic glutamate receptor type 6 (mGluR6) in the dendritic tips of rod connecting bipolar cells. Upon activation, mGluR6 closes the cation channel TRPM1, thereby regulating transmission of the light information towards ganglion cells and the optic nerve. Surprisingly, identity, function and regulation of proteins involved in this rod pathway are still largely enigmatic. This is also evident by the identification of new proteins of this signal pathway: GPR179 und LRRTM4. While GPR179 is expressed in bipolar cells contacting cones and rods, LRRTM4 was described exclusively in rod bipolar cells. GPR179 und LRRTM4 co-localize with mGluR6, TRPM1 and other proteins of the rod signal pathway and are associated with retinal disorders, including macular degeneration und congenital stationary night blindness. Recently, a disturbed localization of GABA receptors was described in rod bipolar cells of LRRTM4 ko animals, accompanied by a reduction of GABAergic currents. In preliminary studies, we demonstrated a direct interaction between intracellular domains of GABAc receptors, GPR179 and LRRTM4. Thus, interactions between these proteins could play a significant role in GABAergic signal transmission of the rod signal pathway and participate in night vision. Aim of this project is to analyze detected interactions between GABAc receptors, GPR179 and LRRTM4 in rod bipolar cells of the mammalian retina. Initially, we will describe molecular mechanisms of these protein interactions: which protein regions mediate the interactions, are these interactions regulated by post-translational modifications and which impact have human mutations. These studies will generate molecular tools and mechanistic knowledge for successive functional experiments analyzing the excitability of rod bipolar cells in the context of GABAc receptors, GPR179 and LRRTM4. Besides molecular biology and protein chemistry, we will use proximity ligation assays, high-resolution STED microscopy, electrophysiology und Ca2+ imaging. Our studies help to understand better the molecular mechanisms in the rod signal pathway. Characterization of protein interactions in this pathway can define new targets for a future treatment of eye diseases and is therefore beneficial for our society.

• DFG Programme: Research Grants