Unc119 gene deletion partially rescues the GRK1 transport defect of Pde6d (- /-) cones.

PrBP/δ, encoded by the Pde6d gene, is an isoprenyl-binding protein that regulates trafficking of isoprenylated proteins, such as PDE6 and GRK1, from photoreceptor inner segments to outer segments. Trafficking of PDE6 and GRK1 to photoreceptor outer segments is impeded in Pde6d knockout mice. In Pde6d (-/-) cones, PDE6 and GRK1 are nearly undetectable and the b-wave amplitudes of photopic ERGs in Pde6d (-/-) mice are reduced by over 50 %. We reported recently that UNC119, a homolog of PrBP/δ highly expressed in photoreceptors, functions as an acyl-binding protein and regulates transport of G-proteins in sensory neurons. Since both PrBP/δ and UNC119 regulate peripheral protein trafficking in photoreceptors, we generated Pde6d; Unc119 double knockout mice in order to study how PrBP/δ and UNC119 may interact. Surprisingly, knockout of Unc119 partially reversed the transport defect of GRK1 in cone photoreceptors caused by deletion of Pde6d, and the b-wave amplitudes of photopic ERGs in the double knockout mice were significantly higher than those in the Pde6d (-/-) mice. These results suggest that cone transport of isoprenylated and acylated proteins is interdependent.