Deletion of PrBP/δ impedes transport of GRK1 and PDE6 catalytic subunits to photoreceptor outer segments

Abstract

The mouse Pde6d gene encodes a ubiquitous prenyl binding protein, termed PrBP/␦, of largely unknown physiological function. PrBP/␦ was originally identified as a putative rod cGMP phosphodiesterase (PDE6) subunit in the retina, where it is relatively abundant. To investigate the consequences of Pde6d deletion in retina, we generated a Pde6d ؊/؊ mouse by targeted recombination. Although manifesting reduced body weight, the Pde6d ؊/؊ mouse was viable and fertile and its retina developed normally. Immunocytochemistry showed that farnesylated rhodopsin kinase (GRK1) and prenylated rod PDE6 catalytic subunits partially mislocalized in Pde6d ؊/؊ rods, whereas rhodopsin was unaffected. In Pde6d ؊/؊ rod single-cell recordings, sensitivity to single photons was increased and saturating flash responses were prolonged. Pde6d ؊/؊ scotopic paired-flash electroretinograms indicated a delay in recovery of the dark state, likely due to reduced levels of GRK1 in rod outer segments. In Pde6d ؊/؊ cone outer segments, GRK1 and cone PDE6␣ were present at very low levels and the photopic b-wave amplitudes were reduced by 70%. Thus the absence of PrBP/␦ in retina impairs transport of prenylated proteins, particularly GRK1 and cone PDE, to rod and cone outer segments, resulting in altered photoreceptor physiology and a phenotype of a slowly progressing rod/cone dystrophy.prenyl binding protein ͉ rod/cone dystrophy ͉ vesicular transport ͉ isoprenylation ͉ membrane association

Structural basis of recognition of farnesylated and methylated KRAS4b by PDEδ

“…Previous studies have shown that KRAS KO in mice is lethal (41,42) but that PDEδ KO is not (43). This difference may be because PDEδ helps in the localization of KRAS4b, not of KRAS4a, and therefore, only affects one isoform of KRAS.…”

The interplay between RPGR, PDEδ and Arl2/3 regulate the ciliary targeting of farnesylated cargo

“…We show that PDEd is bound to one of the highest conserved surface patches where we cannot locate any of the patient mutations. This might indicate that the loss of this interaction is not tolerated [22].…”

GLOBIN-5-Dependent O2Responses Are Regulated by PDL-1/PrBP That Targets Prenylated Soluble Guanylate Cyclases to Dendritic Endings

“…The neuronal functions of mammalian PDE6␦ have been previously studied in rods and cones, where it regulates transport of phosphodiesterase PDE6, rhodopsin kinase, and G t␣ -all prenylated proteins-to the outer segment of these ciliated neurons (Li et al, 1998;Norton et al, 2005;Zhang et al, 2007;Luo et al, 2008). Like cone and rod photoreceptors, BAG has a ciliated dendritic ending, but URX is a nonciliated neuron (Ward et al, 1975).…”

“…Biochemical studies showed that it is a prenyl binding protein (PrBP) that can extract prenylated proteins such as small lipidated GTPases (e.g., Ras) from membranes, sequestering them in the cytoplasm, and facilitating their traffic to different membrane compartments . Mice lacking PDE6␦ are small but viable; they exhibit progressive cone-rod dystrophy and defective localization of prenylated rhodopsin kinase (GRK1) and PDE6 catalytic subunits to rod outer segments (Zhang et al, 2007).…”