Zhang H, Li S, Doan T, Rieke F, Detwiler P B, Frederick J M, Baehr W
John A. Moran Eye Center, University of Utah Health Science Center, Salt Lake City, UT 84132, USA.
Proc Natl Acad Sci U S A. 2007 May 22;104(21):8857-62. doi: 10.1073/pnas.0701681104. Epub 2007 May 11.
The mouse Pde6d gene encodes a ubiquitous prenyl binding protein, termed PrBP/delta, of largely unknown physiological function. PrBP/delta 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 PDE6alpha' were present at very low levels and the photopic b-wave amplitudes were reduced by 70%. Thus the absence of PrBP/delta 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.
小鼠Pde6d基因编码一种普遍存在的异戊二烯结合蛋白，称为PrBP/δ，其生理功能 largely unknown。PrBP/δ最初被鉴定为视网膜中一种假定的视杆细胞环鸟苷酸磷酸二酯酶（PDE6）亚基，在视网膜中相对丰富。为了研究视网膜中Pde6d缺失的后果，我们通过靶向重组产生了Pde6d(-/-)小鼠。尽管体重减轻，但Pde6d(-/-)小鼠存活且可育，其视网膜发育正常。免疫细胞化学显示，法尼基化的视紫红质激酶（GRK1）和异戊二烯化的视杆细胞PDE6催化亚基在Pde6d(-/-)视杆细胞中部分定位错误，而视紫红质未受影响。在Pde6d(-/-)视杆细胞单细胞记录中，对单个光子的敏感性增加，饱和闪光反应延长。Pde6d(-/-)暗视成对闪光视网膜电图表明暗状态恢复延迟，可能是由于视杆细胞外段GRK1水平降低所致。在Pde6d(-/-)视锥细胞外段，GRK1和视锥细胞PDE6α'水平极低，明视b波振幅降低了70%。因此，视网膜中PrBP/δ的缺失会损害异戊二烯化蛋白，特别是GRK1和视锥细胞PDE向视杆细胞和视锥细胞外段的转运，导致光感受器生理学改变和一种缓慢进展的视杆/视锥营养不良表型。
