Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
Northeast Ohio VA Healthcare System, Cleveland, OH 44106, USA.
Hum Mol Genet. 2022 Feb 21;31(4):548-560. doi: 10.1093/hmg/ddab267.
The retinal pigment epithelium of the vertebrate eyes acquires vitamin A from circulating retinol binding protein for chromophore biosynthesis. The chromophore covalently links with an opsin protein in the adjacent photoreceptors of the retina to form the bipartite visual pigment complexes. We here analyzed visual pigment biosynthesis in mice deficient for the retinol-binding protein receptor STRA6. We observed that chromophore content was decreased throughout the life cycle of these animals, indicating that lipoprotein-dependent delivery pathways for the vitamin cannot substitute for STRA6. Changes in the expression of photoreceptor marker genes, including a downregulation of the genes encoding rod and cone opsins, paralleled the decrease in ocular retinoid concentration in STRA6-deficient mice. Despite this adaptation, cone photoreceptors displayed absent or mislocalized opsins at all ages examined. Rod photoreceptors entrapped the available chromophore but exhibited significant amounts of chromophore-free opsins in the dark-adapted stage. Treatment of mice with pharmacological doses of vitamin A ameliorated the rod phenotype but did not restore visual pigment synthesis in cone photoreceptors of STRA6-deficient mice. The imbalance between chromophore and opsin concentrations of rod and cone photoreceptors was associated with an unfavorable retinal physiology, including diminished electrical responses of photoreceptors to light, and retinal degeneration during aging. Together, our study demonstrates that STRA6 is critical to adjust the stoichiometry of chromophore and opsins in rod and cone photoreceptors and to prevent pathologies associated with ocular vitamin A deprivation.
脊椎动物眼睛的视网膜色素上皮从循环视黄醇结合蛋白中获取维生素 A，用于发色团生物合成。发色团与相邻光感受器中的视蛋白共价结合，形成二聚体视觉色素复合物。我们在此分析了视黄醇结合蛋白受体 STRA6 缺失的小鼠中的视觉色素生物合成。我们观察到，这些动物的整个生命周期中，发色团含量都减少了，这表明脂蛋白依赖性维生素传递途径不能替代 STRA6。光感受器标记基因的表达变化，包括对编码杆状和锥状视蛋白的基因的下调，与 STRA6 缺陷小鼠眼内类视黄醇浓度的下降相平行。尽管有这种适应，在所有检查的年龄中，锥状光感受器都显示出缺失或定位错误的视蛋白。杆状光感受器捕获了可用的发色团，但在暗适应阶段表现出大量无发色团的视蛋白。用药物剂量的维生素 A 治疗小鼠可改善杆状细胞表型，但不能恢复 STRA6 缺陷小鼠的锥状光感受器中的视觉色素合成。杆状和锥状光感受器中发色团和视蛋白浓度的不平衡与不利的视网膜生理学有关，包括光感受器对光的电反应减弱，以及衰老过程中的视网膜变性。总之，我们的研究表明，STRA6 对于调节杆状和锥状光感受器中发色团和视蛋白的化学计量以及预防与眼部维生素 A 缺乏相关的病理学至关重要。
