The roles of Gbeta5 and R7 RGS protein in vision

描述（由申请人提供）：异源三聚体G蛋白在人类生物学中的作用最好由视杆细胞光转导中的视紫红质/转导素信号传导来表示。具有讽刺意味的是，其他G蛋白是如何在光感受器之外帮助哺乳动物视觉的，人们对此知之甚少。本申请将通过阐明第五Gb亚基（Gb 5）及其专性伙伴R7 RGS蛋白（RGS 6，RGS 7，RGS 9，RGS 11）在小鼠视网膜中的作用来填补这一知识空白。我们已经在Gb 5-/-小鼠中发现了许多视觉缺陷，包括：1）延迟的光转导恢复; 2）出生后发育期间异常的视网膜波和视网膜小突投射的不完全细化; 3）缺乏ERG b-波; 4）减少的星爆状无长突细胞（SAC）树突场;和5）视网膜外丛状层中的三联带状突触破坏。我们假设Gb 5通过稳定R7 RGS蛋白在体内专门与R7 RGS蛋白一起工作，并且在其不存在的情况下，Gao的信号传导状态异常延长，导致这些视觉缺陷。具有四个独立目标的多学科方法将严格检查上述Gb 5-/-小鼠视觉缺陷的病理机制。Aim-1将通过检查具有四个R7 RGS基因置换和完全缺失的突变小鼠的各种组织中的Gb 5水平来测试Gb 5和R7 RGS蛋白之间相互作用的排他性。目的-2将测试RGS 7和RGS 11的表达是否需要在一个细胞自主的方式去极化双极细胞（DBC）的正常发育和功能。Aim-3将研究正常SAC结构和功能是否需要RGS 6和RGS 7在视网膜发育过程中。Aim-4将测试延长的Gao信号传导是否阻碍各种视网膜细胞（包括DBC、SAC和某些视网膜神经节细胞（RGC））中的树突发育，以及它是否是在不存在Gb 5的情况下在这些视网膜神经元中观察到的树突缺陷的基础。通过完成这些目标，我们希望通过牢固地建立Gb 5，R7 RGS和Gao在视觉系统中的作用，显着推进异源三聚体G蛋白和视野。

DESCRIPTION (provided by applicant): The role of heterotrimeric G-proteins in human biology is best represented by rhodopsin/transducin signaling in rod phototransduction. Ironically, how other G-proteins subserve mammalian vision outside photoreceptors is poorly understood. This application will start to fill this knowledge gap by elucidating the roles of the fifth Gb subunit (Gb5) and its obligate partners R7 RGS proteins (RGS6, RGS7, RGS9, RGS11) in mouse retina. We have found a multitude of visual defects in Gb5-/- mice which include: 1) delayed phototransduction recovery; 2) abnormal retinal waves and incomplete refinement of retinogeniculate projections during postnatal development; 3) lack of ERG b-wave; 4) reduced starburst amacrine cell (SAC) dendritic field; and 5) disrupted triadic ribbon synapses in retinal outer plexiform layer. We hypothesize that Gb5 works exclusively with R7 RGS proteins in vivo by stabilizing them and that in its absence the signaling state of Gao is abnormally prolonged to cause these visual defects. A multidisciplinary approach with four independent aims will critically examine the pathologic mechanisms of aforementioned Gb5-/- mouse visual defects. Aim-1 will test the exclusivity of the interaction between Gb5 and R7 RGS proteins by examining the level of Gb5 in various tissues of mutant mice with permutated and total loss of the four R7 RGS genes. Aim- 2 will test whether RGS7 and RGS11 expression is required in a cell autonomous manner for normal development and function of depolarizing bipolar cell (DBC). Aim-3 will examine whether normal SAC structure and function requires RGS6 and RGS7 during retinal development. Aim-4 will test whether prolonged Gao signaling retards dendritic development in various retinal cells including DBCs, SACs, and certain retinal ganglion cells (RGCs) and whether it underlies the dendritic defects observed in these retinal neurons in the absence of Gb5. By completing these aims we expect to significantly advance the heterotrimeric G-protein and the vision fields by firmly establishing the roles of Gb5, R7 RGS, and Gao in the visual system.