Isolation of Congenital Stationary Night Blindness Genes

描述(申请人提供)：当光在感光器中被转换成电信号时，视觉开始。光的增加减少了神经递质谷氨酸从视锥和视杆感光终末的释放，而光的减少则增加了它的释放。突触谷氨酸浓度的这些变化是由两类双极细胞检测到的，然后它们通过视网膜电路将信号垂直传输到神经节细胞。神经递质的变化也被水平细胞检测到，水平细胞以反馈和前馈抑制的形式提供横向传递。有两类双极细胞，超极化(HBCS)和去极化(DBCS)。HbC利用离子型谷氨酸受体并对闪光做出反应而超极化。DBCS利用一种代谢性谷氨酸受体mGluR6，它向TRPM1发出信号，对闪光做出反应，去极化。DBCS的传输缺陷导致完全性先天性静止性夜盲(CCSNB)。GRM6、NYX、TRPM1和GPR179突变导致cCSNB。MGluR6向TRPM1发出信号的机制在很大程度上还不清楚。该项目的长期目标是研究最近发现的两个视网膜成分GPR179和Cav1.1与其他DBC信号转导成分之间的分子相互作用。其具体目的是：1)确定GPR179在DBC信号复合体组装/功能中的作用；2)确定Cav1.1在DBC信号复合体组装和功能中的作用；3)确定DBC信号复合体组件的功能和运输相互依赖。在这个项目完成时，我们将表征新发现的蛋白质(GPR179和Cav1.1)的功能，这些蛋白质对DBCS中的信号传递至关重要。此外，我们还将确定先天性静止性夜盲的新候选基因。

DESCRIPTION (provided by applicant): Vision begins when light is converted to an electrical signal in the photoreceptors. Increases in light decrease release of the neurotransmitter, glutamate, from cone and rod photoreceptor terminals, and decreases in light increase its release. These changes in synaptic glutamate concentration are detected by two classes of bipolar cells that then transmit the signal vertically through the retinal circuit to the ganglion cells. The neurotransmitter changes also are detected by horizontal cells that provide lateral transmission in the form of feedback and feedforward inhibition. There are two classes of bipolar cells, hyperpolarizing (HBCs) and depolarizing (DBCs). HBCs utilize ionotropic glutamate receptors and hyperpolarize in response to a light flash. DBCs utilize a metabotropic glutamate receptor, mGluR6, that signals to TRPM1, depolarizing in response to a light flash. Defects in transmission in DBCs results in complete congenital stationary night blindness (cCSNB). Mutations in GRM6, NYX, TRPM1 and GPR179 cause cCSNB. The mechanism by which mGluR6 signals TRPM1 is largely unknown. The long term goal of this project is study the molecular interactions between two recently discovered retinal components, GPR179 and Cav1.1, and the other DBC signal transduction components. The specific aims are: 1) Determine the role of GPR179 in DBC signalplex assembly/function, 2) determine the role of Cav1.1 in DBC signalplex assembly and function, and 3) Determine functional and trafficking interdependence of DBC signalplex components. At the completion of this project, we will have characterized the function of newly discovered proteins (GPR179 and Cav1.1) critical to signal transmission in DBCs. Further, we will have identified new candidate genes for congenital stationary night blindness.