CGMP AND PHOTORECEPTOR FUNCTION

环状GMP(CGMP)是视觉的主要细胞内信使 视网膜杆和视锥感光细胞中的转导。而酶制剂 CGMP途径的组成成分已经被鉴定和表征， 决定胞质cGMP的调控机制 光感受器刺激时的浓度还不是很清楚。 杆状外节的一个不同寻常的特征是存在高 CGMP结合蛋白的浓度，它隔离了大部分 细胞内cGMP和降低这第二个细胞胞浆水平 信使。这些cGMP结合位点的功能意义是 目前还不清楚。 有待检验的总体假设是cGMP结合蛋白控制 变构调控对杆状感光细胞内cGMP浓度的影响 CGMP的代谢除了作为细胞质缓冲区外，还可以 降低胞浆中游离cGMP浓度。 拟议研究的具体目标是： (1)定位和确定高亲和力和 杆状细胞中cGMP结合位点的中等亲和力类 外部节段； (2)界定调控cGMP结合的机制和 共同控制cGMP胞浆游离浓度的代谢 在视杆感光细胞的视觉传导过程中。 已知cGMP代谢的遗传性缺陷会导致视网膜 退化和失明。这项研究将为我们深入了解 调控cGMP在杆状体内代谢和结合的正常机制 光感受器，因此可以开发新的策略来干预 某些类型的视网膜光感受器退行性疾病。

Cyclic GMP (cGMP) is the primary intracellular messenger for visual transduction in retinal rod and cone photoreceptors. While the enzymatic components of the cGMP pathway have been identified and characterized, the regulatory mechanisms responsible for determining the cytosolic cGMP concentration during photoreceptor stimulation are not well understood. One unusual feature of rod outer segments is the presence of high concentrations of cGMP binding proteins which sequester most of the intracellular cGMP and lower the cytosolic levels of this second messenger. The functional significance of these cGMP binding sites is currently not understood. The overall hypothesis to be tested is that cGMP binding proteins control the cGMP concentration in rod photoreceptors by allosterically regulating the metabolism of cGMP in addition to acting as a cytoplasmic buffer to reduce the free cGMP concentration in the cytosol. The specific aims of the proposed research are: (1) To localize and identify the functional roles for high affinity and moderate affinity classes of cGMP binding sites which are present in rod outer segments; (2) To define the mechanisms, for the regulation of cGMP binding and metabolism that together control the free cytosolic concentration of cGMP during visual transduction in rod photoreceptor cells. Inherited defects in cGMP metabolism are known to result retinal degeneration and blindness. This study will provide insight into the normal mechanisms controlling cGMP metabolism and binding in rod photoreceptors so that new strategies may be developed to intervene with certain types of degenerative diseases of retinal photoreceptors.