CGMP AND PHOTORECEPTOR FUNCTION

环磷酸鸟苷（cGMP）是视觉信号转导的主要细胞内信使。 视网膜视杆和视锥光感受器中的转导。虽然酶 cGMP途径的组分已经被鉴定和表征， 负责确定胞质cGMP的调节机制 在光感受器刺激期间的浓度还没有很好地理解。 棒外节的一个不寻常的特征是存在高的 浓度的cGMP结合蛋白，其螯合大部分的 细胞内cGMP和降低细胞溶质水平，这第二 使者这些cGMP结合位点的功能意义是 目前还不了解。 待检验的总体假设是cGMP结合蛋白控制 通过变构调节视杆光感受器中的环鸟苷酸浓度 cGMP的代谢除了作为细胞质缓冲液， 降低胞液中游离cGMP浓度。 拟议研究的具体目标是： (1)为了定位和鉴定高亲和力的功能作用， 存在于视杆细胞中的中等亲和力cGMP结合位点 外节; (2)为了确定调节cGMP结合的机制， 它们共同控制cGMP的游离胞质浓度 在视杆细胞的视觉传导过程中。 已知cGMP代谢的遗传缺陷会导致视网膜病变。 退化和失明这项研究将提供深入了解 控制cGMP代谢和结合的正常机制 光感受器，以便开发新的策略来干预 某些类型的视网膜光感受器变性疾病。

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.