REGULATION OF PHOTOTRANSDUCTION IN MAMMALIAN RETINA

哺乳动物视网膜光传导的调节

• 批准号: 6219730
• 负责人: KRZYSZTOF PALCZEWSKI
• 金额: $ 7.46万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6219730
• 关键词: bioimaging /biomedical imaging; enzymes; eye; human tissue; microscopy; nervous system; proteins; technology /technique; vision

Following light exposure, photoreceptors in the vertebrate neural retina re-establish a dark-adapted state. A critical step in this process is the intracellular stimulation of the enzyme guanylate cyclase (GC). GC-activating proteins (GCAP1, GCAP2 and GCAP3) modulate GC activation. GCAP activation of GC is regulated by the intracellular calcium ion concentration [Ca2+]i. In photoreceptors bleached by light, [Ca2+]i decreases, causing GCAP1 to stimulate GC. As [Ca2+]i increases during dark adaptation, GCAP1 is inactivated. Previous studies have localized GCAP1 to rod and cone outer segments, somata and synaptic terminals. Mutations in GCAP1 cause an autosomal dominant form of cone photoreceptor dystrophy in humans. We have found that this mutant form of GCAP1, (Y99C), exhibits altered sensitivity to [Ca2+]i, resulting in persistent stimulation of GC in dark conditions. Constitutive activation of GCAP1 may produce elevated levels of cGMP in dark-adapted cones, resulti ng i n the degeneration of these sensory neurons. On-going studies using primate retinal tissues are focused on understanding the enzymatic interactions between GCAPs and GC. FUNDING NIH grants EY09339, EY08061, and RR00166.

光照后，脊椎动物神经元中的光感受器 视网膜重新建立暗适应状态。 这其中的关键一步 过程是细胞内鸟苷酸酶的刺激 环化酶（GC）。 GC 激活蛋白（GCAP1、GCAP2 和 GCAP3） 调节 GC 激活。 GCAP GC 的激活受以下因素调节 细胞内钙离子浓度[Ca2+]i。 在感光器中 光漂白后，[Ca2+]i 减少，导致 GCAP1 刺激 GC。 随着[Ca2+]i 在暗适应期间增加，GCAP1 失活。 先前的研究已将 GCAP1 定位于杆和锥体的外节， 体细胞和突触末端。 GCAP1 突变导致常染色体 人类视锥光感受器营养不良的主要形式。 我们有 发现 GCAP1 (Y99C) 的这种突变形式表现出改变 对 [Ca2+]i 敏感，导致 GC 持续刺激 黑暗条件。 GCAP1 的组成型激活可能会产生 暗适应视锥细胞中 cGMP 水平升高，导致 这些感觉神经元的退化。 正在进行的使用灵长类动物的研究 视网膜组织的重点是了解酶促 GCAP 和 GC 之间的相互作用。 资助 NIH 授予 EY09339， EY08061 和 RR00166。