REGULATION OF PHOTOTRANSDUCTION IN MAMMALIAN RETINA

光暴露后，脊椎动物神经中的光感受器 视网膜重新建立了一种暗适应状态。这方面的关键一步 过程是鸟苷酸酶在细胞内的刺激 环化酶(GC)。GC激活蛋白(GCAP1、GCAP2和GCAP3) 调节GC的激活。GC的GCap激活受 光感受器细胞内钙离子浓度[Ca~(2+)]i 被光漂白后，[Ca~(2+)]i下降，导致GCAP1刺激GC。 在暗适应过程中，随着[Ca~(2+)]i的升高，GCAP1失活。 以前的研究已经将GCAP1定位于杆状和锥状外节， 体细胞和突触终末。GCAP1基因突变导致常染色体 人类视锥体光感受器营养不良的主要形式。我们有 发现GCAP1的这种突变形式(Y99C)表现出改变 对[Ca~(2+)]i的敏感性，导致持续刺激肾上腺皮质激素 黑暗的环境。GCAP1的结构性激活可能会产生 暗适应锥体中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的研究 视网膜组织专注于了解酶 GCAP和GC之间的相互作用。资助NIH拨款EY09339， EY08061和RR00166。

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.