Mechanism of All-trans-retinal Toxicity with Implications for Stargardt Disease and Age-related Macular Degeneration
Mechanism of All-trans-retinal Toxicity with Implications for Stargardt Disease and Age-related Macular Degeneration
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DOI：
10.1074/jbc.m111.315432
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发表时间：
2012-02-10
影响因子：
4.8
通讯作者：
Palczewski, Krzysztof
中科院分区：
文献类型：
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作者：
Chen, Yu;Okano, Kiichiro;Palczewski, Krzysztof
全反式-视网膜（atRAL），类维生素A循环的一个组成部分，清除受损，增加小鼠视网膜急性光诱导的感光细胞变性的易感性。Abca 4（-/-）Rdh 8（-/-）小鼠具有atRAL清除缺陷，用于检查一种或多种潜在的分子机制，因为暴露于强光会导致这些动物严重的光感受器变性。在这里，我们报告了明亮的光暴露的Abca 4（-/-）Rdh 8（-/-）小鼠增加atRAL水平的视网膜，诱导快速NADPH氧化酶介导的细胞内活性氧（ROS）的过度生产。此外，这种ROS的产生被抑制通过阻断磷脂酶C和肌醇1，4，5-三磷酸诱导的Ca 2+释放，表明激活发生在NADPH氧化酶介导的ROS产生的上游。由于多个上游G蛋白偶联受体可以激活磷脂酶C，我们随后测试了5-羟色胺2A（5-HT 2AR）和M-3-毒蕈碱（M3 R）受体拮抗剂的作用，发现它们都保护Abca 4（-/-）Rdh 8（-/-）小鼠视网膜免受光诱导的变性。因此，一系列信号传导事件似乎介导了atRAL在Abca 4（-/-）Rdh 8（-/-）小鼠光诱导的光感受器变性中的毒性。类似的机制可能在人类Stargardt病和年龄相关性黄斑变性中起作用。
Compromised clearance of all-trans-retinal (atRAL), a component of the retinoid cycle, increases the susceptibility of mouse retina to acute light-induced photoreceptor degeneration. Abca4(-/-)Rdh8(-/-) mice featuring defective atRAL clearance were used to examine the one or more underlying molecular mechanisms, because exposure to intense light causes severe photoreceptor degeneration in these animals. Here we report that bright light exposure of Abca4(-/-)Rdh8(-/-) mice increased atRAL levels in the retina that induced rapid NADPH oxidase-mediated overproduction of intracellular reactive oxygen species (ROS). Moreover, such ROS generation was inhibited by blocking phospholipase C and inositol 1,4,5-trisphosphate-induced Ca2+ release, indicating that activation occurs upstream of NADPH oxidase-mediated ROS generation. Because multiple upstream G protein-coupled receptors can activate phospholipase C, we then tested the effects of antagonists of serotonin 2A (5-HT2AR) and M-3-muscarinic (M3R) receptors and found they both protected Abca4(-/-)Rdh8(-/-) mouse retinas from light-induced degeneration. Thus, a cascade of signaling events appears to mediate the toxicity of atRAL in light-induced photoreceptor degeneration of Abca4(-/-)Rdh8(-/-) mice. A similar mechanism may be operative in human Stargardt disease and age-related macular degeneration.