Mechanism of All-trans-retinal Toxicity with Implications for Stargardt Disease and Age-related Macular Degeneration

被引：182

作者：

Chen, Yu ^{[1
]}

Okano, Kiichiro ^{[1
]}

Maeda, Tadao ^{[1
,2
]}

Chauhan, Vishal ^{[1
,2
]}

Golczak, Marcin ^{[1
]}

Maeda, Akiko ^{[1
,2
]}

Palczewski, Krzysztof ^{[1
]}

机构：

[1] Case Western Reserve Univ, Sch Med, Dept Pharmacol, Cleveland, OH 44106 USA

[2] Case Western Reserve Univ, Sch Med, Dept Ophthalmol, Cleveland, OH 44106 USA

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2012年 / 287卷 / 07期

基金：

美国国家卫生研究院;

关键词：

RECESSIVE RETINITIS-PIGMENTOSA; NEUTROPHIL NADPH-OXIDASE; ACTIVATED PROTEIN-KINASE; VISUAL CYCLE; PHOSPHOLIPASE-C; GENE ABCR; IN-VIVO; BINDING-PROPERTIES; 5-HT1A RECEPTORS; OXIDATIVE STRESS;

D O I：

10.1074/jbc.M111.315432

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：5059 / 5069

页数：11

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