title: Mechanism of all-trans-retinal toxicity with implications for stargardt disease and age-related macular degeneration.
abstract: 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 Ca(2+) 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-HT(2A)R) and M(3)-muscarinic (M(3)R) 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.
authors.affiliation: Department of Pharmacology and §Ophthalmology, School of Medicine, Case Western Reserve University,Cleveland, Ohio 44106-4965, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.forename: Kiichiro
authors.initials: K
authors.lastname: Okano
authors.forename: Tadao
authors.initials: T
authors.lastname: Maeda
authors.forename: Vishal
authors.initials: V
authors.lastname: Chauhan
authors.forename: Marcin
authors.initials: M
authors.lastname: Golczak
authors.forename: Akiko
authors.initials: A
authors.lastname: Maeda
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Palczewski
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000429:Alcohol Oxidoreductases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D003317:Corneal Dystrophies, Hereditary / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000235:genetics / Q000378:metabolism; D008027:Light / Q000009:adverse effects; D008268:Macular Degeneration / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D043587:Receptor, Muscarinic M3 / Q000235:genetics / Q000378:metabolism; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics / Q000378:metabolism; D012172:Retinaldehyde / Q000378:metabolism*; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000494:pharmacology; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000235:genetics / Q000378:metabolism
chemical_list: D018528:ATP-Binding Cassette Transporters; D000429:Alcohol Oxidoreductases; D002118:Calcium; D015544:Inositol 1,4,5-Trisphosphate; D019255:NADPH Oxidases; D017382:Reactive Oxygen Species; D043587:Receptor, Muscarinic M3; D044402:Receptor, Serotonin, 5-HT2A; D012172:Retinaldehyde; D058830:Serotonin 5-HT2 Receptor Antagonists; D010738:Type C Phospholipases; C512841:Abca4 protein, mouse; C525880:HSD17B6 protein, mouse