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.
Highlights
High levels of all-trans-retinal are associated with photoreceptor degeneration
DISCUSSION atRAL is cytotoxic in cultured cells and associated with light-induced photoreceptor cell death in vivo [21], the involved mechanisms remain to be clarified. atRAL induces high levels of superoxide in neutrophils via NADPH oxidase, the primary enzymatic source of generated superoxide [29]
Experimental results described here identify a series of intrinsically linked events, including the participation of G protein-coupled receptors (GPCRs), PLC/IP3/Ca2ϩ signaling, and NADPH oxidase-mediated reactive oxygen species (ROS) production, which are responsible for the pathogenesis of atRAL-mediated light-induced retinal degeneration in Abca4Ϫ/ϪRdh8Ϫ/Ϫ mice, a model for rod/cone degeneration
Summary
High levels of all-trans-retinal (atRAL) are associated with photoreceptor degeneration. We report that bright light exposure of Abca4؊/؊Rdh8؊/؊ mice increased atRAL levels in the retina that induced rapid NADPH oxidasemediated overproduction of intracellular reactive oxygen species (ROS). 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. These observations raise the possibility that certain types of retinal degeneration could be prevented by therapies selectively targeting transient sequestration (buffering) of elevated atRAL, antagonizing a subset of GPCRs, or inhibiting PLC, IP3R, or NADPH oxidase, alone or in combination
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