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The visual (retinoid) cycle is a fundamental metabolic process in vertebrate retina responsible for production of 11-cis-retinal, the chromophore of rhodopsin and cone pigments. 11-cis-Retinal is bound to opsins, forming visual pigments, and when the resulting visual chromophore 11-cis-retinylidene is photoisomerized to all-trans-retinylidene, all-trans-retinal is released from these receptors. Toxic byproducts of the visual cycle formed from all-trans-retinal often are associated with lipofuscin deposits in the retinal pigmented epithelium (RPE), but it is not clear whether aberrant reactions of the visual cycle participate in RPE atrophy, leading to a rapid onset of retinopathy. Here we report that mice lacking both the ATP-binding cassette transporter 4 (Abca4) and enzyme retinol dehydrogenase 8 (Rdh8), proteins critical for all-trans-retinal clearance from photoreceptors, developed severe RPE/photoreceptor dystrophy at an early age. This phenotype includes lipofuscin, drusen, and basal laminar deposits, Bruch's membrane thickening, and choroidal neovascularization. Importantly, the severity of visual dysfunction and retinopathy was exacerbated by light but attenuated by treatment with retinylamine, a visual cycle inhibitor that slows the flow of all-trans-retinal through the visual cycle. These findings provide direct evidence that aberrant production of toxic condensation byproducts of the visual cycle in mice can lead to rapid, progressive retinal degeneration.What discriminates the eye from other organs is its light sensitivity and associated metabolic transformations that restore the light-sensitive chromophore (1). It is unclear if aberrations in the visual cycle and byproduct accumulation could be an underlying cause of retinopathy or merely a nonspecific nonpathogenic reflection of impaired metabolism. To distinguish between these two possibilities, we disrupted two genes critical for clearance of light-generated all-transretinal from rhodopsin and cone visual pigments (2, 3). Both the photoreceptor-specific ATP-binding cassette transporter (ABCA4) (4) and all-trans-retinol dehydrogenases (RDHs) 2 are involved in removal of all-trans-retinal from photoreceptors (5) (Scheme 1).ABCA4, also known as ABCR or the rim protein, localizes to the rim of photoreceptor discs and transfers all-trans-retinal from the inside to the outside of disc membranes once alltrans-retinal is released from visual pigments (4). Diretinoidpyridinium-ethanolamine (A2E) (6, 7) and retinal dimer (RALdi) conjugates (8) are the major fluorophores of lipofuscins produced from all-trans-retinal. Even in the presence of a functional transporter, both A2E and RALdi can accumulate as a consequence of aging (9) and produce toxic effects on RPE cells (10, 11). Patients affected by age-related macular degeneration (AMD), Stargardt disease with a disabled ABCA4 gene, or other retinal diseases associated with lipofuscin accumulation develop retinal degeneration. ABCA4 mutations also are linked with a high risk of AMD (12). However, no such ...

CaBP1-8 are neuronal Ca 2+ -binding proteins with similarity to calmodulin (CaM). Here we show that CaBP4 is specifically expressed in photoreceptors, where it is localized to synaptic terminals. The outer plexiform layer, which contains the photoreceptor synapses with secondary neurons, was thinner in the Cabp4 −/− mice than in control mice. Cabp4 −/− retinas also had ectopic synapses originating from rod bipolar and horizontal cells that extended into the outer nuclear layer. Responses of Cabp4 −/− rod bipolars were reduced in sensitivity about 100-fold. Electroretinograms (ERGs) indicated a reduction in cone and rod synaptic function. The phenotype of Cabp4 −/− mice shares similarities with that of incomplete congenital stationary night blindness (CSNB2) patients. CaBP4 directly associated with the C-terminal domain of the Ca v 1.4 α 1 -subunit and shifted the activation of Ca v 1.4 to hyperpolarized voltages in transfected cells. These observations indicate that CaBP4 is important for normal synaptic function, probably through regulation of Ca 2+ influx and neurotransmitter release in photoreceptor synaptic terminals.L-type Ca 2+ channels are involved in neuronal differentiation and outgrowth and in synaptic plasticity 1,2 . At many ribbon synapses, Ca 2+ influx through L-type Ca 2+ channels triggers neurotransmitter release 3-5 . The α 1 -subunit of the L-type Ca v 1.4 channel (Ca v 1.4α1) is specific to photoreceptors and is present at highest density in the synaptic terminals 5,6 . Compared with other L-type Ca 2+ channels, Ca v 1.4 channels are activated at relatively more negative voltages and show slow inactivation 7-9 , important properties for the ability of photoreceptors to sustain continual glutamate release in the dark 4,10 . Null mutations in Ca v 1.4α1 are responsible for an X-linked disorder, CSNB2 (refs. 11 ,12 ). ERGs of these patients indicate that a deficit may occur in transmission of signals from rod photoreceptors to bipolar cells. In mice, deletion of the β 2 -subunit, another component of the photoreceptor L-type channel, alters the expression of Ca v 1.4 and produces a phenotype similar to that seen in CSNB2 patients 13 .CaBPs, a subfamily of calmodulin (CaM)-like neuronal Ca 2+ -binding proteins 14 , modulate voltage-dependent Ca 2+ channels (VDCCs) and inositol triphosphate receptors 15-17 . Here we show that CaBP4, which has only been partially characterized in silico 14 , is found specifically