Muller A, Chabbert C. TRPV4 channels mediate the infrared laserevoked response in sensory neurons.

FATP1 is involved in lipid transport into cells and in intracellular lipid metabolism. We showed previously that this protein interacts with and inhibits the limiting-step isomerase of the visual cycle RPE65. Here, we aimed to analyze the effect of Fatp1-deficiency in vivo on the visual cycle, structure and function, and on retinal aging. Among the Fatp family members, we observed that only Fatp1 and 4 are expressed in the control retina, in both the neuroretina and the retinal pigment epithelium. In the neuroretina, Fatp1 is mostly expressed in photoreceptors. In young adult Fatp1−/− mice, Fatp4 expression was unchanged in retinal pigment epithelium and reduced two-fold in the neuroretina as compared to Fatp1+/+ mice. The Fatp1−/− mice had a preserved retinal structure but a decreased electroretinogram response to light. These mice also displayed a delayed recovery of the b-wave amplitude after bleaching, however, visual cycle speed was unchanged, and both retinal pigment epithelium and photoreceptors presented the same fatty acid pattern compared to controls. In 2 year-old Fatp1−/− mice, transmission electron microscopy studies showed specific abnormalities in the retinas comprising choroid vascularization anomalies and thickening of the Bruch membrane with material deposits, and sometimes local disorganization of the photoreceptor outer segments. These anomalies lead us to speculate that the absence of FATP1 accelerates the aging process.

The isomerization of all-trans retinol (vitamin A) to 11-cis retinol in the retinal pigment epithelium (RPE) is a key step in the visual process for the regeneration of the visual pigment chromophore, 11-cis retinal. LRAT and RPE65 are recognized as the minimal isomerase catalytic components. However, regulators of this rate-limiting step are not fully identified and could account for the phenotypic variability associated with inherited retinal degeneration (RD) caused by mutations in the RPE65 gene. To identify new RPE65 partners, we screened a porcine RPE mRNA library using a yeast two-hybrid assay with full-length human RPE65. One identified clone (here named FATP1c), containing the cytosolic C-terminal sequence from the fatty acid transport protein 1 (FATP1 or SLC27A1, solute carrier family 27 member 1), was demonstrated to interact dose-dependently with the native RPE65 and with LRAT. Furthermore, these interacting proteins colocalize in the RPE. Cellular reconstitution of human interacting proteins shows that FATP1 markedly inhibits 11-cis retinol production by acting on the production of all-trans retinyl esters and the isomerase activity of RPE65. The identification of this new visual cycle inhibitory component in RPE may contribute to further understanding of retinal pathogenesis.In vertebrates, vision begins in photoreceptors (rod and cone) with the absorption of light by the visual pigments, rhodopsin and cone opsins, which consist of two components: opsin (apoprotein) and 11-cis retinaldehyde (11cRAL, 2 chromophore). Light causes photoisomerization of 11cRAL to alltrans retinal (atRAL) that dissociates from opsin. The atRAL is reduced to all-trans-retinol (atROL, vitamin A), which is in turn converted to 11-cis retinol (11cROL) and oxidized to 11cRAL in the neighboring retinal pigment epithelium (RPE). The whole process involves both retinoid transport proteins and enzymes and is termed the visual (retinoid) cycle (1-3).In the RPE, atROL is first esterified in the smooth endoplasmic reticulum membrane by a lecithin:retinol acyltransferase, LRAT (4, 5), to fatty acids to form all-trans-retinyl-esters (atRE). The latter are recognized by the RPE-specific protein RPE65 (MIM 180069) that catalyzes their cleavage and isomerization to the 11cROL (6, 7). 11cROL is then oxidized to 11cRAL by the 11cROL dehydrogenase (11cRDH), a member of the short chain alcohol dehydrogenases (8). Cellular retinaldehyde-binding protein (CRALBP) is an abundant carrier of both 11cROL and 11cRAL that facilitates the 11cROL formation and its oxidation to 11cRAL (9, 10).Isomerization is a rate-determining step in the visual cycle. In mice, the level of RPE65 expression is strain-dependent and determine the rate-limited rhodopsin regeneration (11,12). Recently, in vitro assays have shown that multiple disease-associated mutations in human RPE65 shown to decrease protein concentration, directly affect the isomerase activity (13,14). This rate-determining step may be regulated. For example, phosphate-containing compounds, such as AT...