Docosahexaenoic Acid Modulates the Interactions of the Interphotoreceptor Retinoid-binding Protein with 11-cis-Retinal

Abstract

Rapid transport of retinoids across the interphotoreceptor matrix is a critical part of the visual cycle, since it serves to replenish bleached rhodopsin with its chromophore 11-cis-retinal. The transport of retinoids in the interphotoreceptor matrix is believed to be mediated by the interphotoreceptor retinoid-binding protein (IRBP), a protein that, in addition to possessing two retinoidbinding sites, associates in vivo with long chain fatty acids. Here, the interrelationships between binding of the two types of ligands to IRBP were studied. The composition of fatty acids associated with IRBP in bovine retina was determined, and it was found that polyunsaturated fatty acids constitute a significant fraction of those. It was further found that docosahexaenoic acid, but not palmitic acid, induced a rapid and specific release of 11-cis-retinal from one of the protein's retinoidbinding sites. Based on these results and on the additional observation that a steep concentration gradient of docosahexaenoic acid exists between photoreceptor and pigment epithelium cells, a model for the mechanism by which IRBP may target 11-cis-retinal to photoreceptor cells is proposed.Vitamin A is essential for vision, since one of its metabolites, 11-cis-retinal, serves as the chromophore for the visual protein rhodopsin. Vitamin A circulates in blood and enters the eye in the form of all-trans-retinol. This form is taken up from the circulation by retinal pigment epithelium (RPE) 1 cells, which contain the enzymatic machinery necessary for conversion of all-trans-retinol to 11-cis-retinal. The later retinoid is transported to photoreceptor outer segments (ROS), where it associates with opsin to form rhodopsin. Exposure to light leads to isomerization of rhodopsin-bound 11-cis-retinal to the all-trans form, which is then hydrolyzed from the protein and reduced to all-trans-retinol. All-trans-retinol is transferred back to the RPE for reisomerization and oxidation (for review see Ref. 1). Thus, continuous shuttling of retinoids between photoreceptor and pigment epithelium cells across the aqueous compartment that separates them, the interphotoreceptor matrix (IPM), is a critical part of the visual cycle.The hydrophobic nature of retinoids and their lability when dissolved in water raise the question of how their rapid transport across an aqueous compartment is accomplished. The details of this process are not clear at present, but it is generally believed to be mediated by a protein in the IPM, the interphotoreceptor retinoid-binding protein (IRBP) (see Ref. 2 for review). IRBP, which is a 140-kDa glycoprotein and is the major soluble protein component of the IPM, is known to bind various isomeric and chemical forms of retinoids as well as long chain fatty acids (3, 4). Participation of this protein in shuttling of retinoids in the IPM has been implied by the observations that its retinoid content is modulated by light (5) and that binding of retinoids to IRBP stabilizes them against degradation (6, 7). It was also reported that IRBP c...

Identification of Apolipoprotein A-I as a Retinoic Acid-binding Protein in the Eye

“…the sclera), it would be expected that uncharged atRA could move spontaneously across cellular membranes to rapidly enter the cell. Additionally, the presence of apoA-I-associated lipids may regulate retinoid binding specificity and diffusion of atRA into cells similarly to the proposed role of the fatty acid docosahexaenoic acid in association with interphotoreceptor retinoid-binding protein (58).…”

Regulation of human Δ-6 desaturase gene transcription: identification of a functional direct repeat-1 element

“…However, the open reading frame sequence for ⌬ -6 desaturase and ⌬ -5 desaturase suggests that, unlike stearoyl-CoA desaturase, the human ⌬ -6 desaturase and ⌬ -5 desaturase enzymes contain a cytochrome b 5 domain as part of the peptide itself (15,16). This cytochrome b 5 domain is also present in the Tang et al Regulation of human ⌬ -6 desaturase gene transcription rat ⌬ -6 desaturase and the mouse ⌬ -5 desaturase (15)(16)(17)(18). In addition to the b 5 domain, the ⌬ -6 desaturase and ⌬ -5 desaturase proteins possess several other common features, including an identical peptide size, two membranespanning regions, and three histidine-rich regions (15)(16)(17)(18).…”

“…⌬ -6 Desaturase and ⌬ -5 desaturase are microsomal enzymes that are expressed in nearly all human tissues, with the greatest activities found in the liver, heart, and brain (14)(15)(16). Traditionally, ⌬ -6 desaturase and ⌬ -5 desaturase were thought to be components of a three-enzyme system that involves NADH-cytochrome b 5 reductase and cytochrome b 5 (14). However, the open reading frame sequence for ⌬ -6 desaturase and ⌬ -5 desaturase suggests that, unlike stearoyl-CoA desaturase, the human ⌬ -6 desaturase and ⌬ -5 desaturase enzymes contain a cytochrome b 5 domain as part of the peptide itself (15,16).…”

“…Over 30% of the fatty acid in brain phospholipid consists of 20:4(n-6) and 22:6(n-3), and ‫ف‬ 50% of the fatty acid in the retina is 22:6(n-3) (5,6). An inadequate availability of 20:4(n-6) such as occurs in diabetes is associated with impaired nerve transmission (7,8).…”

Postępowanie w zwyrodnieniu barwnikowym siatkówki – przegląd piśmiennictwa

“…Wiadomo, że znajdują się one w fotoreceptorach i odgrywają istotną rolę w ich prawidłowym funkcjonowaniu [27,28].…”