Phospholipid meets all-trans-retinal: the making of RPE bisretinoids

Abstract

segments ( 1 ). The lipid phase of the disc membrane is dominated by phospholipids (87 mol % of total lipid in human outer segment membrane) with the major species being phosphatidylcholine (PC) (32.5 mol %), phosphatidylethanolamine (PE) (37.6 mol %), and phosphatidylserine (PS) (12.1 mol %) ( 2 ). A remarkable feature of the phospholipids of the outer segment disc membrane is their unusually high content of long-chain polyunsaturated (e.g., 22:6 n -3) fatty acids; in human outer segments, 22:6 n -3 accounts for 34.2% of the fatty acid in PE, 19.5% of the fatty acid in PC and 34.1% of the fatty acid in PC ( 2 ). Indeed, docosahexaenoic acid (DHA) is more abundant in photoreceptor outer segments that in any other mammalian cell membrane ( 2 ). These unsaturated acyl chains provide the high fl uidity necessary for proper signal transduction in the disc membrane.Following absorption of a photon, the 11-cis -retinal chromophore of visual pigment rhodopsin isomerizes to all-trans -retinal and initiates a series of conformational rearrangements leading to formation of metarhodopsin II, a 380-nm absorbing species that consists of all-trans -retinal bound to opsin by a deprotonated Schiff base linkage ( Fig. 1 ). Metarhodopsin II is distinguished by its ability to activate the G protein transducin ( 3 ). This activation initiates the phototransduction cascade leading to hyperpolarization of the photoreceptor cell and altered neurotransmitter release. Movement of phospholipid species during the rhodopsin to metarhodopsin II transition has been reported by multiple groups ( 4, 5 ). PHOSPHOLIPID ASSOCIATIONS WITH RHODOPSINThroughout the outer segment compartment of the photoreceptor cell, visual pigments (rhodopsin in rods and cone pigments) are densely packed within the plasma membrane and disc membranes; low levels of rhodopsin are also present in the plasma membrane of the rod inner

ATP-binding cassette transporter ABCA4 and chemical isomerization protect photoreceptor cells from the toxic accumulation of excess 11- cis -retinal

“…4C). A2PE and retinal dimer formation (21,22) was also observed when 11-cis-or all-trans-retinal was added to liposomes consisting of synthetic lipids (Fig. S2 B and C).…”

Toll-like Receptor 3 Is Required for Development of Retinopathy Caused by Impaired All-trans-retinal Clearance in Mice

“…Importantly, RPE cell death was caused by products released from degenerated retinal cells killed by all-trans-retinal toxicity. By inducing mitochondria-associated apoptosis (29,46), all-transretinal is directly toxic to cells. Our array analyses demonstrated activation of several TLRs in age-related retinal degeneration of Rdh8 Ϫ/Ϫ Abca4 Ϫ/Ϫ mice (Table 1), and the products released from these degenerating retinal cells might activate other TLRs and/or inflammatory pathways.…”

Lipofuscin and N-Retinylidene-N-Retinylethanolamine (A2E) Accumulate in Retinal Pigment Epithelium in Absence of Light Exposure

“…Lipofuscin is a complex mixture of partially digested lipid and protein components, with recent analysis showing that protein contributes ϳ2% by weight (7). The best characterized components are bis-retinoids (8), with A2E, the product of the condensation of two molecules of all-trans-retinal with ethanolamine, being one of the most abundant (9,10). As lipofuscin and A2E have been shown to be cytotoxic in vitro (9,(11)(12)(13), it has been suggested that their accumulation contributes to retinal degenerative diseases such as age-related macular degeneration (14,15) and Stargardt disease (16,17).…”

“…The mechanism of A2E and lipofuscin accumulation in the RPE is not well understood, but it is likely that components generated from retinal in the outer segment are introduced to the RPE through phagocytosis of photoreceptors. According to current models (1,8,22), A2E formation begins with the photoactivation of rhodopsin, the initial step in the detection of light by photoreceptor cells. Rho-dopsin photoactivation involves the isomerization of its 11-cis retinyl chromophore to all-trans (25).…”