UC Irvine UC Irvine Previously Published Works Title Retinoids in the visual cycle: role of the retinal G protein-coupled receptor. Permalink https://escholarship.org/uc/item/8fp452q4 Authors Choi, Elliot H Daruwalla, Anahita Suh, Susie et al. Publication Date 2021-02-06 DOI 10.1194/jlr.tr120000850 Peer reviewed eScholarship.org Powered by the California Digital Library University of California THEMATIC REVIEW SERIES Thematic Review Series: Seeing 2020:Lipids and Lipid-Soluble Molecules in the Eye Retinoids in the visual cycle: role of the retinal G protein-coupled receptor Elliot H. Choi1,2,* , Anahita Daruwalla2,3, Susie Suh1,2, Henri Leinonen1 , and Krzysztof Palczewski1,3,* 1Department of Ophthalmology, Gavin Herbert Eye Institute, Center for Translational Vision Research, University of California, Irvine, CA, USA; 2Department of Pharmacology, Case Western Reserve University, Cleveland, OH, USA; 3Departments of Physiology and Biophysics, and Chemistry, University of California, Irvine, CA, USA Abstract Driven by the energy of a photon, the visual embryogenesis, the development of organs, reproduc- pigments in rod and cone photoreceptor cells isomerize – cis trans tion, immunity, and vision (1 8). Besides these important 11- -retinal to the all- configuration. This photo- roles, new physiological functions of vitamin A are chemical reaction initiates the signal transduction pathway that eventually leads to the transmission of a continuously being discovered in the fields of neuro- visual signal to the brain and leaves the opsins insensi- science and lipid research (9, 10). Perhaps in recognition tive to further light stimulation. For the eye to restore of these facts, the role of vitamin A in various organ light sensitivity, opsins require recharging with 11-cis- systems has been an exciting area of research for de- retinal. This trans-cis back conversion is achieved cades. Most notably, the eye requires vitamin A and its through a series of enzymatic reactions composing the derivatives for the maintenance of its function retinoid (visual) cycle. Although it is evident that the throughout the entire life cycle. Thus, a considerable classical retinoid cycle is critical for vision, the exis- tence of an adjunct pathway for 11-cis-retinal regenera- number of studies has been devoted over past decades tion has been debated for many years. Retinal pigment to our understanding of the complex biochemical epithelium (RPE)-retinal G protein-coupled receptor processes that make vision possible. This process re- (RGR) has been identified previously as a mammalian quires the absorption of vitamin A from the systemic retinaldehyde photoisomerase homologous to reti- circulation into the retinal pigment epithelium (RPE) nochrome found in invertebrates. Using pharmacolog- lying adjacent to the photoreceptor layer of the retina. ical, genetic, and biochemical approaches, researchers Thus, vitamin A deficiency or mutations in the enzymes have now established the physiological relevance of the RGR in 11-cis-retinal regeneration. The photoisomerase involved in the retinoid cycle result in a broad spec- activity of RGR in the RPE and Müller glia explains how trum of retinal diseases. the eye can remain responsive in daylight. In this re- view, we will focus on retinoid metabolism in the eye and visual chromophore regeneration mediated by ABSORPTION OF DIETARY VITAMIN A RGR. One of the characteristics of vitamin A is that it Supplementary key words vision • vitamin A • retina • retinal cannot be synthesized by the human body and there- pigment epithelium • visual pigments • visual chromophore • fore must be obtained from a dietary source. Dietary photoisomerase • retinal pigment epithelium-retinal G protein- vitamin A is mainly available in two forms, preformed coupled receptor opsin vitamin A and provitamin A. Preformed vitamin A is generally found in animal sources including liver, eggs, Vitamin A is an essential fat-soluble micronutrient fish, and dairy products. Conversely, provitamin A ca- that has different functional roles in the human body. rotenoids are abundant in fruits and vegetables. The By definition, vitamin A is all-trans-retinol; however, the majority of preformed vitamin A consists of long-chain term vitamin A is often used to refer collectively to the fatty acid esters of retinol, particularly REs. These esters derivatives of all-trans-retinol, including retinyl esters are hydrolyzed into retinols by pancreatic lipase in the (REs), retinaldehyde, and retinoic acid. It is well docu- duodenum or phospholipase B at the brush border of mented that vitamin A is essential for human survival enterocytes, and the resulting retinols are taken up by at every stage of life. It has critical functions during the enterocytes (11–13). Although each individual has a different extent of conversion efficiency, approxi- mately half of provitamin A carotenoids are converted *For correspondence: Krzysztof Palczewski, [email protected]; into retinol in the human intestine and then absorbed. Elliot H. Choi, [email protected]. J. Lipid Res. (2021) 62 100040 1 © 2021 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. https://doi.org/10.1194/jlr.TR120000850 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). The retinol derived either from preformed vitamin A The first step of vision begins when 11-cis-retinal bound or provitamin A carotenoids can be reesterified to REs by to rhodopsin or cone opsins is photoisomerized to all- an enzyme called lecithin:retinol acyltransferase (LRAT) trans-retinal (28, 29). The resulting all-trans-retinal is (14–16). Then, the majority of REs are incorporated into reduced to all-trans-retinol and transported to the RPE, the lipid core of the chylomicrons and further distrib- where trans-to-cis isomerization occurs to regenerate the uted to other tissues through the circulation. The chy- visual chromophore. The key enzyme responsible for this lomicrons are metabolized into chylomicron remnants reaction is RPE-specific 65 kDa (RPE65) localized to the by lipoprotein lipase. The chylomicron remnants con- endoplasmic reticulum of RPE cells (30–34). The impor- taining most of the REs are then directed mainly to the tance of RPE65 in visual function is underscored by the liver (17, 18). As a result of these processes, the liver serves finding that more than 100 mutations in RPE65 are asso- as the main reservoir of vitamin A. The remaining REs in ciated with retinal diseases (35, 36). The inheritance pat- the circulation are taken up by peripheral tissues terns of these mutations include autosomal dominant and including the adipose, heart, muscle, and lungs (19). autosomal recessive forms. Without a functional RPE65, an adequate amount of visual chromophore cannot be TRANSPORT OF VITAMIN A INTO THE EYE generated to meet the demand for visual function. Besides the retinoid cycle, an opsin homolog in the Depending on the demand, the stored REs in the liver RPE and the Müller glia of the retina was identified as a are mobilized and secreted as retinol into the systematic potential isomerase contributing to visual chromophore circulation. Retinol mainly circulates in the blood as a regeneration in daylight conditions (37). This putative complex with retinol-binding protein 4 and transthyretin opsin homolog was first cloned from a bovine RPE cDNA (20, 21). In the eye, uptake of retinol from the chorioca- library in 1993 and referred to as RPE-retinal G protein- pillaris is mediated by the transmembrane cell-surface coupled receptor (RGR) (38). The cloned sequence con- STRA6 receptor of the RPE, a pigmented monolayer of tained homologous features and sequence motifs cells located between the photoreceptors and choroid (20, consistent with the structure of a G protein-coupled re- 22). STRA6 catalyzes the release of retinol from retinol- ceptor (GPCR) (38). Although biochemical studies of binding protein 4 and then transports retinol to the RGR demonstrated its role as a possible photoisomerase cytosol. Besides the retinol from the systemic circulation, that counteracts the cis-trans photoisomerization by retinol released from the photoreceptor outer segments is rhodopsin and cone opsins (37, 39), several early obser- another source of retinoids to the RPE. Interphotor- vations argued against its photoisomerase activity. For − − eceptor retinoid-binding protein (IRBP) mediates the example, Rpe65 knockout (Rpe65 / ) mice were unable to transport of retinoids between the photoreceptors and generate a detectable amount of visual chromophore RPE by first sequestering them in the interphotoreceptor under photic conditions despite the expression of RGR. matrix (23, 24). Then, retinol is incorporated into the Other findings indicated that RGR could stimulate metabolic pathway of RPE cells that regenerates visual RPE65 activity independent of light and increases all- chromophore through a series of enzymatic reactions (8). trans-RE hydrolase activity (40, 41). Because the findings Because vitamin A is a critical source of substrate for the surrounding RGR were inconsistent, more thorough metabolic pathway in the eye, a deficiency of dietary investigations were necessary to determine the photo- vitamin A can be a leading cause of blindness. isomerase activity of RGR and delineate its involvement in chromophore regeneration (42, 43). RETINOIDS IN VISION In this review, we focus on the regeneration of visual chromophore by