The Logistical Backbone of Photoreceptor Cell Function: Complementary Mechanisms of Dietary Vitamin A Receptors and Rhodopsin Transporters

Abstract

In this review, we outline our current understanding of the mechanisms involved in the absorption, storage, and transport of dietary vitamin A to the eye, and the trafficking of rhodopsin protein to the photoreceptor outer segments, which encompasses the logistical backbone required for photoreceptor cell function. Two key mechanisms of this process are emphasized in this manuscript: ocular and systemic vitamin A membrane transporters, and rhodopsin transporters. Understanding the complementary mechanisms responsible for the generation and proper transport of the retinylidene protein to the photoreceptor outer segment will eventually shed light on the importance of genes encoded by these proteins, and their relationship on normal visual function and in the pathophysiology of retinal degenerative diseases.

Keywords: MYO1C; MYO7A; RBP4; RBPR2; STRA6; photoreceptor; rhodopsin; visual function; vitamin A.

Figure 1

Overview of vitamin A absorption and storage. Dietary vitamin A, either in the form of retinyl esters or β-carotene, is absorbed by the intestinal enterocyte. Retinyl esters, when reduced into retinol by extracellular esterases, readily diffuses into the enterocyte. Conversely, β-carotene enters the enterocyte through the SCARB1 transporter, which is then cleaved into two molecules of all-trans retinal by BCO1, and then reduced into all-trans retinol in the cytosol. All-trans retinol from both sources associate with RBP2, is converted inro retinyl esters by LRAT, and released into the bloodstream in chylomicrons. A total of 70% of chylomicron bound retinyl esters are absorbed by the liver for storage. Once inside the hepatocyte, retinyl esters are converted back to all-trans retinol by LRAT, which can then enter the hepatic stellate cell for storage. Otherwise, all-trans retinol can be released into circulation when it is bound to RBP4 and TTR (holo-RBP4). Holo-RBP4 in the bloodstream can be transported back into the hepatocyte through the action of RBPR2. ROL, all-trans retinol; RBPR2, retinol binding protein 4 receptor 2; LRAT, lecithin retinol acyltransferase; SCARB1, scavenger receptor binding protein 1; RE, retinyl esters; RAL, all-trans retinal; RBP2, cellular retinol binding protein 2; TTR, transthyretin; atROL, all-trans retinol; RBP4, retinol binding protein 4; β-carotene monooxygenase 1, BCO1.

Figure 2

Transport of vitamin A into the eye by STRA6. Vitamin A (holo-RBP4) in the circulation is taken up by the STRA6 membrane receptor in the retinal pigment epithelium (RPE). In the RPE, all-trans retinol is esterified into retinyl esters by LRAT, converted into 11-cis retinol by RPE65, and finally converted to 11-cis retinal by RDH5. 11-cis retinal is transported into the OS, either through actions of IRBP or otherwise, and is associated with opsin to form light sensitive retinylidene protein. After phototransduction, all-trans retinal is converted into all-trans retinol by RDH8, which then is transported back into the RPE, by IRBP or otherwise, thus completing the visual cycle. RPE: retinal pigment epithelium, OS: outer segment, atROL: all-trans retinol, 11cRal: 11-cis retinal, IRBP: interphotoreceptor retinoid-binding protein, CRBP: cellular retinol-binding protein, LRAT: lecithin:retinol acyltransferase, TTR: transthyretin.

Figure 3

Photoreceptor structure, intraflagellar transport (IFT), and rhodopsin mistrafficking as the result of MYO1C and MYO7A inhibition in mice. (A) Wild-type model showing the effects of rhodopsin present in the outer segments (OS). (B) A model of IFT in the rod cell that occurs in all cilia and flagella. This model was created based on an immunoEM image of rhodopsin within the mouse photoreceptor [45]. Flagellar membrane proteins are carried by vesicles from the Golgi apparatus and are shown to be associated with the flagellar shaft by IFT particles on their way to the OS. When IFT particles reach the base of the OS, membrane discs are formed from membrane proteins. Black arrows demonstrate the flow of IFT through the flagellar pore complex and microtubule of the connecting cilium (CC). The CC consists of the basal body (BB), IFT particle, dynein, and kinesin II. (C) Model showing the adverse effects of Myo1c and Myo7a deletion in mice on rhodopsin trafficking from the photoreceptor IS to OS. In these genetic models’ rhodopsin was found mislocalized. BioRender^® 2.0 was used in the creation of this diagram.

Figure 4

Logistical role for vitamin A receptors and motor proteins in visual function. For the human eye to detect light, two events must take place in the photoreceptors for the generation of the retinylidene protein. Dietary vitamin A precursors must be absorbed and transported to the eye for the generation of 11-cis retinal, which serves as the chromophore for rod and cone opsins in the photoreceptor outer segments. Herein, two vitamin A receptors, retinol binding protein 4 receptor 2 (RBPR2), and stimulated by retinoic acid 4 (STRA6) receptors, fulfil this role. Likewise, GPCR opsin proteins that are synthesized in the photoreceptor inner segments must be trafficked to the photoreceptor outer segments. Herein, unconventional motor proteins (MYO1C, MYO7A), among dynein’s, and kinesins, have been shown to be involved in rhodopsin trafficking. In the photoreceptor outer segments, the retinylidene protein, which upon the absorption of light causes the cis-to-trans isomerization of a double bond within the chromophore, inducing conformational changes in opsin and subsequently activation of the phototransduction cascade of events.