The RPE has a number of physiologic roles (Fig 13-3). Crucial among these functions are
These functions are discussed briefly in the following sections. Other important functions subserved by the RPE include its role in synthesis and remodeling of the interphotoreceptor matrix, formation of the outer blood–retina barrier, and formation of the basal lamina of Bruch membrane.
Vitamin A Regeneration
The RPE, second only to the liver in its concentration of vitamin A, plays a major role in the uptake, storage, and mobilization of vitamin A. The RPE supplies the photoreceptor outer segments with vitamin A, which is tethered to rhodopsin in rods and to the 3 different cone opsins (red, green, and blue). Although the different opsins have specific absorption spectra, vitamin A changes its configuration identically in response to the particular wavelength of light (see Chapter 12).
The basic function of the RPE cell is to generate 11-cis-retinal (also called 11-cis-retinaldehyde) (Fig 13-4). Light-induced activation of rhodopsin leads to isomerization of 11-cis-retinal to all-trans-retinal and initiates the phototransduction cascade. Light-activated rhodopsin releases all-trans-retinal and must bind with another 11-cis-retinal to be ready for activation by the next photon of light. The free all-trans-retinal isomer undergoes a series of enzymatic reactions, called the visual cycle or retinoid cycle, to regenerate 11-cis-retinal. The visual cycle ensures a steady supply of 11-cis-retinal for the opsins for maintaining vision and requires close interaction between the RPE and photoreceptor outer segments. Similar processes occur in all photoreceptors; the process specific to rods is discussed below.
Free all-trans-retinal is cleared from the rod discs by ABCA4, an ATP-binding cassette (ABC) transporter protein. After transport from the rod discs to the cytosol of the outer segments, all-trans-retinal is enzymatically reduced to all-trans-retinol by retinol dehydrogenase. All-trans-retinol is rapidly released by photoreceptor cells to the interphotoreceptor matrix, where it binds to interphotoreceptor retinoid-binding protein (IRBP). RPE cells contain cellular retinol-binding protein 1 (CRBP1), which promotes the uptake of all-trans-retinol into the RPE. The RPE also obtains vitamin A from the blood, where it is complexed with retinol-binding protein (RBP) and transthyretin. Phagocytosis of shed photoreceptor outer-segment discs (see the following section) by the RPE also allows recycling of vitamin A.
Within the RPE cells, CRBP1-bound all-trans-retinol is enzymatically esterified by lecithin retinol acyltransferase (LRAT). The resultant retinyl ester is hydrolyzed and isomerized to the 11-cis configuration by the retinoid isomerohydrolase RPE65. 11-cis-Retinol is then oxidized to 11-cis-retinal by 11-cis-retinol dehydrogenase. The newly formed 11-cis-retinal is released from RPE cells to the interphotoreceptor matrix. From there it is transported by IRBP (IRBP binds both retinol and retinal forms) to the photoreceptor outer-segment discs to generate another visual transduction cycle.
Figure 13-4 The visual cycle (also known as retinoid cycle) involves a series of reactions in the photoreceptor outer segments and RPE to regenerate 11-cis-retinal (also known as 11-cis-retinaldehyde). 11-cis Retinal attaches to a lysine residue on rhodopsin. When the complex absorbs light, 11-cis-retinal transforms into all-trans-retinal via a process known as photo-isomerization. This induces a conformational change in the attached rhodopsin molecule, activating the second-messenger system and initiating the phototransduction cascade within the photoreceptor. The all-trans-retinal is shed from rhodopsin and transported by ABCA4 from the rod disc to the cytosol, where it is converted to all-trans-retinol. Then, all-trans-retinol is delivered to the RPE via interphotoreceptor retinoid-binding protein (IRBP), which acts as a shuttle and also shields the cell membranes from the membranolytic retinoid molecules. Once in the RPE, this molecule is esterified by lecithin retinol acyltransferase (LRAT). The resultant retinyl ester is converted to 11-cis-retinol by the isomerohydrolase RPE65. 11-cis-Retinol is then oxidized to 11-cis-retinal by retinol dehydrogenase (RDH) and shuttled back to the photoreceptor outer-segment discs by IRBP to participate in another visual cycle. ABCA4 = ATP-binding cassette transporter protein; Apo-opsin = apo-rhodopsin; CRBP1 = cellular retinol-binding protein 1; PR = photoreceptor; RAL = retinal; RBP = retinol-binding protein; RE = retinyl ester; ROL = retinol; TTR = transthyretin; VitA = vitamin A.
(Modified with permission from Singh RSJ, Kim JE. Visual cycle modulation. In: Lim J, ed.
Age-related Macular Degeneration.
3rd ed. Boca Raton, FL: CRC Press; 2012:330.)
Excerpted from BCSC 2020-2021 series: Section 2 - Fundamentals and Principles of Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.