Continuous rapid shuttling of retinoids between photoreceptors and RPE cells during cycles of light and dark exposure is an essential part of the visual cycle. This movement requires transfer of retinoids, which are poorly soluble in water, through an aqueous phase, the interphotoreceptor matrix (IPM). The mechanism(s) of intra- and inter-cellular transport of retinoids in the eye are not known. Several retinoid-binding proteins have been implicated in mediating retinoid transport and in modulating retinoid metabolism in the eye. These proteins are: retinol-binding protein (RBP), the binding protein for vitamin A in blood; the interphotoreceptor matrix retinol-binding protein (IRBP), a soluble protein in IPM that binds retinoids and long chain fatty acids; cellular retinal-binding protein (CRALBP), a unique eye protein with high specificity towards 11-cis-retinoids; and cellular retinol-binding protein I, which binds all-trans retinol and is present in many tissues, including the eye. The main goals of this project are to clarify the factors that regulate movement of retinoids between different locations in the eye and the role(s) of retinoid-binding proteins in transport and metabolism of these compounds. To investigate these questions, the interactions of retinoids with the various environments which they encounter in the eye, i.e., cellular membranes, binding proteins and aqueous spaces, will be studied. The rates by which retinoids move between binding proteins and membranes that are their site of metabolism or are located in the path by which retinoids leave or enter the RPE will be examined. These studies are anticipated to lead to identification of rate-determining steps of retinoid metabolism and the origin of the influence of binding proteins on the activities of enzymes catalyzing retinoid metabolism. The results will also clarify whether uptake and secretion of retinoids by RPE cells occur spontaneously or whether they are facilitated in vivo, and the roles of binding proteins in retinoid transport in the eye.
