title: Receptor-mediated cellular uptake mechanism that couples to intracellular storage.
abstract: Cells are known to take up molecules through membrane transport mechanisms such as active transport, channels, and facilitated transport. We report here a new membrane transport mechanism that employs neither cellular energy like active transport nor a preexisting electrochemical gradient of the free substrate like channels or facilitated transport. Through this mechanism, cells take up vitamin A bound with high affinity to retinol binding protein (RBP) in the blood. This mechanism is mediated by the RBP receptor STRA6, which defines a new type of cell-surface receptor. STRA6 is essential for the proper functioning of multiple human organs, but the mechanisms that enable and control its cellular vitamin A uptake activity are unknown. We found that STRA6-mediated vitamin A uptake is tightly coupled to specific intracellular retinoid storage proteins, but no single intracellular protein is absolutely required for its transport activity. By developing sensitive real-time monitoring techniques, we found that STRA6 is not only a membrane receptor but also catalyzes vitamin A release from RBP. However, vitamin A released from RBP by STRA6 inhibits further vitamin A release by STRA6 unless specific intracellular retinoid storage proteins relieve this inhibition. This mechanism is responsible for its coupling to intracellular storage proteins. The coupling of uptake to storage provides high specificity in cellular uptake of vitamin A and prevents the excessive accumulation of free vitamin A. We have also identified a robust small-molecule-based technique to specifically stimulate cellular vitamin A uptake. This technique has implications in treating human diseases.
authors.affiliation: Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, United States.
authors.forename: Riki
authors.initials: R
authors.lastname: Kawaguchi
authors.forename: Jiamei
authors.initials: J
authors.lastname: Yu
authors.forename: Mariam
authors.initials: M
authors.lastname: Ter-Stepanian
authors.forename: Ming
authors.initials: M
authors.lastname: Zhong
authors.forename: Guo
authors.initials: G
authors.lastname: Cheng
authors.forename: Quan
authors.initials: Q
authors.lastname: Yuan
authors.forename: Minghao
authors.initials: M
authors.lastname: Jin
authors.forename: Gabriel H
authors.initials: GH
authors.lastname: Travis
authors.forename: David
authors.initials: D
authors.lastname: Ong
authors.forename: Hui
authors.initials: H
authors.lastname: Sun
mesh_terms: D000818:Animals; D001692:Biological Transport; D002462:Cell Membrane / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D012177:Retinol-Binding Proteins / Q000378:metabolism*; D014801:Vitamin A / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; D012177:Retinol-Binding Proteins; D014801:Vitamin A