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Vitamin A receptor found

Study pinpoints long-sought receptor for retinol-binding protein

By | January 25, 2007

Researchers have answered a question that's dogged science for decades -- they've identified a receptor that allows vitamin A uptake into cells, according to a report in this week's Science. The study reveals evidence that a previously discovered but uncharacterized protein called STRA6 is a receptor for retinol-binding protein (RBP), which forms a complex with vitamin A. RBP's binding to STRA6 allows the attached vitamin A to be absorbed into the cell, according to the authors. "People have looked for a long time for a retinol-binding protein receptor and the data... have never been quite convincing," said Catharine Ross of Pennsylvania State University in University Park, who was not involved in the study. RBP binds to vitamin A stored in the liver and carries it through the blood to other organs. Although vitamin A itself can diffuse freely across cell membranes, the vitamin A-RBP complex cannot. Scientists have been gathering evidence of the existence of an RBP receptor since the mid-1970s, according to senior author Hui Sun of the University of California, Los Angeles (UCLA). However, technical challenges -- namely, the transient binding of RBP to its putative receptor as well as the receptor's fragility -- had likely heretofore prevented the identification of the receptor protein, Sun said. Sun and his colleagues -- led by first author Riki Kawaguchi, also of UCLA -- designed a strategy to stabilize and purify the RBP-receptor complex. Mass spectrometry revealed the receptor to be a protein called STRA6, which researchers had previously identified in a screen for genes induced by retinoic acid in cancer cells. "I think that this is something that was waiting to be discovered, and a number of approaches have been tried," said David Ong of Vanderbilt University in Nashville, who was not involved in the study. "They just were very skillful." To test whether STRA6 really is a receptor for RBP, the researchers transfected cells with STRA6 and found that these cells bound to RBP with high affinity. Several experiments also showed that increasing STRA6 expression increases cellular vitamin A uptake from the vitamin A-RBP complex. "They've done good experiments to demonstrate all the things one would expect for a receptor that's going to recognize RBP and internalize the retinol," Ong said. STRA6 is also expressed in the organs where a RBP receptor would be expected, according to Sun -- such as the retinal pigmented epithelium of the adult eye, the brain, spleen, placenta, female genital tract, testis, lung, and skin. "I think they have identified a receptor for RBP," Ross told The Scientist. Still, she cautioned that because the experiments were done in transfected cells instead of in vivo, "we don't know from this work whether the overexpression is necessary to see this." "All of their data, on the surface, are very convincing," said William Blaner of Columbia University in New York, but "will STRA6 prove to be a cell-surface receptor for RBP? This remains to be established in a physiologic context," Blaner told The Scientist. It's still possible that cells absorb vitamin A solely through diffusion, Blaner said, and STRA6 could weakly bind the vitamin A-RBP complex without functioning as a true receptor. "Nevertheless, the data that are presented in the manuscript are very compelling," Blaner added. They may be relevant to diabetes research, since RBP is thought to be involved in insulin resistance, he said. "I suspect that this paper is going to be met with a lot of renewed research interest in this area." Melissa Lee Phillips mphillips@the-scientist.com Links within this article T. Goodwin, "On the trail of vitamin A with a distinguished biochemist," The Scientist, July 25, 1988. http://www.the-scientist.com/article/display/8594 R. Kawaguchi et al., "A membrane receptor for retinol binding protein mediates cellular uptake of vitamin A," The Science, published online January 25, 2007. http://www.sciencemag.org Catharine Ross http://nutrition.hhdev.psu.edu/grad/faculty/ross.html J. Heller, "Interactions of plasma retinol-binding protein with its receptor. Specific binding of bovine and human retinol-binding protein to pigment epithelium cells from bovine eyes," Journal of Biological Chemistry, May 25, 1975. http://www.the-scientist.com/pubmed/1092676 Hui Sun http://www.physiology.ucla.edu/faculty/sun.html P. Bouillet et al., "Developmental expression pattern of Stra6, a retinoic acid-responsive gene encoding a new type of membrane protein," Mechanisms of Development, May 1997. http://www.the-scientist.com/pubmed/9203140 C. Choi, "Retinoic acid may control germ cells," The Scientist, March 31, 2006. http://www.the-scientist.com/news/display/23260/ David Ong http://www.vicc.org/dd/display.php?id=3770 William Blaner http://asp.cpmc.columbia.edu/facdb/profile_list.asp?uni=wsb2&DepAffil=Medicine Q. Yang et al., "Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes," Nature, July 21, 2005. http://www.the-scientist.com/pubmed/16034410
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Avatar of: KonradK

KonradK

Posts: 1

January 25, 2007

/begin rant/\n\nWhen I read the title, I immediately thought of the nuclear transcription factor RAR (retinoic acid/Vitamin A receptor) which was identified quite a number of years ago. The article subtitle "retinol-binding protein" is better.\n\nThe term receptor usually implies a protein that initiates a cellular response upon binding to its cognate ligand. The retinol-binding protein described in the article is involved in transport and not directly in function.\n\n/end rant/\n\n

January 31, 2007

The roles of the RBP receptor (STRA6) in development has been demonstrated in the following human genetic study by Dr. Anita Rauch and colleagues. Consistent with the diverse functions of vitamin A and expression of STRA6 in development, mutations in the human STRA6 gene are associated with severe birth defects including anophthalmia, mental retardation, congenital heart defects, and lung hypoplasia. \n\n\nReference:\n\nMutations in STRA6 Cause a Broad Spectrum of Malformations Including Anophthalmia, Congenital Heart Defects, Diaphragmatic Hernia, Alveolar Capillary Dysplasia, Lung Hypoplasia, and Mental Retardation \nFrancesca Pasutto, Heinrich Sticht, Gerhard Hammersen, Gabriele Gillessen-Kaesbach, David R. FitzPatrick, Gudrun Nürnberg, Frank Brasch, Heidemarie Schirmer-Zimmermann, John L. Tolmie, David Chitayat, Gunnar Houge, Lorena Fernández-Martínez, Sarah Keating, Geert Mortier, Raoul C. M. Hennekam, Axel von der Wense, Anne Slavotinek, Peter Meinecke, Pierre Bitoun, Christian Becker, Peter Nürnberg, André Reis, and Anita Rauch \nThe American Journal of Human Genetics, In press (2007)

February 4, 2007

Dear Ms. Philips,\n\nIn your recent article entitled "Vitamin A receptor found: Study pinpoints long-sought receptor for retinol-binding protein" you failed to mention that another well-characterized retinol binding receptor has previously been described. This cell surface receptor, called megalin/LRP2, binds to retinol binding protein and mediates uptake of retinol. Furthermore, in the article that you highlighted in Science by Kawaguchi et al., describing STRA6 as a retinol binding protein receptor, there was no mention of megalin. Importantly, the in vivo significance of STRA6 to retinol metabolism was not demonstrated in the Kawaguchi et al. paper whereas studies of megalin-deficient mice have clearly demonstrated the essential role for megalin in retinol homeostasis. \n\nI recommend the following articles:\n\nMegalin-mediated reuptake of retinol in the kidneys of mice is essential for vitamin A homeostasis. J Nutr. 2005 Nov;135(11):2512-6. PMID: 16251603\n\nEvidence for an essential role of megalin in transepithelial transport of retinol. J Am Soc Nephrol. 1999 Apr;10(4):685-95. PMID: 10203351\n\nSincerely,\n\nScott Argraves

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