Vitamin A receptor found

Study pinpoints long-sought receptor for retinol-binding protein

Melissa Lee Phillips
Jan 24, 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.comLinks within this articleT. Goodwin, "On the trail of vitamin A with a distinguished biochemist," The Scientist, July 25, 1988. 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.orgCatharine Ross 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. Sun 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. Choi, "Retinoic acid may control germ cells," The Scientist, March 31, 2006. Ong Blaner Yang et al., "Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes," Nature, July 21, 2005.