| OAT2 catalyzes efflux of glutamate and uptake of orotic acid. | |
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MedLine Citation:
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PMID: 21446918 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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OAT2 (human gene symbol SLC22A7) is a member of the SLC22 family of transport proteins. In rat, the principal site of expression of OAT2 is the sinusoidal membrane domain of hepatocytes. The particular physiological function of OAT2 in liver has been unresolved so far. Here, we have used the strategy of LC-MS difference shading to search for specific and cross-species substrates of OAT2. Heterologous expression of human and rat OAT2 in 293 cells stimulated accumulation of the zwitterion trigonelline; subsequently, orotic acid was identified as excellent and specific substrate of OAT2 from rat (clearance = 106 µl min-1 mg protein-1) and human (46 µl min-1 mg protein-1). The force driving uptake of orotic acid was identified as glutamate antiport. Efficient transport of glutamate by OAT2 was directly demonstrated by uptake of 3H-glutamate. However, because of high intracellular glutamate, OAT2 operates as glutamate efflux transporter. Thus, expression of OAT2 markedly increased release of glutamate (measured by LC-MS) from cells - even without extracellular exchange substrate. Orotic acid strongly trans-stimulated efflux of glutamate. We thus propose that OAT2 physiologically functions as glutamate efflux transporter. OAT2 mRNA was detected, after laser capture microdissection of rat liver slices, equally in periportal and pericentral regions; previous reports of hepatic release of glutamate into blood can now be explained by OAT2 activity. A specific OAT2 inhibitor could, by lowering plasma glutamate and thus promoting brain-to-blood efflux of glutamate, alleviate glutamate exotoxicity in acute brain conditions. |
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Authors:
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Christian Fork; Tim Bauer; Stefan Golz; Andreas Geerts; Jessica Weiland; Domenico Del Turco; Edgar Schömig; Dirk Gruendemann |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-3-30 |
Journal Detail:
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Title: The Biochemical journal Volume: - ISSN: 1470-8728 ISO Abbreviation: - Publication Date: 2011 Mar |
Date Detail:
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Created Date: 2011-3-30 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 2984726R Medline TA: Biochem J Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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