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Modulation of the neuronal glutamate transporter EAAC1 by the interacting protein GTRAP3-18

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Abstract

Excitatory amino-acid carrier 1 (EAAC1) is a high-affinity Na+-dependent l-glutamate/d, l-aspartate cell-membrane transport protein1. It is expressed in brain as well as several non-nervous tissues. In brain, EAAC1 is the primary neuronal glutamate transporter2,3. It has a polarized distribution in cells and mainly functions perisynaptically to transport glutamate from the extracellular environment2,3,4. In the kidney it is involved in renal acidic amino-acid re-absorption and amino-acid metabolism5,6,7. Here we describe the identification and characterization of an EAAC1-associated protein, GTRAP3-18. Like EAAC1, GTRAP3-18 is expressed in numerous tissues8,9. It localizes to the cell membrane and cytoplasm, and specifically interacts with carboxy-terminal intracellular domain of EAAC1. Increasing the expression of GTRAP3-18 in cells reduces EAAC1-mediated glutamate transport by lowering substrate affinity. The expression of GTRAP3-18 can be upregulated by retinoic acid, which results in a specific reduction of EAAC1-mediated glutamate transport. These studies show that glutamate transport proteins can be regulated potently and that GTRAP can modulate the transport functions ascribed to EAAC1. GTRAP3-18 may be important in regulating the metabolic function of EAAC1.

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Figure 1: GTRAP3-18 interacts with EAAC1 in vitro and in vivo.
Figure 2: Tissue and cellular distribution of GTRAP3-18 protein and mRNA.
Figure 3: GTRAP3-18 negatively modulates EAAC1-mediated glutamate transport.
Figure 4: Retinoic acid upregulates GTRAP3-18 expression and consequently inhibits EAAC1 transport in HEK293 cells in brain.

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GenBank/EMBL/DDBJ

Data deposits

GenBank accession number for GTRAP3-18 is AF240182.

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Acknowledgements

We thank R. Huganir for the pRK5 vector; J. Sepkuty, R. Ganel, and W. Song for helpful suggestions and discussions; and L. Jin, C. Coccia and B. Kim for technical support.

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Author notes

  1. Chien-liang Glenn Lin and Irina Orlov: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Neurology and Neuroscience, Johns Hopkins University, Meyer 6-109, 600 North Wolfe Street, Baltimore, 21287, Maryland, USA

    Chien-liang Glenn Lin, Irina Orlov, Alicia M. Ruggiero, Margaret Dykes-Hoberg, Andy Lee, Mandy Jackson & Jeffrey D. Rothstein

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  1. Chien-liang Glenn Lin
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  2. Irina Orlov
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  3. Alicia M. Ruggiero
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  7. Jeffrey D. Rothstein
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Correspondence to Jeffrey D. Rothstein.

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Lin, Cl., Orlov, I., Ruggiero, A. et al. Modulation of the neuronal glutamate transporter EAAC1 by the interacting protein GTRAP3-18. Nature 410, 84–88 (2001). https://doi.org/10.1038/35065084

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