Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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

Nature volume 410, pages 84–88 (2001)Cite this article

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

Data deposits

GenBank accession number for GTRAP3-18 is AF240182.

References

  1. Kanai, Y. & Hediger, M. A. Primary structure and functional characterization of a high-affinity glutamate transporter. Nature 360, 467– 471 (1992).

    Article  ADS  CAS  Google Scholar 

  2. Rothstein, J. D. et al. Localization of neuronal and glial glutamate transporters. Neuron 13, 713– 725 (1994).

    Article  CAS  Google Scholar 

  3. Rothstein, J. D. et al. Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron 16, 675– 686 (1996).

    Article  CAS  Google Scholar 

  4. He, Y., Janssen, W. G. M., Rothstein, J. D. & Morrison, J. H. Differential synaptic localization of the glutamate transporter EAAC1 and glutamate receptor subunit GluR2 in the rat hippocampus. J. Comp. Neurol. 418, 255– 269 (2000).

    Article  CAS  Google Scholar 

  5. Shayakul, C. et al. Localization of the high-affinity glutamate transporter EAAC1 in rat kidney. Am. J. Physiol. Renal Physiol. 42, F1023– F1029 (1997).

    Article  Google Scholar 

  6. Peghini, P., Janzen, J. & Stoffel, W. Glutamate transporter EAAC-1-deficient mice develop dicarboxylic aminoaciduria and behavioral abnormalities but no neurodegeneration. EMBO J. 16, 3822– 3832 (1997).

    Article  CAS  Google Scholar 

  7. Sims, K. D., Straff, D. J. & Robinson, M. B. Platelet-derived growth factor rapidly increases activity and cell surface expression of the EAAC1 subtype of glutamate transporter through activation of phosphatidylinositol 3-kinase. J. Biol. Chem. 275, 5228– 5237 (2000).

    Article  CAS  Google Scholar 

  8. Hediger, M. A. & Welbourne, T. C. Introduction: glutamate transport, metabolism, and physiological responses. Am. J. Physiol. 277, F477– F480 (1999).

    CAS  PubMed  Google Scholar 

  9. Hediger, M. A. Glutamate transporters in kidney and brain. Am. J. Physiol. 277, F487– F492 (1999).

    CAS  PubMed  Google Scholar 

  10. Lin, C. G. et al. Aberrant RNA processing in a neurodegenerative disease: The cause for absent EAAT2 a glutamate transporter, in amyotrophic lateral sclerosis. Neuron 20, 589– 602 (1998).

    Article  CAS  Google Scholar 

  11. Robinson, M. B. The family of sodium-dependent glutamate transporters: a focus on the GLT-1/EAAT2 subtype. Neurochem. Int. 33, 479– 491 (1998).

    Article  CAS  Google Scholar 

  12. Bergles, D. E. & Jahr, C. E. Synaptic activation of glutamate transporters in hippocampal astrocytes. Neuron 19, 1297– 1308 (1997).

    Article  CAS  Google Scholar 

  13. Bergles, D. E., Dzubay, J. A. & Jahr, C. E. Glutamate transporter currents in bergmann glial cells follow the time course of extrasynaptic glutamate. Proc. Natl Acad. Sci. USA 94, 14821– 14825 (1997).

    Article  ADS  CAS  Google Scholar 

  14. Diamond, J. S. & Jahr, C. E. Transporters buffer synaptically released glutamate on a submillisecond time scale. J. Neurosci. 17, 4672– 4687 (1997).

    Article  CAS  Google Scholar 

  15. Davis, K. E. et al. Multiple signaling pathways regulate cell surface expression and activity of the excitatory amino acid carrier 1 subtype of Glu transporter in C6 glioma. J. Neurosci. 18, 2475– 2485 (1998).

    Article  CAS  Google Scholar 

  16. Conti, F., DeBiasi, S., Minelli, A., Rothstein, J. D. & Melone, M. EAAC1, a high-affinity glutamate transporter, is localized to astrocytes and gabaergic neurons besides pyramidal cells in the rat cerebral cortex. Cereb. Cortex. 8, 108– 116 (1998).

    Article  CAS  Google Scholar 

  17. Sepkuty, J., Eccles, C. U., Lesser, R. P., Dykes-Hoberg, M. & Rothstein, J. D. Molecular knockdown of neuronal glutamate transporter EAAT3 produces epilepsy and dysregulation of GABA metabolism. Soc. Neurosci. Abstracts 23, 1484 (1997).

    Google Scholar 

  18. Lin, C. L. G. et al. Molecular cloning and expression of the rat EAAT4 glutamate transporter subtype. Mol. Brain Res. 63, 174– 179 (1998).

    Article  CAS  Google Scholar 

  19. Furuta, A., Martin, L. J., Lin, C. L. G., Dykes-Hoberg, M. & Rothstein, J. D. Cellular and synaptic localization of the neuronal glutamate transporters excitatory amino acid transporter 3 and 4. Neuroscience 81, 1031– 1042 (1997).

    Article  CAS  Google Scholar 

Download references

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.

Author information

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

Authors
  1. Chien-liang Glenn Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Irina Orlov
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alicia M. Ruggiero
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Margaret Dykes-Hoberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Andy Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mandy Jackson
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jeffrey D. Rothstein
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jeffrey D. Rothstein.

Supplementary information

Supplementary Figure

Supplementary Information

Supplementary Information (PDF 14 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/35065084

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing