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The Journal of Neuroscience, June 2, 2004, 24(22):5183-5192; doi:10.1523/JNEUROSCI.0839-04.2004

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Cellular/Molecular
Identification of Motifs Involved in Endoplasmic Reticulum Retention–Forward Trafficking of the GLT-1 Subtype of Glutamate Transporter

Avtandil Kalandadze, Ying Wu, Keith Fournier, and Michael B. Robinson

Departments of Pediatrics and Pharmacology, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania 19104

Glutamate transporters may exist as homomultimers, but little is known about the mechanisms that ensure proper assembly and surface expression. In the present study, we investigated the mechanisms that contribute to posttranslational processing of the GLT-1 subtype of glutamate transporter. An extracellular leucine-based motif was identified that after mutation to alanine (6L/6A GLT-1) prevented export of GLT-1 from the endoplasmic reticulum (ER) to the plasma membrane and displayed a glycosylation pattern characteristic of "immature" transporter. This 6L/6A variant had a selective dominant-negative effect on wild-type GLT-1 expression and formed coimmunoprecipitable complexes with GLT-1. Mutation of two downstream arginine residues to alanine partially restored maturation and functional activity of the 6L/6A variant. The fact that this additional mutation rescued maturation of GLT-1 essentially excludes the possibility that the 6L/6A mutant variant is not appropriately processed because of simple misfolding. When the domain containing these motifs was introduced into a topologically similar location in the interleukin 2 receptor subunit (Tac protein), the mutations had a similar effect on protein maturation. Topological models place at least the leucine-based motif in an extracellular domain, which would face the lumen of the ER during assembly. On the basis of these data, we suggest that an evolutionarily conserved arginine-based motif functions as an ER retention signal and a lumenal leucine motif is required for suppression of this signal. Interestingly, a high percentage of variably spliced GLT-1 mRNAs lacking parts of this domain are found in the CNS, suggesting that GLT-1 expression may be regulated during assembly.

Key words: glutamate transporter; GLT-1; assembly; trafficking; ER retention; uptake

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Received March 8, 2004; revised April 20, 2004; accepted April 25, 2004.

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