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A more recent version of this article appeared on March 9, 2007
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M609720200v1
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Papers In Press, published online ahead of print January 8, 2007
J. Biol. Chem, 10.1074/jbc.M609720200
Submitted on October 16, 2006
Revised on December 7, 2006
Accepted on January 8, 2007

Concentrative export from the ER of the GABA-transporter 1 requires binding to SEC24D

Hesso Farhan, Veronika Reiterer, Vladimir M. Korkhov, Johannes A. Schmid, Michael Freissmuth, and Harald H. Sitte

Pharmacology, University of Vienna, Vienna A-1090

Corresponding Author: michael.freissmuth{at}meduniwien.ac.at

Re-uptake of GABA into presynaptic specializations is mediated by the GABA transporter 1 (GAT1), a member of the SLC6 gene family. Here, we show that a motif in the C-terminus of GAT1 (566RL567), which is conserved in SLC6 family members, is a binding site for the COPII coat component Sec24D. We also identified residues in Sec24D (733DD734) that are required to support the interaction with GAT1 and two additional family members, i.e. the transporters for serotonin and dopamine. We used three strategies to prevent recruitment of Sec24D to GAT1: knock-down of Sec24D by RNA interference, overexpression of Sec24D-VN (replacement of 733DD734 by 733VN734) and mutation of 566RL567 to 566AS567(GAT1-RL/AS). In each instance, ER export of GAT1 was impaired: in the absence of Sec24D or upon coexpression of dominant negative Sec24D-VN, GAT1 failed to undergo concentrative ER export; GAT1-RL/AS also accumulated in the ER and exerted a dominant negative effect on cell surface targeting of wild type GAT1. Our observations show that concentrative ER-export is contingent on a direct interaction of GAT1 with Sec24D; this also provides a mechanistic explanation for the finding that oligomeric assembly of transporters is required for their ER export: transporter oligomerization supports efficient recruitment of COPII components.




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