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J. Biol. Chem., Vol. 281, Issue 31, 22092-22099, August 4, 2006

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Identification of a Lithium Interaction Site in the -Aminobutyric Acid (GABA) Transporter GAT-1^*

From the Department of Biochemistry, Hebrew University Hadassah Medical School, P. O. Box 12272, Jerusalem 91120, Israel

The sodium- and chloride-dependent electrogenic -aminobutyric acid (GABA) transporter GAT-1, which transports two sodium ions together with GABA, is essential for synaptic transmission by this neurotransmitter. Although lithium by itself does not support GABA transport, it has been proposed that lithium can replace sodium at one of the binding sites but not at the other. To identify putative lithium selectivity determinants, we have mutated the five GAT-1 residues corresponding to those whose side chains participate in the sodium binding sites Na1 and Na2 of the bacterial leucine-transporting homologue LeuT_Aa. In GAT-1 and in most other neurotransmitter transporter family members, four of these residues are conserved, but aspartate 395 replaces the Na2 residue threonine 354.Atvaryingextracellularsodium,lithiumstimulatedsodiumdependent transport currents as well as [³H]GABA uptake in wild type GAT-1. The extent of this stimulation was dependent on the GABA concentration. In mutants in which aspartate 395 was replaced by threonine or serine, the stimulation of transport by lithium was abolished. Moreover, these mutants were unable to mediate the lithium leak currents. This phenotype was not observed in mutants at the four other positions, although their transport properties were severely impacted. Thus at saturating GABA, the site corresponding to Na2 behaves as a low affinity sodium binding site where lithium can replace sodium. We propose that GABA participates in the other sodium binding site, just like leucine does in the Na1 site, and that at limiting GABA, this site determines the apparent sodium affinity of GABA transport.

Received for publication, March 13, 2006 , and in revised form, June 6, 2006.

^* This work was supported by The Israel Science Foundation Grant 488/03-16.1. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 972-2-6758506; Fax: 972-2-6757379; E-mail: kannerb{at}cc.huji.ac.il.

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				A. Rosenberg and B. I. Kanner The Substrates of the {gamma}-Aminobutyric Acid Transporter GAT-1 Induce Structural Rearrangements around the Interface of Transmembrane Domains 1 and 6 J. Biol. Chem., May 23, 2008; 283(21): 14376 - 14383. [Abstract] [Full Text] [PDF]