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J. Biol. Chem., Vol. 278, Issue 26, 23720-23730, June 27, 2003

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Functional Properties and Cellular Distribution of the System A Glutamine Transporter SNAT1 Support Specialized Roles in Central Neurons^*

Bryan Mackenzie , Martin K.-H. Schäfer , Jeffrey D. Erickson ¶ || , Matthias A. Hediger , Eberhard Weihe  and Hélène Varoqui ¶ ** 

From the Membrane Biology Program and Renal Division, Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, the Department of Molecular Neuroscience, Institute of Anatomy and Cell Biology, Philipps University Marburg, D-35033 Marburg, Germany, and the ^¶Neuroscience Center and the Departments of ^||Pharmacology and ^**Ophthalmology, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112

Glutamine, the preferred precursor for neurotransmitter glutamate and GABA, is likely to be the principal substrate for the neuronal System A transporter SNAT1 in vivo. We explored the functional properties of SNAT1 (the product of the rat Slc38a1 gene) by measuring radiotracer uptake and currents associated with SNAT1 expression in Xenopus oocytes and determined the neuronal-phenotypic and cellular distribution of SNAT1 by confocal laser-scanning microscopy alongside other markers. We found that SNAT1 mediates transport of small, neutral, aliphatic amino acids including glutamine (K_0.5 0.3 mM), alanine, and the System A-specific analogue 2-(methylamino)isobutyrate. Amino acid transport is driven by the Na⁺ electrochemical gradient. The voltage-dependent binding of Na⁺ precedes that of the amino acid in a simultaneous transport mechanism. Li⁺ (but not H⁺) can substitute for Na⁺ but results in reduced V_max. In the absence of amino acid, SNAT1 mediates Na⁺-dependent presteady-state currents (Q_max 9 nC) and a nonsaturable cation leak with selectivity Na⁺, Li⁺ » H⁺, K⁺. Simultaneous flux and current measurements indicate coupling stoichiometry of 1 Na⁺ per 1 amino acid. SNAT1 protein was detected in somata and proximal dendrites but not nerve terminals of glutamatergic and GABAergic neurons throughout the adult CNS. We did not detect SNAT1 expression in astrocytes but detected its expression on the luminal membranes of the ependyma. The functional properties and cellular distribution of SNAT1 support a primary role for SNAT1 in glutamine transport serving the glutamate/GABA-glutamine cycle in central neurons. Localization of SNAT1 to certain dopaminergic neurons of the substantia nigra and cholinergic motoneurons suggests that SNAT1 may play additional specialized roles, providing metabolic fuel (via -ketoglutarate) or precursors (cysteine, glycine) for glutathione synthesis.

Received for publication, December 13, 2002 , and in revised form, March 19, 2003.

^* This research was supported by Grants NSF/LEQSF (2001-04)-RII-01 (to H. V.) from the National Science Foundation, 1P29RR16816 (to H. V.), and NS36936 (to J. D. E.) from the National Institutes of Health, and SFB 297 and BMB+F (to E. W. and M. K.-H. S.) from the German Research Foundation. 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.

To whom correspondence may be addressed: Neuroscience Center, University of Louisiana Health Sciences Center, 2020 Gravier St., Suite D, New Orleans, LA 70112. E-mail: hvaroq{at}lsuhsc.edu or jerick{at}lsuhsc.edu.

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