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Rxt1, a transporter-like protein structurally related to the large family of Na(+)/Cl(-)-dependent carriers, was isolated from the rat brain. In the present study, Hxt1, the homologue of Rxt1, was isolated from human cortex cDNA. Comparison of their respective nucleotidic sequences revealed a 96% conservation between Hxt1 and Rxt1. Genetic mapping with human genome radiation hybrids allowed the location of the gene coding for Hxt1 between 323ya5 and 084xb3 AFM markers, on a portion of chromosome 1p which spans over 7 cM or 118 cRay. Northern blot analyses demonstrated that Hxt1 mRNA ( approximately 7.5 Kb) is expressed in the human brain but not in peripheral tissues. The immunodistribution of Hxt1 was determined with antibodies raised against the C-terminus of Rxt1. Hxt1 is concentrated in the cerebral cortex, caudate-putamen, substantia nigra, hippocampus, and cerebellum, appearing as a diffuse or a punctate labeling at the light microscope level. This regional and cellular distribution suggests that Hxt1, as its rat homologue, could be present in axon terminals of glutamatergic neurons. The high pressure of selection exerted upon this protein, its strategic anatomical and subcellular distributions suggest that this orphan transporter could be involved in critical functions in the central nervous system., (Copyright 1999 Wiley-Liss, Inc.)