The SLC38 family of transporters has in total 11 members in humans and they encode amino acid transporters called sodium-coupled amino acid transporters (SNAT). To date, five SNATs have been characterized and functionally subdivided into systems A (SLC38A1, SLC38A2, and SLC38A4) and N (SLC38A3 and SLC38A5) showing the highest transport for glutamine and alanine. Here we present identification of a novel glutamine transporter encoded by the Slc38a7 gene, which we propose should be named SNAT7. This transporter has L-glutamine as the preferred substrate but also transports other amino acids with polar side chains, as well as L-histidine and L-alanine. The expression pattern and substrate profile for SLC38A7 shows highest similarity to the known system N transporters. Therefore, we propose that SLC38A7 is a novel member of this system. We used in situ hybridization and immunohistochemistry with a custom-made antibody to show that SLC38A7 is expressed in all neurons, but not in astrocytes, in the mouse brain. SLC38A7 is unique in being the first system N transporter expressed in GABAergic and also other neurons. The preferred substrate and axonal localization of SLC38A7 close to the synaptic cleft indicates that SLC38A7 could have an important function for the reuptake and recycling of glutamate.Solute carriers (SLCs), 3 are the largest group of transporters in the human genome (1, 2). Many of the SLCs are coupled transporters with important functions in cellular processes, including roles as transporters for amino acids and neurotransmitter cycling, whereas others are passive transporters or exchangers (2-4). It has been suggested that there are close to 100 SLC transporters for amino acids in the human genome, of these around 60 have been characterized regarding substrate and the rest are postulated as probable amino acid transporters (5). This large number indicates the importance of having a regulated membrane transport of amino acids over the cell membrane as well as over mitochondrial and vesicular membranes. The SLCs have been categorized into at least 46 different families with varied biochemical properties (5) and recently two more families have been identified (6). In mammals, phylogenetic classification of SLCs show that the SLC proteins form four major phylogenetic groups, termed ␣, ␤, ␥, and ␦, with proteins in each group having a common evolutionary origin. The ␤-group includes the SLC32, SLC36, and SLC38 families and is the second largest phylogenetic cluster of amino acid transporters. Some members of the ␤-group are known to be expressed in the brain and most are located in the plasma membrane, whereas SLC32A1 is found in neuronal vesicles. Yet, others are still orphans and very little is known about their tissue distribution, functional characteristics, or substrate specificity (5, 7).The SLC38 family consists of 11 members. The orphans SLC38A7-11 were only recently identified and have thus far not been characterized regarding their substrate of transport (7), whereas the other members, SLC38A1-6, ...

BackgroundTMEM18 is a hypothalamic gene that has recently been linked to obesity and BMI in genome wide association studies. However, the functional properties of TMEM18 are obscure.MethodsThe evolutionary history of TMEM18 was inferred using phylogenetic and bioinformatic methods. The gene's expression profile was investigated with real-time PCR in a panel of rat and mouse tissues and with immunohistochemistry in the mouse brain. Also, gene expression changes were analyzed in three feeding-related mouse models: food deprivation, reward and diet-induced increase in body weight. Finally, we genotyped 502 severely obese and 527 healthy Swedish children for two SNPs near TMEM18 (rs6548238 and rs756131).ResultsTMEM18 was found to be remarkably conserved and present in species that diverged from the human lineage over 1500 million years ago. The TMEM18 gene was widely expressed and detected in the majority of cells in all major brain regions, but was more abundant in neurons than other cell types. We found no significant changes in the hypothalamic and brainstem expression in the feeding-related mouse models. There was a strong association for two SNPs (rs6548238 and rs756131) of the TMEM18 locus with an increased risk for obesity (p = 0.001 and p = 0.002).ConclusionWe conclude that TMEM18 is involved in both adult and childhood obesity. It is one of the most conserved human obesity genes and it is found in the majority of all brain sites, including the hypothalamus and the brain stem, but it is not regulated in these regions in classical energy homeostatic models.

BackgroundThe SLC17 family of transporters transports the amino acids: glutamate and aspartate, and, as shown recently, also nucleotides. Vesicular glutamate transporters are found in distinct species, such as C. elegans, but the evolutionary origin of most of the genes in this family has been obscure.ResultsOur phylogenetic analysis shows that the SLC17 family consists of four main phylogenetic clades which were all present before the divergence of the insect lineage. One of these clades has not been previously described and it is not found in vertebrates. The clade containing Slc17a9 had the most restricted evolutionary history with only one member in most species. We detected expression of Slc17a1-17a4 only in the peripheral tissues but not in the CNS, while Slc17a5- Slc17a9 are highly expressed in both the CNS and periphery.ConclusionsThe in situ hybridization studies on vesicular nucleotide transporter revealed high expression throughout the cerebral cortex, certain areas in the hippocampus and in specific nuclei of the hypothalamus and thalamus. Some of the regions with high expression, such as the medial habenula and the dentate gyrus of the hippocampus, are important sites for purinergic neurotransmission. Noteworthy, other areas relying on purine-mediated signaling, such as the molecular layer of the dentate gyrus and the periaqueductal gray, lack or have a very low expression of Slc17a9, suggesting that there could be another nucleotide transporter in these regions.

DJ-1 is a ubiquitous protein regulating cellular viability. Recessive mutations in the PARK7/DJ-1 gene are linked to Parkinson's disease (PD). Although the most dramatic L166P point mutation practically eliminates DJ-1 protein and function, the effects of other PD-linked mutations are subtler. Here, we investigated two recently described PD-associated DJ-1 point mutations, the A179T substitution and the P158D in-frame deletion.[A179T]DJ-1 protein was as stable as wildtype [wt]DJ-1, but the P158D mutant protein was less stable. In accord with the notion that dimer formation is essential for DJ-1 protein stability, [P158D]DJ-1 was impaired in dimer formation. Similar to our previous findings for [M26I]DJ-1, [P158D]DJ-1 bound aberrantly to apoptosis signal-regulating kinase 1. Thus, the PD-associated P158D mutation destabilizes DJ-1 protein and function. As there is also evidence for an involvement of DJ-1 in multiple system atrophy, a PDrelated a-synucleinopathy characterized by oligodendroglial cytoplasmic inclusions, we studied an oligodendroglial cell line stably expressing a-synuclein. a-Synuclein aggregate dependent microtubule retraction upon co-transfection with tubulin polymerization-promoting protein p25a was ameliorated by [wt]DJ-1. In contrast, DJ-1 mutants including P158D failed to protect in this system, where we found evidence of apoptosis signal-regulating kinase 1 (ASK1) involvement. In conclusion, the P158D point mutation may contribute to neurodegeneration by protein destabilization and hence loss of DJ-1 function.