The Evolutionary History and Tissue Mapping of Amino Acid Transporters Belonging to Solute Carrier Families SLC32, SLC36, and SLC38

Sundberg, Björn; Wååg, Elin; Jacobsson, Josefin A.; Stephansson, Olga; Rumaks, Juris; Svirskis, Šimons; Alsiö, Johan; Roman, Erika; Ebendal, Ted; Kluša, Vija; Fredriksson, Robert

doi:10.1007/s12031-008-9046-x

Cited by 72 publications

(79 citation statements)

References 37 publications

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“…Many of these members are known to be important in the brain [25] such as the vesicular inhibitory amino acid transporter (VIAAT, SLC32A1) and many of the SLC38 transporters. We recently identified five new members in the family (SLC38A7-11) [26] and all these place basal in the SLC38 family with relatively long branches.…”

Section: Resultsmentioning

confidence: 99%

The solute carrier (SLC) complement of the human genome: Phylogenetic classification reveals four major families

et al. 2008

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Solute carriers (SLCs) is the largest group of transporters, embracing transporters for inorganic ions, amino acids, neurotransmitters, sugars, purines and fatty acids among other substrates. We mined the finished assembly of the human genome using Hidden Markov Models (HMMs) obtaining a total of 384 unique SLC sequences. Detailed clustering and phylogenetic analysis of the entire SLC family showed that 15 of the families place into four large phylogenetic clusters with the largest containing eight SLC families, suggesting that many of the distinct families of SLCs have a common evolutionary origin. This study represents the first overall genomic roadmap of the SLCs providing large sequence sets and clarifies the phylogenetic relationships among the families of the second largest group of membrane proteins.

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Section: Resultsmentioning

confidence: 99%

The solute carrier (SLC) complement of the human genome: Phylogenetic classification reveals four major families

et al. 2008

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“…In the same way, most transporter proteins are also prone to phosphorylation at specific sites by PKC, and this regulates the number of proteins residing on the plasma membrane and their activity (Robinson, 2002;Wang et al, 2003;Melikian, 2004). SN1 belongs to a growing family of transporters that includes system A and system N transporters (Chaudhry et al, 2002a;Sundberg et al, 2008). A hallmark of these two systems is that they are subject to extensive adaptive, hormonal, and osmotic regulation (Collarini and Oxender, 1987;Palacín et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Protein Kinase C-Mediated Phosphorylation of a Single Serine Residue on the Rat Glial Glutamine Transporter SN1 Governs Its Membrane Trafficking

Nissen‐Meyer¹,

Popescu²,

Hamdani³

et al. 2011

J. Neurosci.

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Molecular mechanisms involved in the replenishment of the fast neurotransmitters glutamate and GABA are poorly understood. Glutamine sustains their generation. However, glutamine formation from the recycled transmitters is confined to glial processes and requires facilitators for its translocation across the glial and neuronal membranes. Indeed, glial processes are enriched with the system N transporter SN1 (Slc38a3), which, by bidirectional transport, maintains steady extracellular glutamine levels and thereby furnishes neurons with the primary precursor for fast neurotransmitters. We now demonstrate that SN1 is phosphorylated by protein kinase C␣ (PKC␣) and PKC␥. Electrophysiological characterization shows that phosphorylation reduces V max dramatically, whereas no significant effects are seen on the K m . Phosphorylation occurs specifically at a single serine residue (S52) in the N-terminal rat (Rattus norvegicus) SN1 and results in sequestration of the protein into intracellular reservoirs. Prolonged activation of PKC results in partial degradation of SN1. These results provide the first demonstration of phosphorylation of SN1 and regulation of its activity at the plasma membrane. Interestingly, membrane trafficking of SN1 resembles that of the glutamate transporter GLT and the glutamate-aspartate transporter GLAST: it involves the same PKC isoforms and occurs in the same glial processes. This suggests that the glutamate/GABA-glutamine cycle may be modified at two key points by similar signaling events and unmasks a prominent role for PKC-dependent phosphorylation. Our data suggest that extracellular glutamine levels may be fine-tuned by dynamic regulation of glial SN1 activity, which may impact on transmitter generation, contribute to defining quantal size, and have profound effects on synaptic plasticity.

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“…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).…”

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“…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, are functionally classified as sodium-coupled neutral amino acid transporters, also known as sodium-coupled amino acid transporters (SNATs). The SNAT1 (SLC38A1 (8 -9)), SNAT2 (SLC38A2 (10 -13)), and SNAT4 (SLC38A4 (14,15)) have been further classified into system A, whereas SNAT3 (SLC38A3) and SNAT5 (SLC38A5) belong to system N transporters (16 -18).…”

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Identification of SLC38A7 (SNAT7) Protein as a Glutamine Transporter Expressed in Neurons

Hägglund

Sreedharan

Nilsson

et al. 2011

Journal of Biological Chemistry

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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, ...

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The Evolutionary History and Tissue Mapping of Amino Acid Transporters Belonging to Solute Carrier Families SLC32, SLC36, and SLC38

Cited by 72 publications

References 37 publications

The solute carrier (SLC) complement of the human genome: Phylogenetic classification reveals four major families

The solute carrier (SLC) complement of the human genome: Phylogenetic classification reveals four major families

Protein Kinase C-Mediated Phosphorylation of a Single Serine Residue on the Rat Glial Glutamine Transporter SN1 Governs Its Membrane Trafficking

Identification of SLC38A7 (SNAT7) Protein as a Glutamine Transporter Expressed in Neurons

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