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

Abstract

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, ...

Neuronal vs glial glutamate uptake: Resolving the conundrum

“…After all, there are at least 14 different solute carrier proteins with the ability to transport glutamine (Bhutia and Ganapathy, 2015). For instance SNAT7 (slc38a7) and SNAT8 (slc38a7) have recently been reported to be expressed in axon-terminals (Hagglund et al, 2011;Hagglund et al, 2015). In line with this, there is electrophysiological evidence for glutamine uptake at the Calyx of Held synapse (Billups et al, 2013).…”

Brain interstitial fluid glutamine homeostasis is controlled by blood–brain barrier SLC7A5/LAT1 amino acid transporter

“…The Na þ -dependent system A transporters SLC38A1 (SNAT1) and SLC38A2 (SNAT2) expressed by neurons 12,13 participate in Gln uptake for Glu or GABA synthesis 7 ; however, some other Gln transporters were also found in neurons. [14][15][16][17] Astrocytes express a wide range of Gln transporters such as SLC1A5 (ASCT2), SCL38A2 (SNAT2), SCL38A3 (SNAT3), SLC38A5 (SNAT5), SLC7A6 (y þ LAT2), SLC7A5 (LAT1) and SLC7A8 (LAT2), 14,[18][19][20][21] although in adults ASCT2 and y þ LAT2 levels are minimal. 18,22 The abundantly expressed Na þ -dependent pH sensitive SNAT3 and SNAT5 are thought to be the main astrocytic transporters for Gln efflux to neurons for the Glu/GABAGln cycle.…”

“…The data are based on in vivo and in vitro studies. 2,3,[12][13][14][15][16][17][18][19][20][21][22][23]24 AA content was quantified and AA regulation investigated by in vivo microdialysis in freely moving mice.…”

Long-distance mechanism of neurotransmitter recycling mediated by glial network facilitates visual function in Drosophila

“…hippocampal astrocytes in connexin knockout mice are unable to clear glutamate from extracellular spaces (11); second, gap junctions in astrocytes are permeable to neurotransmitters such as glutamate and ATP (41,42); third, sodium-dependent amino acid transporter (SNAT)7, a transporter for the glutamate metabolite glutamine, is concentrated in neuronal cell bodies in mouse cortex and spinal cord (43), suggesting the involvement of neuronal cell bodies in the recycling of glutamate; fourth, a rat glycine transporter GlyT1 is found in the cell body and dendrites of hippocampal pyramidal neurons and in the cell body of retinal amacrine neurons (44). Confirming the involvement of mammalian glial networks in neurotransmitter recycling will not only advance our knowledge of glial physiology but also help us to understand the pathology of glia-involved neurological diseases.…”