Cell‐specific expression of the glutamine transporter SN1 suggests differences in dependence on the glutamine cycle

Abstract

Glutamine is involved in a variety of metabolic processes, including recycling of the neurotransmitters glutamate and gamma-aminobutyric acid (GABA). The system N transporter SN1 mediates efflux as well as influx of glutamine in glial cells [Chaudhry et al. (1999), Cell, 99, 769-780]. We here report qualitative and quantitative data on SN1 protein expression in rat. The total tissue concentrations of SN1 in brain and in kidney are half and one-quarter, respectively, of that in liver, but the average concentration of SN1 could be higher in astrocytes than in hepatocytes. Light and electron microscopic immunocytochemistry shows that glutamatergic, GABAergic and, surprisingly, purely glycinergic boutons are ensheathed by astrocytic SN1 laden processes, indicating a role of glutamine in the production of all three rapid transmitters. A dedication of SN1 to neurotransmitter recycling is further supported by the lack of SN1 immunoreactivity in oligodendrocytes (cells rich in glutamine but without perisynaptic processes). All neuronal structures appear unlabelled implying that a different protein mediates glutamine uptake into nerve endings. In several regions, SN1 immunoreactivity is higher in association with GABAergic than glutamatergic synapses, in agreement with observations that exogenous glutamine increases output of transmitter glutamate but not GABA. Nerve terminals with low transmitter reuptake or high prevailing firing frequency are associated with high SN1 immunoreactivity in adjacent glia. Bergmann glia and certain other astroglia contain very low levels of SN1 immunoreactivity compared to most astroglia, including retinal Müller cells, indicating the possible existence of SN isoforms and alternative mechanisms for transmitter recycling.

Loss of function mutation of the Slc38a3 glutamine transporter reveals its critical role for amino acid metabolism in the liver, brain, and kidney

“…SNAT3 is highly expressed in brain astrocytes, and is believed to play a role in the glutamate-glutamine cycle involved in neurotransmission [5,15,22]. The lethargy and an altered, uncoordinated gait observed in mutant mice suggested impaired neurotransmission after Snat3 deletion in brain.…”

“…have been hypothesized to be responsible for the efflux of glutamine from astrocytes which is a crucial step in the recycling of glutamate and GABA neurotransmitters between astrocytes and neurons [5,22]. In the liver, SNAT3 is likely to be a candidate for both periportal uptake and perivenous efflux of glutamine, which is essential for the detoxification of ammonia delivered via the portal blood and excreted as urea [6,21].…”

Methylmercury induces oxidative injury, alterations in permeability and glutamine transport in cultured astrocytes

“…The molecular bases of Gln passage across the astrocytic membrane and neuronal plasma membranes have been investigated extensively over the last few years [12,20,44]. Gln efflux from astrocytes appears to be mediated by sodium-coupled neutral amino acid transporter 3 (SNAT3, SN1), a system N amino acid transporter that is localized to perisynaptic astrocytes and specifically accepts only glutamine, histidine and asparagine [13,19,21]. Gln uptake into neurons is mediated by sodium-dependent transporters of the system A family, two of which, SNAT1 (GlnT, SAT1, ATA1, SA2) and SNAT2 (SAT2, ATA2), are thought to be capable of affecting Glu and/or GABA recycling, and, thereby, synaptic function.…”

Expression of glutamine transporter isoforms in cerebral cortex of rats with chronic hepatic encephalopathy

“…SN1 was the first isoform characterized and it has been described as the primary transporter responsible for the release of glutamine from astrocytes. It preferentially transports glutamine, promoting its efflux under physiological concentrations of this amino acid (~400 μM) (Boulland et al, 2002;Chaudhry et al, 1999). One important property of this amino acid transporter is its capacity of flux reversal, which is dependent on pH and also on the extracellular Na + concentration, i.e.…”

“…The importance of this transporter in relation to the glutamate/GABA-glutamine cycle is highlighted by the observation that exogenous glutamate mediates a decrease in the Km for SN1 in astrocyte cultures (Bröer et al, 2004). Similarly, the SN2 isoform is also functionally related to glutamine efflux from astrocytes, although it also releases glycine serving as a co-transmitter at NMDA receptors Hamdani et al, 2012).With respect to the CNS localization of these transporters, SN1 has been shown to be confined to astroglial processes ensheathing glutamatergic and GABAergic synapses in different brain structures (Boulland et al, 2002;Chaudhry et al, 1999), while SN2 has also been found in astrocytes predominantly close to glutamatergic synapses .…”