Abstract
Kinetics of glial glutamine (GLN) transport to the extracellular fluid (ECF) and the mechanism of GLN(ECF) transport into the neuron--crucial pathways in the glutamine-glutamate cycle--were studied in vivo in mildly hyperammonemic rat brain, by NMR and microdialysis to monitor intra- and extracellular GLN. The minimum rate of glial GLN efflux, determined from the rate of GLN(ECF) increase during perfusion of alpha-(methylamino)isobutyrate (MeAIB), which inhibits neuronal GLN(ECF) uptake by sodium-coupled amino-acid transporter (SAT), was 2.88 +/- 0.22 micromol/g/h at steady-state brain [GLN] of 8.5 +/- 0.8 micromol/g. Our previous study showed that the rate of glutamine synthesis under identical experimental conditions was 3.3 +/- 0.3 micromol/g/h. At steady-state glial [GLN], this is equal to its efflux rate to the ECF. Comparison of the two rates suggests that SAT mediates at least 87 +/- 8% (= 2.88/3.3 x 100%) of neuronal GLN(ECF) uptake. While MeAIB induced > 2-fold elevation of GLN(ECF), no sustained elevation was observed during perfusion of the selective inhibitor of LAT, 2-amino-bicyclo[1,1,2]heptane-2-carboxylic acid (BCH), or of d-threonine, a putative selective inhibitor of ASCT2-mediated GLN uptake. The results strongly suggest that SAT is the predominant mediator of neuronal GLN(ECF) uptake in adult rat brain in vivo.
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