Abstract
System A transporters SNAT1 and SNAT2 mediate uptake of neutral alpha-amino acids (e.g. glutamine, alanine, and proline) and are expressed in central neurons. We tested the hypothesis that SNAT2 is required to support neurotransmitter glutamate synthesis by examining spontaneous excitatory activity after inducing or repressing SNAT2 expression for prolonged periods. We stimulated de novo synthesis of SNAT2 mRNA and increased SNAT2 mRNA stability and total SNAT2 protein and functional activity, whereas SNAT1 expression was unaffected. Increased endogenous SNAT2 expression did not affect spontaneous excitatory action-potential frequency over control. Long term glutamine exposure strongly repressed SNAT2 expression but increased excitatory action-potential frequency. Quantal size was not altered following SNAT2 induction or repression. These results suggest that spontaneous glutamatergic transmission in pyramidal neurons does not rely on SNAT2. To our surprise, repression of SNAT2 activity was not limited to System A substrates. Taurine, gamma-aminobutyric acid, and beta-alanine (substrates of the SLC6 gamma-aminobutyric acid transporter family) repressed SNAT2 expression more potently (10x) than did System A substrates; however, the responses to System A substrates were more rapid. Since ATF4 (activating transcription factor 4) and CCAAT/enhancer-binding protein are known to bind to an amino acid response element within the SNAT2 promoter and mediate induction of SNAT2 in peripheral cell lines, we tested whether either factor was similarly induced by amino acid deprivation in neurons. We found that glutamine and taurine repressed the induction of both transcription factors. Our data revealed that SNAT2 expression is constitutively low in neurons under physiological conditions but potently induced, together with the taurine transporter TauT, in response to depletion of neutral amino acids.
Highlights
Central neurons express the sodium-coupled neutral amino acid transporters SNAT1 and SNAT2 [1,2,3,4,5,6,7,8,9,10], two of the three SLC38 gene family members that collectively account for the System A amino acid transport activity classically described in most cell types [12, 13]
Adaptive Regulation of the Taurine Transporter TauT Is Repressed by Taurine and Glutamine—Since transported substrates of the amino acid osmolyte transporters within the SLC6 GABA transporter subfamily are potent repressors of SNAT2, we examined whether GABA transporters or the taurine transporter (TauT) exhibit adaptive regulation following ϪAA treatment in neurons and assessed the effectiveness of System
Adaptive Regulation of SNAT2 mRNA Expression by Amino Acid Deprivation in Neurons Is Not Selective for System A Substrates—We have demonstrated for the first time that SNAT2 is subject to adaptive regulation following total amino acid deprivation in neurons and that such adaptive regulation of SNAT2 is not limited to the effects of System A substrates
Summary
Central neurons express the sodium-coupled neutral amino acid transporters SNAT1 and SNAT2 ( known as SLC38A1, GlnT, SAT1, or ATA1 and SLC38A2, SAT2, or ATA2, respectively) [1,2,3,4,5,6,7,8,9,10], two of the three SLC38 gene family members (reviewed in Ref. 11) that collectively account for the System A amino acid transport activity classically described in most cell types [12, 13]. Reexamination of the Substrate Profile of System A—Since 8-h refeeding with taurine resulted in the disappearance of SNAT2 mRNA and protein expression (Fig. 6, A and B) and System A functional activity (Fig. 6C), we reexamined the gamut of amino acids capable of adaptively regulating System A in neurons.
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