title: SNAT2 amino acid transporter is regulated by amino acids of the SLC6 gamma-aminobutyric acid transporter subfamily in neocortical neurons and may play no role in delivering glutamine for glutamatergic transmission.
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.
authors.affiliation: Neuroscience Center, Louisiana State University Health Science Center, New Orleans, Louisiana 70112, USA.
authors.forename: Sukhjeevan
authors.initials: S
authors.lastname: Grewal
authors.forename: Norah
authors.initials: N
authors.lastname: Defamie
authors.forename: Xiong
authors.initials: X
authors.lastname: Zhang
authors.forename: Stéphanie
authors.initials: S
authors.lastname: De Gois
authors.forename: Ali
authors.initials: A
authors.lastname: Shawki
authors.forename: Bryan
authors.initials: B
authors.lastname: Mackenzie
authors.forename: Chu
authors.initials: C
authors.lastname: Chen
authors.forename: Hélène
authors.initials: H
authors.lastname: Varoqui
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Erickson
mesh_terms: D026924:Amino Acid Transport System A; D026905:Amino Acid Transport Systems / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D050485:GABA Plasma Membrane Transport Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D005973:Glutamine / Q000378:metabolism*; D019579:Neocortex / Q000166:cytology*; D009474:Neurons / Q000378:metabolism*; D009865:Oocytes / Q000378:metabolism; D020033:Protein Isoforms; D051381:Rats; D014982:Xenopus laevis
chemical_list: D026924:Amino Acid Transport System A; D026905:Amino Acid Transport Systems; D050485:GABA Plasma Membrane Transport Proteins; D020033:Protein Isoforms; C412568:Slc38a2 protein, rat; D005973:Glutamine