Synaptic Vesicle Protein NTT4/XT1 (SLC6A17) Catalyzes Na+-coupled Neutral Amino Acid Transport.
The SLC6 family of structurally related, Na(+)-dependent transporter proteins is responsible for presynaptic reuptake of the majority of neurotransmitters. Within this family are a number of orphan transporters, including NTT4/XT1 (SLC6A17), a protein first identified over 15 years ago. NTT4/XT1 is expressed exclusively in the nervous system and specifically on synaptic vesicles in glutamatergic and some GABAergic neurons. Despite extensive efforts by a number of groups, no substrate has been reported for NTT4/XT1. Here we use a combination of molecular manipulations to increase expression of the NTT4/XT1 protein at the plasma membrane and to directly demonstrate that it catalyzes neutral amino acid transport. The substrate profile of the NTT4/XT1-dependent activity is similar to that of the closely related B(0)AT2/SBAT1 (SLC6A15), including a submillimolar apparent affinity for proline and leucine and a low millimolar apparent affinity for glutamine. The transport activity is Na(+)-dependent and Cl(-)-independent and is inhibited by low pH as is SLC6A15, suggesting redundant roles for these proteins. This characterization of NTT4/XT1 offers important insights into neurotransmitter metabolism as well as the mechanistic differences among the structurally related, but functionally divergent, SLC6 proteins.
Zaia
Kimberly A
KA
Department of Neurology and Neurological Sciences and Neuroscience Graduate Program, Stanford University, Stanford, California 94305, USA.
Reimer
Richard J
RJ
D026921:Amino Acid Transport Systems, Neutral / Q000235:genetics / Q000378:metabolism; D021542:Amino Acids, Neutral / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000502:physiology; D002384:Catalysis; D002460:Cell Line; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000235:genetics / Q000378:metabolism*; D016716:PC12 Cells; D050480:Plasma Membrane Neurotransmitter Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D012964:Sodium / Q000378:metabolism*; D013572:Synaptic Vesicles / Q000235:genetics / Q000378:metabolism*
D026921:Amino Acid Transport Systems, Neutral; D021542:Amino Acids, Neutral; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; D050480:Plasma Membrane Neurotransmitter Transport Proteins; C506212:SLC6A15 protein, human; C079036:Slc6a17 protein, rat; D012964:Sodium