SLC6A15

SLC6A15 (B0AT2) is a sodium-dependent neutral amino acid transporter expressed predominantly in neurons that supplies branched-chain amino acids, methionine, proline, and phenylalanine to the intracellular compartment, thereby coupling amino acid availability to glutamatergic neurotransmission, redox homeostasis, and stress-related behavior. Heterologous expression and knockout studies establish its preference for leucine, isoleucine, valine, and methionine (K0.5 80–160 µM), with transport that is temperature-sensitive, inhibited at acidic pH, and downregulated by PKC-mediated reduction of surface expression (PMID:16226721, PMID:17931606). In the hippocampus, SLC6A15 loss reduces tissue glutamate and glutamine yet raises extracellular glutamate, decreases glutamate release probability, alters GluR1 expression, and modulates anxiety- and depressive-like behaviors, while cell-type-specific manipulation in nucleus accumbens D2-medium spiny neurons bidirectionally controls stress susceptibility (PMID:26228428, PMID:26585320, PMID:28576941, PMID:33007132). Outside the brain, SLC6A15 transports phenylalanine into melanocytes to support melanin synthesis and is transcriptionally upregulated by UVB (PMID:41352278).

1. 2000 Low

   Establishing that SLC6A15 encodes a 12-transmembrane-domain SLC6-family protein that reaches the plasma membrane resolved its topology and set the stage for functional transport studies.

   Evidence Epitope-tagged expression with immunofluorescence in transfected cells

   PMID:11112352

   Open questions at the time

   • No transport activity measured; surface localization based on single tagged construct without endogenous validation
   • Glycosylation sites predicted but functional significance untested
2. 2005 High

   Defining SLC6A15 as a Na+-coupled transporter selective for branched-chain amino acids and methionine, with PKC-regulated surface expression, established its substrate profile and a first regulatory mechanism.

   Evidence Radiolabeled uptake in Xenopus oocytes with kinetic, pH, temperature, and PKC analyses

   PMID:16226721

   Open questions at the time

   • Structural basis for substrate selectivity unknown
   • PKC-mediated internalization pathway not delineated
3. 2007 High

   Demonstrating reduced synaptosomal proline and leucine uptake in Slc6a15-knockout mice proved that SLC6A15 contributes substantially to neutral amino acid transport at synapses in vivo.

   Evidence Slc6a15 KO mice with synaptosomal radiolabeled amino acid uptake

   PMID:17931606

   Open questions at the time

   • Residual uptake indicates redundant transporters not identified
   • Regional heterogeneity of contribution not mapped
4. 2013 High

   Showing that SLC6A15 knockout attenuates leucine-induced anorexia and VMH neuronal activation, and that coding variants alter transport activity, connected SLC6A15 to nutrient sensing and demonstrated functional significance of human genetic variation.

   Evidence KO mice with ICV leucine injection, food intake, c-Fos IHC; cellular 3H-proline uptake with variant constructs

   PMID:23505546 PMID:23874702 PMID:24023709

   Open questions at the time

   • Downstream signaling from leucine sensing in VMH not characterized
   • Coding variants not tested in vivo
5. 2015 High

   Bidirectional manipulation of hippocampal SLC6A15 revealed that it controls tissue glutamate/glutamine levels, extracellular glutamate tone, and GluR1 expression, linking its transport function to glutamatergic circuit modulation and anxiety/stress behavior.

   Evidence Slc6a15 KO and viral overexpression with HPLC, NMR, microdialysis, behavioral tests, and Western blot

   PMID:26228428 PMID:26585320

   Open questions at the time

   • Mechanism connecting neutral amino acid import to glutamate pool regulation not fully delineated
   • GluR1 regulation could be indirect
6. 2017 High

   Cell-type-specific manipulation in NAc D2-medium spiny neurons demonstrated that SLC6A15 in this specific circuit node bidirectionally controls social stress susceptibility, placing the transporter in a defined neural circuit for stress resilience.

   Evidence Cre-inducible viral KD/OE in D2-Cre and A2A-Cre mice with social defeat paradigm

   PMID:28576941

   Open questions at the time

   • Amino acid changes in D2-MSNs upon manipulation not measured
   • Whether glutamatergic mechanism generalizes from hippocampus to NAc untested
7. 2020 Medium

   In primary hippocampal neurons, SLC6A15 loss reduced glutamate release probability, enhanced mitochondrial function, shifted redox balance, and promoted neurite outgrowth, revealing pleiotropic neuronal consequences of altered amino acid import.

   Evidence KO hippocampal neurons with electrophysiology, Seahorse assay, glutathione quantification, and morphometry

   PMID:33007132

   Open questions at the time

   • Causal chain from amino acid depletion to mitochondrial and redox changes not resolved
   • In vivo relevance of neurite outgrowth phenotype unclear
8. 2025 Medium

   Discovery that SLC6A15 transports phenylalanine into melanocytes to support melanogenesis expanded its physiological role beyond the CNS, showing it drives MITF/TYR/DCT expression and UVB-induced pigmentation.

   Evidence siRNA KD in MNT1 cells and primary melanocytes with melanin, phenylalanine, and gene expression assays

   PMID:41352278

   Open questions at the time

   • Whether phenylalanine effect is direct or via tyrosine conversion not distinguished
   • In vivo pigmentation phenotype in Slc6a15 KO mice not reported

• The structural basis for SLC6A15 substrate selectivity, the precise metabolic pathway linking neutral amino acid import to glutamate pool regulation, and the therapeutic potential of selective SLC6A15 inhibitors in stress-related disorders remain to be established.
• No crystal or cryo-EM structure available
• Metabolic flux from imported amino acids to glutamate/glutamine not traced
• Selective inhibitors validated only in vitro and in primary neurons (preprint)