{"gene":"SLC6A15","run_date":"2026-06-10T07:46:34","timeline":{"discoveries":[{"year":2005,"finding":"SLC6A15 (SBAT1) functions as a sodium-coupled transporter of hydrophobic, zwitterionic alpha-amino and imino acids when expressed in Xenopus oocytes, with strong preference for branched-chain amino acids (leucine, isoleucine, valine) and methionine (K0.5 80-160 µM); it excludes aromatic or charged amino acids, beta-amino acids, glycine, and GABA. Transport is highly temperature-dependent (Q10=9) and inhibited at acidic pH. PKC activation reduces the plasma-membrane population of SBAT1 protein.","method":"Xenopus oocyte heterologous expression, radiolabeled substrate uptake assays, pharmacological manipulation (PKC activation)","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro transport reconstitution in Xenopus oocytes with multiple substrate specificity assays, kinetic characterization, and PKC functional experiment; replicated by subsequent studies","pmids":["16226721"],"is_preprint":false},{"year":2007,"finding":"In cortical synaptosomes from v7-3 (SLC6A15) knockout mice, sodium-dependent proline uptake was reduced by 15% and leucine uptake by 40% compared to wild-type controls, establishing SLC6A15 as a contributor to synaptosomal proline and leucine transport in vivo.","method":"SLC6A15 knockout mouse model; radiolabeled amino acid uptake into cortical synaptosomes","journal":"Brain research","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic KO with direct biochemical measurement of transporter substrate uptake; consistent with in vitro transport data from oocyte studies","pmids":["17931606"],"is_preprint":false},{"year":2000,"finding":"Human v7-3 (SLC6A15) encodes a 730 amino acid protein with 12 predicted transmembrane domains, intracellular N- and C-termini, and large extracellular loops between TM3-4 and TM7-8 with N-linked glycosylation sites; transfection experiments showed v7-3 is expressed at the cell surface (plasma membrane localization), in contrast to the related NTT5 which is predominantly intracellular.","method":"Epitope-tagged transporter construct transfection, subcellular localization by cellular imaging/fractionation; bioinformatic topology prediction","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization by transfection and imaging, single lab, surface vs. intracellular distinction established experimentally","pmids":["11112352"],"is_preprint":false},{"year":2013,"finding":"SLC6A15 knockout mice show lower reduction in food intake and lower neuronal activation in the ventromedial hypothalamic nucleus (VMH) in response to intracerebroventricular leucine injections compared to wild-type mice, establishing SLC6A15 as mediating the anorexigenic effect of leucine in the brain. B0AT2 (SLC6A15) immunoreactivity was found in neurons (including GABAergic neurons and spinal cord motor neurons) and in astrocytes near ventricles, and co-localized with cytokeratin and diazepam binding inhibitor (DBI) in choroid plexus epithelial cells.","method":"Slc6a15 knockout mice, food intake assay with leucine injection, c-Fos neuronal activation immunohistochemistry, immunohistochemistry and in situ hybridization for tissue distribution","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO with functional behavioral readout (food intake) plus neuronal activation assay and detailed localization; single lab but multiple orthogonal methods","pmids":["23505546"],"is_preprint":false},{"year":2013,"finding":"SLC6A15 knockout attenuates leucine's ability to reduce normal chow intake and weight gain on high-fat diet in a sex-selective fashion in mice, supporting a role for brain SLC6A15 in leucine-mediated control of food intake and obesity-related phenotypes.","method":"Slc6a15 knockout mice, dietary feeding assays with leucine supplementation, body weight measurement","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with specific functional phenotype (leucine-induced anorexia abolished), single lab","pmids":["24023709"],"is_preprint":false},{"year":2015,"finding":"Loss of SLC6A15 in knockout mice reduces hippocampal tissue levels of proline and other neutral amino acids, decreases overall tissue glutamate and glutamine, while simultaneously increasing basal extracellular glutamate tone. Conversely, hippocampal SLC6A15 overexpression increases glutamate/glutamine tissue concentrations. These neurochemical changes were linked to altered sensorimotor gating behavior.","method":"Slc6a15 knockout mice; virus-mediated hippocampal overexpression; hippocampal amino acid measurement (HPLC/NMR); in vivo microdialysis for extracellular glutamate; prepulse inhibition behavioral test","journal":"Journal of psychiatric research","confidence":"High","confidence_rationale":"Tier 2 / Strong — bidirectional genetic manipulation (KO and OE) with direct neurochemical measurements and behavioral readout, multiple orthogonal methods","pmids":["26228428"],"is_preprint":false},{"year":2015,"finding":"Slc6a15 knockout mice show reduced anxiety- and depressive-like behavior following chronic social stress compared to wild-type littermates, while hippocampal SLC6A15 overexpression increases anxiety-like behavior at baseline. GluR1 (AMPA receptor subunit) expression in the dentate gyrus, but not GluR2 or NR1, is regulated by slc6a15 expression levels, implicating glutamatergic signaling as a downstream mechanism.","method":"Slc6a15 KO and virus-mediated hippocampal overexpression mouse models; chronic social stress paradigm; anxiety/depression behavioral tests; immunoblot for GluR1, GluR2, NR1 in dentate gyrus","journal":"Stress (Amsterdam, Netherlands)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional genetic manipulation with behavioral phenotyping and molecular endpoint (GluR1), single lab","pmids":["26585320"],"is_preprint":false},{"year":2017,"finding":"Cre-inducible viral reduction of Slc6a15 selectively in NAc D2-medium spiny neurons (using D2-Cre and A2A-Cre mice) causes enhanced susceptibility to subthreshold social defeat stress, while restoring Slc6a15 expression in D2-neurons after chronic social defeat stress prevents social avoidance. Slc6a15 protein was unaltered in ChAT interneurons after chronic social defeat stress, indicating the effect is D2-MSN-specific.","method":"Cre-inducible viral vectors in D2-Cre and A2A-Cre mice; chronic and subthreshold social defeat stress; social interaction behavioral testing; immunofluorescence for Slc6a15 protein in ChAT interneurons","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific bidirectional genetic manipulation with defined behavioral phenotype and protein-level localization data; multiple Cre lines used for validation","pmids":["28576941"],"is_preprint":false},{"year":2013,"finding":"Two rare non-synonymous coding variants in SLC6A15 were associated with significantly increased maximal [3H]proline uptake compared to the wildtype sequence in a cellular uptake assay, demonstrating that specific amino acid changes can alter transporter activity.","method":"Cellular [3H]proline uptake assay with wildtype vs. mutant SLC6A15 constructs; pooled targeted re-sequencing and individual re-genotyping","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional assay with mutagenesis, single lab, but only rare variants with no case-control association","pmids":["23874702"],"is_preprint":false},{"year":2020,"finding":"Loss of SLC6A15 in primary hippocampal neurons results in: reduced release probability at glutamatergic synapses, increased mitochondrial function, higher GSH/GSSG redox ratio, and improved neurite outgrowth. Proteomics of Slc6a15-KO hippocampal tissue revealed differentially regulated proteins in metabolic, mitochondrial, and structural functional domains.","method":"Primary hippocampal neurons from Slc6a15-KO mice; proteomics (mass spectrometry); electrophysiology (glutamatergic synapse release probability); Seahorse metabolic assay (mitochondrial function); GSH/GSSG redox assay; neurite outgrowth imaging","journal":"The European journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with multiple orthogonal cellular assays, single lab","pmids":["33007132"],"is_preprint":false},{"year":2021,"finding":"Ectopic overexpression of SLC6A15 in papillary thyroid cancer (PTC) cells impaired their migratory and invasive abilities in vitro, and intercellular adhesion molecule-1 (ICAM-1) was identified as involved in mediating these effects.","method":"SLC6A15 overexpression in PTC cell lines; Transwell migration and invasion assays; ICAM-1 expression analysis","journal":"Journal of cellular biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single overexpression experiment in cancer cell lines, single lab, limited mechanistic follow-up on ICAM-1 pathway","pmids":["33690923"],"is_preprint":false},{"year":2025,"finding":"SLC6A15 knockdown in MNT1 cells and primary melanocytes reduced melanin synthesis, downregulated melanogenesis-related genes (MITF, TYR, DCT), decreased tyrosinase activity, and reduced intracellular phenylalanine levels. UVB exposure upregulated SLC6A15, and SLC6A15 silencing abrogated UVB-induced pigmentation, establishing SLC6A15-mediated phenylalanine transport as a mechanism regulating melanogenesis.","method":"SLC6A15 knockdown (siRNA/shRNA) in melanocyte cell lines and primary melanocytes; Fontana-Masson staining; tyrosinase activity assay; RT-qPCR for melanogenesis genes; intracellular amino acid measurement; UVB irradiation experiments","journal":"Journal of photochemistry and photobiology. B, Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with multiple orthogonal functional readouts (pigmentation, enzyme activity, gene expression, amino acid levels) in relevant cell types, single lab","pmids":["41352278"],"is_preprint":false},{"year":2025,"finding":"Ectopic overexpression of SLC6A15 in CD8+ T-cells was sufficient to restore effector function (cytotoxic capacity and protein synthesis) in tumor-infiltrating lymphocytes, demonstrating that SLC6A15-mediated amino acid transport can relieve amino acid insufficiency-driven translational suppression in the tumor microenvironment.","method":"SLC6A15 overexpression in primary CD8+ T-cells; tumor infiltrating lymphocyte functional assays; protein synthesis measurement; cytotoxicity assays","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single overexpression experiment in immune cells, functional readout without detailed mechanistic dissection of SLC6A15's transport mechanism per se","pmids":[],"is_preprint":true},{"year":2026,"finding":"High-throughput screening of 200,000 compounds identified the first selective inhibitors of B0AT2/SLC6A15, with a 1,5-benzodiazepine series showing IC50 ~250 nM in [3H]proline uptake assays in SLC6A15-overexpressing HEK293 cells and primary neurons, no detectable inhibition of SERT, DAT, GAT1, or NTT4/SLC6A17 (>80 µM), and dose-dependent stimulation of neurite outgrowth in primary neurons.","method":"High-throughput [3H]proline cellular uptake assay in SLC6A15-overexpressing HEK293 cells; selectivity profiling against related SLC6 transporters; neurite outgrowth assay in primary hippocampal neurons","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro transport assay with pharmacological inhibition and selectivity profiling plus functional neuronal readout; preprint, single lab","pmids":[],"is_preprint":true},{"year":2026,"finding":"Phosphoproteomic curation identified three predominant phosphorylation sites on SLC6A15: pS701, pS699, and pS687, with predicted upstream kinases MAPK3 and CDK12. Binary interactors identified include tyrosine-protein kinase Lyn, epidermal growth factor receptor, and calnexin.","method":"Computational curation and bioinformatic analysis of 3825 global phosphoproteomic datasets; kinase prediction; binary interactor analysis","journal":"Omics : a journal of integrative biology","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational/bioinformatic analysis only, no direct experimental validation of phosphorylation sites or interactions reported in this paper","pmids":["41649124"],"is_preprint":false}],"current_model":"SLC6A15 (B0AT2/SBAT1) is a sodium-coupled plasma membrane transporter predominantly expressed in neurons that mediates uptake of neutral branched-chain amino acids (leucine, isoleucine, valine), proline, and methionine; in the hippocampus, it controls intracellular pools of proline and other neutral amino acids that feed into glutamate/glutamine synthesis, thereby regulating both tissue and extracellular glutamate levels, glutamatergic synapse release probability, and downstream GluR1-dependent signaling, while PKC activation reduces its surface expression; in the nucleus accumbens, cell-type-specific reduction of SLC6A15 in D2-medium spiny neurons underlies stress susceptibility and depressive-like behavior, and in the hypothalamus it mediates the anorexigenic effects of leucine."},"narrative":{"mechanistic_narrative":"SLC6A15 (B0AT2/SBAT1) is a sodium-coupled plasma-membrane transporter of hydrophobic, zwitterionic amino acids that controls neuronal amino acid pools and feeds glutamate/glutamine metabolism, with downstream consequences for glutamatergic signaling and stress-related behavior [PMID:16226721, PMID:26228428]. Heterologous expression established it as a Na+-dependent symporter with strong preference for branched-chain amino acids (leucine, isoleucine, valine) and methionine that excludes aromatic, charged, and beta-amino acids, while PKC activation reduces its surface population [PMID:16226721]; genetic knockout confirmed it contributes to synaptosomal proline and leucine uptake in vivo [PMID:17931606]. In the brain, SLC6A15 mediates the anorexigenic effect of leucine via the ventromedial hypothalamus [PMID:23505546, PMID:24023709]. In the hippocampus, it sets intracellular proline and neutral amino acid levels and thereby tissue glutamate/glutamine, and bidirectionally controls extracellular glutamate tone, glutamatergic synapse release probability, and GluR1-dependent signaling in the dentate gyrus [PMID:26228428, PMID:26585320, PMID:33007132]. Reduction of SLC6A15 in nucleus accumbens D2-medium spiny neurons specifically drives susceptibility to social defeat stress, and restoring its expression in these neurons prevents stress-induced social avoidance [PMID:28576941]. The protein adopts a 12-transmembrane-domain topology with intracellular termini and glycosylated extracellular loops and traffics to the cell surface [PMID:11112352]; selective small-molecule inhibitors of the transporter have been identified that stimulate neurite outgrowth.","teleology":[{"year":2000,"claim":"Defining the protein architecture and surface destination of SLC6A15 established it as a candidate plasma-membrane transporter rather than an intracellular protein.","evidence":"Epitope-tagged construct transfection with subcellular imaging and topology prediction","pmids":["11112352"],"confidence":"Medium","gaps":["No substrate or transport activity demonstrated at this stage","Trafficking determinants and regulation of surface delivery not defined"]},{"year":2005,"claim":"Heterologous reconstitution answered what SLC6A15 actually transports, defining it as a Na+-coupled symporter selective for branched-chain amino acids, methionine, and imino acids and revealing PKC-dependent surface regulation.","evidence":"Xenopus oocyte expression with radiolabeled uptake, kinetics, and PKC manipulation","pmids":["16226721"],"confidence":"High","gaps":["Stoichiometry of Na+ coupling not resolved","Molecular mechanism of PKC-driven surface loss (direct phosphorylation vs. trafficking) not established"]},{"year":2007,"claim":"Knockout synaptosome uptake confirmed the in vitro substrate profile reflects a genuine in vivo contribution to neuronal proline and leucine transport.","evidence":"Slc6a15 knockout mouse cortical synaptosome radiolabeled uptake","pmids":["17931606"],"confidence":"High","gaps":["Residual uptake indicates redundancy with other transporters","Does not localize transport to specific synaptic compartments"]},{"year":2013,"claim":"Knockout phenotyping linked SLC6A15 transport function to a physiological output, showing it mediates leucine-induced hypothalamic neuronal activation and reduction of food intake.","evidence":"Slc6a15 KO mice with ICV leucine, c-Fos activation, feeding assays, and tissue distribution mapping","pmids":["23505546","24023709"],"confidence":"High","gaps":["Sex-selective effects not mechanistically explained","Downstream signaling from leucine uptake to satiety circuitry unresolved"]},{"year":2015,"claim":"Bidirectional genetic manipulation established the central mechanistic role: SLC6A15 controls hippocampal neutral amino acid and glutamate/glutamine pools, extracellular glutamate tone, and stress/anxiety behavior via glutamatergic GluR1 signaling.","evidence":"Slc6a15 KO and viral overexpression with HPLC/NMR amino acid measurement, microdialysis, behavioral tests, and GluR1/GluR2/NR1 immunoblot","pmids":["26228428","26585320"],"confidence":"High","gaps":["Causal chain from amino acid pool changes to GluR1 regulation not directly demonstrated","Cell type responsible for the hippocampal glutamate changes not pinpointed"]},{"year":2017,"claim":"Cell-type-specific manipulation pinpointed the circuit basis of stress behavior, showing SLC6A15 in NAc D2-medium spiny neurons bidirectionally gates social defeat stress susceptibility.","evidence":"Cre-inducible viral knockdown/restoration in D2-Cre and A2A-Cre mice with social defeat paradigms and protein localization","pmids":["28576941"],"confidence":"High","gaps":["Transport substrate driving the D2-MSN phenotype not identified","Connection to the hippocampal glutamate mechanism not established"]},{"year":2020,"claim":"Cellular profiling of knockout neurons extended SLC6A15's role beyond glutamate to mitochondrial function, redox balance, and neurite outgrowth, broadening its metabolic footprint.","evidence":"Primary KO hippocampal neurons with proteomics, electrophysiology, Seahorse, GSH/GSSG, and neurite outgrowth assays","pmids":["33007132"],"confidence":"Medium","gaps":["Mechanism linking amino acid transport to mitochondrial/redox changes unresolved","Single-lab cellular study without in vivo confirmation of metabolic effects"]},{"year":2025,"claim":"Loss-of-function in melanocytes uncovered a non-neuronal role, with SLC6A15-mediated phenylalanine transport driving UVB-responsive melanogenesis.","evidence":"siRNA/shRNA knockdown in MNT1 cells and primary melanocytes with pigmentation, tyrosinase, gene expression, amino acid, and UVB assays","pmids":["41352278"],"confidence":"Medium","gaps":["Phenylalanine as a direct SLC6A15 substrate conflicts with the neuronal aromatic-amino-acid exclusion and needs reconciliation","Transcriptional link from amino acid levels to MITF not defined"]},{"year":2026,"claim":"Pharmacological tool development provided the first selective inhibitors of SLC6A15, validating it as a druggable target and reproducing the neurite outgrowth phenotype.","evidence":"High-throughput [3H]proline uptake screen in overexpressing HEK293 cells with SLC6 selectivity profiling and neurite outgrowth (preprint)","pmids":[],"confidence":"Medium","gaps":["In vivo efficacy and behavioral effects of inhibitors untested","Preprint, single lab"]},{"year":null,"claim":"How SLC6A15 transport activity is regulated post-translationally and how substrate uptake mechanistically couples to glutamate signaling and stress circuitry remain open.","evidence":"No direct experimental validation of phosphorylation sites or interactors beyond computational curation","pmids":[],"confidence":"Low","gaps":["pS701/pS699/pS687 sites and predicted kinases MAPK3/CDK12 not experimentally confirmed","Binary interactors (Lyn, EGFR, calnexin) lack direct validation","Structure of SLC6A15 and substrate-binding determinants not solved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,1,3,8,11,13]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[0,5]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[5,6,7]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H2J7","full_name":"Sodium-dependent neutral amino acid transporter B(0)AT2","aliases":["Sodium- and chloride-dependent neurotransmitter transporter NTT73","Sodium-coupled branched-chain amino-acid transporter 1","Solute carrier family 6 member 15","Transporter v7-3"],"length_aa":730,"mass_kda":81.8,"function":"Functions as a sodium-dependent neutral amino acid transporter. Exhibits preference for the branched-chain amino acids, particularly leucine, valine and isoleucine and methionine. Can also transport low-affinity substrates such as alanine, phenylalanine, glutamine and pipecolic acid. Mediates the saturable, pH-sensitive and electrogenic cotransport of proline and sodium ions with a stoichiometry of 1:1. May have a role as transporter for neurotransmitter precursors into neurons. In contrast to other members of the neurotransmitter transporter family, does not appear to be chloride-dependent","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q9H2J7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SLC6A15","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000072041","cell_line_id":"CID001371","localizations":[{"compartment":"vesicles","grade":3}],"interactors":[{"gene":"VAMP3;VAMP2","stoichiometry":10.0},{"gene":"RAB11A","stoichiometry":4.0},{"gene":"STX12","stoichiometry":4.0},{"gene":"CANX","stoichiometry":0.2},{"gene":"KIF2C","stoichiometry":0.2},{"gene":"PIP4P1","stoichiometry":0.2},{"gene":"RAB14","stoichiometry":0.2},{"gene":"RAB1A","stoichiometry":0.2},{"gene":"NCOA1","stoichiometry":0.2},{"gene":"MFAP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001371","total_profiled":1310},"omim":[{"mim_id":"608520","title":"MAJOR DEPRESSIVE DISORDER 1","url":"https://www.omim.org/entry/608520"},{"mim_id":"607972","title":"SOLUTE CARRIER FAMILY 6 (NEUROTRANSMITTER TRANSPORTER), MEMBER 16; SLC6A16","url":"https://www.omim.org/entry/607972"},{"mim_id":"607971","title":"SOLUTE CARRIER FAMILY 6 (NEUROTRANSMITTER TRANSPORTER), MEMBER 15; SLC6A15","url":"https://www.omim.org/entry/607971"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoli","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":13.0},{"tissue":"retina","ntpm":14.6}],"url":"https://www.proteinatlas.org/search/SLC6A15"},"hgnc":{"alias_symbol":["hv7-3","NTT73","FLJ10316","V7-3","SBAT1"],"prev_symbol":[]},"alphafold":{"accession":"Q9H2J7","domains":[{"cath_id":"1.20.1740","chopping":"66-344_437-639","consensus_level":"high","plddt":91.6902,"start":66,"end":639},{"cath_id":"-","chopping":"363-432","consensus_level":"medium","plddt":83.3317,"start":363,"end":432}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H2J7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H2J7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H2J7-F1-predicted_aligned_error_v6.png","plddt_mean":79.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLC6A15","jax_strain_url":"https://www.jax.org/strain/search?query=SLC6A15"},"sequence":{"accession":"Q9H2J7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H2J7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H2J7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H2J7"}},"corpus_meta":[{"pmid":"21521612","id":"PMC_21521612","title":"The neuronal transporter gene SLC6A15 confers risk to major depression.","date":"2011","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/21521612","citation_count":168,"is_preprint":false},{"pmid":"16226721","id":"PMC_16226721","title":"Characterization of a branched-chain amino-acid transporter SBAT1 (SLC6A15) that is expressed in human brain.","date":"2005","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/16226721","citation_count":72,"is_preprint":false},{"pmid":"28576941","id":"PMC_28576941","title":"Reduced Slc6a15 in Nucleus Accumbens D2-Neurons Underlies Stress Susceptibility.","date":"2017","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/28576941","citation_count":39,"is_preprint":false},{"pmid":"11112352","id":"PMC_11112352","title":"Cloning and characterization of human NTT5 and v7-3: two orphan transporters of the Na+/Cl- -dependent neurotransmitter transporter gene family.","date":"2000","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/11112352","citation_count":39,"is_preprint":false},{"pmid":"22475622","id":"PMC_22475622","title":"A variant of the neuronal amino acid transporter SLC6A15 is associated with ACTH and cortisol responses and cognitive performance in unipolar depression.","date":"2012","source":"The international journal of neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/22475622","citation_count":32,"is_preprint":false},{"pmid":"24023709","id":"PMC_24023709","title":"Involvement of the neutral amino acid transporter SLC6A15 and leucine in obesity-related phenotypes.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24023709","citation_count":25,"is_preprint":false},{"pmid":"23505546","id":"PMC_23505546","title":"B(0)AT2 (SLC6A15) is localized to neurons and astrocytes, and is involved in mediating the effect of leucine in the 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(Amsterdam, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/26585320","citation_count":21,"is_preprint":false},{"pmid":"17931606","id":"PMC_17931606","title":"Deletion of v7-3 (SLC6A15) transporter allows assessment of its roles in synaptosomal proline uptake, leucine uptake and behaviors.","date":"2007","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/17931606","citation_count":20,"is_preprint":false},{"pmid":"37940347","id":"PMC_37940347","title":"The SLC6A15-SLC6A20 Neutral Amino Acid Transporter Subfamily: Functions, Diseases, and Their Therapeutic Relevance.","date":"2023","source":"Pharmacological reviews","url":"https://pubmed.ncbi.nlm.nih.gov/37940347","citation_count":19,"is_preprint":false},{"pmid":"8738154","id":"PMC_8738154","title":"Widespread brain distribution of mRNA encoding the orphan neurotransmitter transporter v7-3.","date":"1996","source":"Brain research. Molecular brain research","url":"https://pubmed.ncbi.nlm.nih.gov/8738154","citation_count":19,"is_preprint":false},{"pmid":"27723767","id":"PMC_27723767","title":"Effects of a Polymorphism of the Neuronal Amino Acid Transporter SLC6A15 Gene on Structural Integrity of White Matter Tracts in Major Depressive Disorder.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27723767","citation_count":18,"is_preprint":false},{"pmid":"30913280","id":"PMC_30913280","title":"Fine-scale haplotype mapping of MUT, AACS, SLC6A15 and PRKCA genes indicates association with insulin resistance of metabolic syndrome and relationship with branched chain amino acid metabolism or regulation.","date":"2019","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/30913280","citation_count":15,"is_preprint":false},{"pmid":"23874702","id":"PMC_23874702","title":"Functional coding variants in SLC6A15, a possible risk gene for major depression.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23874702","citation_count":12,"is_preprint":false},{"pmid":"33007132","id":"PMC_33007132","title":"Loss of the psychiatric risk factor SLC6A15 is associated with increased metabolic functions in primary hippocampal neurons.","date":"2020","source":"The European journal of neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/33007132","citation_count":11,"is_preprint":false},{"pmid":"29882086","id":"PMC_29882086","title":"Withdrawal of caffeine after its chronic administration modifies the antidepressant-like activity of atypical antidepressants in mice. Changes in cortical expression of Comt, Slc6a15 and Adora1 genes.","date":"2018","source":"Psychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/29882086","citation_count":8,"is_preprint":false},{"pmid":"33690923","id":"PMC_33690923","title":"SLC6A15 acts as a tumor suppressor to inhibit migration and invasion in human papillary thyroid cancer.","date":"2021","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/33690923","citation_count":7,"is_preprint":false},{"pmid":"23271449","id":"PMC_23271449","title":"A conserved threonine in the S1-S2 loop of KV7.2 and K V7.3 channels regulates voltage-dependent activation.","date":"2012","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/23271449","citation_count":7,"is_preprint":false},{"pmid":"28915082","id":"PMC_28915082","title":"A Combined Study of SLC6A15 Gene Polymorphism and the Resting-State Functional Magnetic Resonance Imaging in First-Episode Drug-Naive Major Depressive Disorder.","date":"2017","source":"Genetic testing and molecular biomarkers","url":"https://pubmed.ncbi.nlm.nih.gov/28915082","citation_count":3,"is_preprint":false},{"pmid":"38407689","id":"PMC_38407689","title":"LncRNA DGUOK-AS1 Promotes Cell Progression in Lung Squamous Cell Carcinoma by Regulation of miR-653-5p/SLC6A15 Axis.","date":"2024","source":"Molecular biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/38407689","citation_count":0,"is_preprint":false},{"pmid":"41352278","id":"PMC_41352278","title":"UVB enhances SLC6A15-mediated phenylalanine transport to promote melanogenesis.","date":"2025","source":"Journal of photochemistry and photobiology. B, Biology","url":"https://pubmed.ncbi.nlm.nih.gov/41352278","citation_count":0,"is_preprint":false},{"pmid":"41649124","id":"PMC_41649124","title":"Phosphorylation-Dependent Regulation and Interactions of the Neutral Amino Acid Transporter SLC6A15: Implications for Major Depression and Neuropsychiatric Disorders.","date":"2026","source":"Omics : a journal of integrative biology","url":"https://pubmed.ncbi.nlm.nih.gov/41649124","citation_count":0,"is_preprint":false},{"pmid":"42118683","id":"PMC_42118683","title":"Unlocking SLC6A15 (B0AT2): A Dual-Platform Approach To Accelerate Drug Discovery for Neuropsychiatric Disorders.","date":"2026","source":"Analytical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/42118683","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.03.25.645215","title":"Identification and characterization of potent and selective inhibitors for the B  <sup>0</sup>  AT2/SLC6A15 amino acid transporter","date":"2025-03-25","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.25.645215","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.04.28.651077","title":"Intratumoral amino acid insufficiency limits CD8  <sup>+</sup>  T-cell effector function","date":"2025-05-01","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.28.651077","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16214,"output_tokens":4158,"usd":0.055506,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12057,"output_tokens":3208,"usd":0.070242,"stage2_stop_reason":"end_turn"},"total_usd":0.125748,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"SLC6A15 (SBAT1) functions as a sodium-coupled transporter of hydrophobic, zwitterionic alpha-amino and imino acids when expressed in Xenopus oocytes, with strong preference for branched-chain amino acids (leucine, isoleucine, valine) and methionine (K0.5 80-160 µM); it excludes aromatic or charged amino acids, beta-amino acids, glycine, and GABA. Transport is highly temperature-dependent (Q10=9) and inhibited at acidic pH. PKC activation reduces the plasma-membrane population of SBAT1 protein.\",\n      \"method\": \"Xenopus oocyte heterologous expression, radiolabeled substrate uptake assays, pharmacological manipulation (PKC activation)\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro transport reconstitution in Xenopus oocytes with multiple substrate specificity assays, kinetic characterization, and PKC functional experiment; replicated by subsequent studies\",\n      \"pmids\": [\"16226721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In cortical synaptosomes from v7-3 (SLC6A15) knockout mice, sodium-dependent proline uptake was reduced by 15% and leucine uptake by 40% compared to wild-type controls, establishing SLC6A15 as a contributor to synaptosomal proline and leucine transport in vivo.\",\n      \"method\": \"SLC6A15 knockout mouse model; radiolabeled amino acid uptake into cortical synaptosomes\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic KO with direct biochemical measurement of transporter substrate uptake; consistent with in vitro transport data from oocyte studies\",\n      \"pmids\": [\"17931606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Human v7-3 (SLC6A15) encodes a 730 amino acid protein with 12 predicted transmembrane domains, intracellular N- and C-termini, and large extracellular loops between TM3-4 and TM7-8 with N-linked glycosylation sites; transfection experiments showed v7-3 is expressed at the cell surface (plasma membrane localization), in contrast to the related NTT5 which is predominantly intracellular.\",\n      \"method\": \"Epitope-tagged transporter construct transfection, subcellular localization by cellular imaging/fractionation; bioinformatic topology prediction\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization by transfection and imaging, single lab, surface vs. intracellular distinction established experimentally\",\n      \"pmids\": [\"11112352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SLC6A15 knockout mice show lower reduction in food intake and lower neuronal activation in the ventromedial hypothalamic nucleus (VMH) in response to intracerebroventricular leucine injections compared to wild-type mice, establishing SLC6A15 as mediating the anorexigenic effect of leucine in the brain. B0AT2 (SLC6A15) immunoreactivity was found in neurons (including GABAergic neurons and spinal cord motor neurons) and in astrocytes near ventricles, and co-localized with cytokeratin and diazepam binding inhibitor (DBI) in choroid plexus epithelial cells.\",\n      \"method\": \"Slc6a15 knockout mice, food intake assay with leucine injection, c-Fos neuronal activation immunohistochemistry, immunohistochemistry and in situ hybridization for tissue distribution\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with functional behavioral readout (food intake) plus neuronal activation assay and detailed localization; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"23505546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SLC6A15 knockout attenuates leucine's ability to reduce normal chow intake and weight gain on high-fat diet in a sex-selective fashion in mice, supporting a role for brain SLC6A15 in leucine-mediated control of food intake and obesity-related phenotypes.\",\n      \"method\": \"Slc6a15 knockout mice, dietary feeding assays with leucine supplementation, body weight measurement\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with specific functional phenotype (leucine-induced anorexia abolished), single lab\",\n      \"pmids\": [\"24023709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Loss of SLC6A15 in knockout mice reduces hippocampal tissue levels of proline and other neutral amino acids, decreases overall tissue glutamate and glutamine, while simultaneously increasing basal extracellular glutamate tone. Conversely, hippocampal SLC6A15 overexpression increases glutamate/glutamine tissue concentrations. These neurochemical changes were linked to altered sensorimotor gating behavior.\",\n      \"method\": \"Slc6a15 knockout mice; virus-mediated hippocampal overexpression; hippocampal amino acid measurement (HPLC/NMR); in vivo microdialysis for extracellular glutamate; prepulse inhibition behavioral test\",\n      \"journal\": \"Journal of psychiatric research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — bidirectional genetic manipulation (KO and OE) with direct neurochemical measurements and behavioral readout, multiple orthogonal methods\",\n      \"pmids\": [\"26228428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Slc6a15 knockout mice show reduced anxiety- and depressive-like behavior following chronic social stress compared to wild-type littermates, while hippocampal SLC6A15 overexpression increases anxiety-like behavior at baseline. GluR1 (AMPA receptor subunit) expression in the dentate gyrus, but not GluR2 or NR1, is regulated by slc6a15 expression levels, implicating glutamatergic signaling as a downstream mechanism.\",\n      \"method\": \"Slc6a15 KO and virus-mediated hippocampal overexpression mouse models; chronic social stress paradigm; anxiety/depression behavioral tests; immunoblot for GluR1, GluR2, NR1 in dentate gyrus\",\n      \"journal\": \"Stress (Amsterdam, Netherlands)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional genetic manipulation with behavioral phenotyping and molecular endpoint (GluR1), single lab\",\n      \"pmids\": [\"26585320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Cre-inducible viral reduction of Slc6a15 selectively in NAc D2-medium spiny neurons (using D2-Cre and A2A-Cre mice) causes enhanced susceptibility to subthreshold social defeat stress, while restoring Slc6a15 expression in D2-neurons after chronic social defeat stress prevents social avoidance. Slc6a15 protein was unaltered in ChAT interneurons after chronic social defeat stress, indicating the effect is D2-MSN-specific.\",\n      \"method\": \"Cre-inducible viral vectors in D2-Cre and A2A-Cre mice; chronic and subthreshold social defeat stress; social interaction behavioral testing; immunofluorescence for Slc6a15 protein in ChAT interneurons\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific bidirectional genetic manipulation with defined behavioral phenotype and protein-level localization data; multiple Cre lines used for validation\",\n      \"pmids\": [\"28576941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Two rare non-synonymous coding variants in SLC6A15 were associated with significantly increased maximal [3H]proline uptake compared to the wildtype sequence in a cellular uptake assay, demonstrating that specific amino acid changes can alter transporter activity.\",\n      \"method\": \"Cellular [3H]proline uptake assay with wildtype vs. mutant SLC6A15 constructs; pooled targeted re-sequencing and individual re-genotyping\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional assay with mutagenesis, single lab, but only rare variants with no case-control association\",\n      \"pmids\": [\"23874702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Loss of SLC6A15 in primary hippocampal neurons results in: reduced release probability at glutamatergic synapses, increased mitochondrial function, higher GSH/GSSG redox ratio, and improved neurite outgrowth. Proteomics of Slc6a15-KO hippocampal tissue revealed differentially regulated proteins in metabolic, mitochondrial, and structural functional domains.\",\n      \"method\": \"Primary hippocampal neurons from Slc6a15-KO mice; proteomics (mass spectrometry); electrophysiology (glutamatergic synapse release probability); Seahorse metabolic assay (mitochondrial function); GSH/GSSG redox assay; neurite outgrowth imaging\",\n      \"journal\": \"The European journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with multiple orthogonal cellular assays, single lab\",\n      \"pmids\": [\"33007132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Ectopic overexpression of SLC6A15 in papillary thyroid cancer (PTC) cells impaired their migratory and invasive abilities in vitro, and intercellular adhesion molecule-1 (ICAM-1) was identified as involved in mediating these effects.\",\n      \"method\": \"SLC6A15 overexpression in PTC cell lines; Transwell migration and invasion assays; ICAM-1 expression analysis\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single overexpression experiment in cancer cell lines, single lab, limited mechanistic follow-up on ICAM-1 pathway\",\n      \"pmids\": [\"33690923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SLC6A15 knockdown in MNT1 cells and primary melanocytes reduced melanin synthesis, downregulated melanogenesis-related genes (MITF, TYR, DCT), decreased tyrosinase activity, and reduced intracellular phenylalanine levels. UVB exposure upregulated SLC6A15, and SLC6A15 silencing abrogated UVB-induced pigmentation, establishing SLC6A15-mediated phenylalanine transport as a mechanism regulating melanogenesis.\",\n      \"method\": \"SLC6A15 knockdown (siRNA/shRNA) in melanocyte cell lines and primary melanocytes; Fontana-Masson staining; tyrosinase activity assay; RT-qPCR for melanogenesis genes; intracellular amino acid measurement; UVB irradiation experiments\",\n      \"journal\": \"Journal of photochemistry and photobiology. B, Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with multiple orthogonal functional readouts (pigmentation, enzyme activity, gene expression, amino acid levels) in relevant cell types, single lab\",\n      \"pmids\": [\"41352278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Ectopic overexpression of SLC6A15 in CD8+ T-cells was sufficient to restore effector function (cytotoxic capacity and protein synthesis) in tumor-infiltrating lymphocytes, demonstrating that SLC6A15-mediated amino acid transport can relieve amino acid insufficiency-driven translational suppression in the tumor microenvironment.\",\n      \"method\": \"SLC6A15 overexpression in primary CD8+ T-cells; tumor infiltrating lymphocyte functional assays; protein synthesis measurement; cytotoxicity assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single overexpression experiment in immune cells, functional readout without detailed mechanistic dissection of SLC6A15's transport mechanism per se\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"High-throughput screening of 200,000 compounds identified the first selective inhibitors of B0AT2/SLC6A15, with a 1,5-benzodiazepine series showing IC50 ~250 nM in [3H]proline uptake assays in SLC6A15-overexpressing HEK293 cells and primary neurons, no detectable inhibition of SERT, DAT, GAT1, or NTT4/SLC6A17 (>80 µM), and dose-dependent stimulation of neurite outgrowth in primary neurons.\",\n      \"method\": \"High-throughput [3H]proline cellular uptake assay in SLC6A15-overexpressing HEK293 cells; selectivity profiling against related SLC6 transporters; neurite outgrowth assay in primary hippocampal neurons\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro transport assay with pharmacological inhibition and selectivity profiling plus functional neuronal readout; preprint, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Phosphoproteomic curation identified three predominant phosphorylation sites on SLC6A15: pS701, pS699, and pS687, with predicted upstream kinases MAPK3 and CDK12. Binary interactors identified include tyrosine-protein kinase Lyn, epidermal growth factor receptor, and calnexin.\",\n      \"method\": \"Computational curation and bioinformatic analysis of 3825 global phosphoproteomic datasets; kinase prediction; binary interactor analysis\",\n      \"journal\": \"Omics : a journal of integrative biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational/bioinformatic analysis only, no direct experimental validation of phosphorylation sites or interactions reported in this paper\",\n      \"pmids\": [\"41649124\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLC6A15 (B0AT2/SBAT1) is a sodium-coupled plasma membrane transporter predominantly expressed in neurons that mediates uptake of neutral branched-chain amino acids (leucine, isoleucine, valine), proline, and methionine; in the hippocampus, it controls intracellular pools of proline and other neutral amino acids that feed into glutamate/glutamine synthesis, thereby regulating both tissue and extracellular glutamate levels, glutamatergic synapse release probability, and downstream GluR1-dependent signaling, while PKC activation reduces its surface expression; in the nucleus accumbens, cell-type-specific reduction of SLC6A15 in D2-medium spiny neurons underlies stress susceptibility and depressive-like behavior, and in the hypothalamus it mediates the anorexigenic effects of leucine.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SLC6A15 (B0AT2/SBAT1) is a sodium-coupled plasma-membrane transporter of hydrophobic, zwitterionic amino acids that controls neuronal amino acid pools and feeds glutamate/glutamine metabolism, with downstream consequences for glutamatergic signaling and stress-related behavior [#0, #5]. Heterologous expression established it as a Na+-dependent symporter with strong preference for branched-chain amino acids (leucine, isoleucine, valine) and methionine that excludes aromatic, charged, and beta-amino acids, while PKC activation reduces its surface population [#0]; genetic knockout confirmed it contributes to synaptosomal proline and leucine uptake in vivo [#1]. In the brain, SLC6A15 mediates the anorexigenic effect of leucine via the ventromedial hypothalamus [#3, #4]. In the hippocampus, it sets intracellular proline and neutral amino acid levels and thereby tissue glutamate/glutamine, and bidirectionally controls extracellular glutamate tone, glutamatergic synapse release probability, and GluR1-dependent signaling in the dentate gyrus [#5, #6, #9]. Reduction of SLC6A15 in nucleus accumbens D2-medium spiny neurons specifically drives susceptibility to social defeat stress, and restoring its expression in these neurons prevents stress-induced social avoidance [#7]. The protein adopts a 12-transmembrane-domain topology with intracellular termini and glycosylated extracellular loops and traffics to the cell surface [#2]; selective small-molecule inhibitors of the transporter have been identified that stimulate neurite outgrowth [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Defining the protein architecture and surface destination of SLC6A15 established it as a candidate plasma-membrane transporter rather than an intracellular protein.\",\n      \"evidence\": \"Epitope-tagged construct transfection with subcellular imaging and topology prediction\",\n      \"pmids\": [\"11112352\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No substrate or transport activity demonstrated at this stage\", \"Trafficking determinants and regulation of surface delivery not defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Heterologous reconstitution answered what SLC6A15 actually transports, defining it as a Na+-coupled symporter selective for branched-chain amino acids, methionine, and imino acids and revealing PKC-dependent surface regulation.\",\n      \"evidence\": \"Xenopus oocyte expression with radiolabeled uptake, kinetics, and PKC manipulation\",\n      \"pmids\": [\"16226721\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of Na+ coupling not resolved\", \"Molecular mechanism of PKC-driven surface loss (direct phosphorylation vs. trafficking) not established\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Knockout synaptosome uptake confirmed the in vitro substrate profile reflects a genuine in vivo contribution to neuronal proline and leucine transport.\",\n      \"evidence\": \"Slc6a15 knockout mouse cortical synaptosome radiolabeled uptake\",\n      \"pmids\": [\"17931606\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Residual uptake indicates redundancy with other transporters\", \"Does not localize transport to specific synaptic compartments\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Knockout phenotyping linked SLC6A15 transport function to a physiological output, showing it mediates leucine-induced hypothalamic neuronal activation and reduction of food intake.\",\n      \"evidence\": \"Slc6a15 KO mice with ICV leucine, c-Fos activation, feeding assays, and tissue distribution mapping\",\n      \"pmids\": [\"23505546\", \"24023709\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Sex-selective effects not mechanistically explained\", \"Downstream signaling from leucine uptake to satiety circuitry unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Bidirectional genetic manipulation established the central mechanistic role: SLC6A15 controls hippocampal neutral amino acid and glutamate/glutamine pools, extracellular glutamate tone, and stress/anxiety behavior via glutamatergic GluR1 signaling.\",\n      \"evidence\": \"Slc6a15 KO and viral overexpression with HPLC/NMR amino acid measurement, microdialysis, behavioral tests, and GluR1/GluR2/NR1 immunoblot\",\n      \"pmids\": [\"26228428\", \"26585320\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal chain from amino acid pool changes to GluR1 regulation not directly demonstrated\", \"Cell type responsible for the hippocampal glutamate changes not pinpointed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Cell-type-specific manipulation pinpointed the circuit basis of stress behavior, showing SLC6A15 in NAc D2-medium spiny neurons bidirectionally gates social defeat stress susceptibility.\",\n      \"evidence\": \"Cre-inducible viral knockdown/restoration in D2-Cre and A2A-Cre mice with social defeat paradigms and protein localization\",\n      \"pmids\": [\"28576941\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transport substrate driving the D2-MSN phenotype not identified\", \"Connection to the hippocampal glutamate mechanism not established\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Cellular profiling of knockout neurons extended SLC6A15's role beyond glutamate to mitochondrial function, redox balance, and neurite outgrowth, broadening its metabolic footprint.\",\n      \"evidence\": \"Primary KO hippocampal neurons with proteomics, electrophysiology, Seahorse, GSH/GSSG, and neurite outgrowth assays\",\n      \"pmids\": [\"33007132\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking amino acid transport to mitochondrial/redox changes unresolved\", \"Single-lab cellular study without in vivo confirmation of metabolic effects\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Loss-of-function in melanocytes uncovered a non-neuronal role, with SLC6A15-mediated phenylalanine transport driving UVB-responsive melanogenesis.\",\n      \"evidence\": \"siRNA/shRNA knockdown in MNT1 cells and primary melanocytes with pigmentation, tyrosinase, gene expression, amino acid, and UVB assays\",\n      \"pmids\": [\"41352278\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phenylalanine as a direct SLC6A15 substrate conflicts with the neuronal aromatic-amino-acid exclusion and needs reconciliation\", \"Transcriptional link from amino acid levels to MITF not defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Pharmacological tool development provided the first selective inhibitors of SLC6A15, validating it as a druggable target and reproducing the neurite outgrowth phenotype.\",\n      \"evidence\": \"High-throughput [3H]proline uptake screen in overexpressing HEK293 cells with SLC6 selectivity profiling and neurite outgrowth (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo efficacy and behavioral effects of inhibitors untested\", \"Preprint, single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SLC6A15 transport activity is regulated post-translationally and how substrate uptake mechanistically couples to glutamate signaling and stress circuitry remain open.\",\n      \"evidence\": \"No direct experimental validation of phosphorylation sites or interactors beyond computational curation\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"pS701/pS699/pS687 sites and predicted kinases MAPK3/CDK12 not experimentally confirmed\", \"Binary interactors (Lyn, EGFR, calnexin) lack direct validation\", \"Structure of SLC6A15 and substrate-binding determinants not solved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 1, 3, 8, 11, 13]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [5, 6, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}