{"gene":"SLC6A15","run_date":"2026-04-28T20:42:08","timeline":{"discoveries":[{"year":2005,"finding":"SLC6A15 (SBAT1) encodes a Na+-coupled transporter with strong preference for branched-chain amino acids (leucine, isoleucine, valine) and methionine (K0.5 80-160 µM), excluding aromatic or charged amino acids, β-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 expression system with radiolabeled substrate uptake assays and PKC activation experiments","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 — reconstituted transport in Xenopus oocytes with substrate specificity, kinetics, pH, temperature, and PKC regulation characterized","pmids":["16226721"],"is_preprint":false},{"year":2007,"finding":"Deletion of SLC6A15 (v7-3) in mice causes 15% and 40% reductions in sodium-dependent proline and leucine uptake into cortical synaptosomes, respectively, establishing SLC6A15 as a contributor to synaptosomal neutral amino acid transport in vivo.","method":"V7-3 knockout mice with synaptosomal amino acid uptake assays","journal":"Brain research","confidence":"High","confidence_rationale":"Tier 2 — clean KO with direct biochemical readout in native tissue; reductions quantified for two substrates","pmids":["17931606"],"is_preprint":false},{"year":2013,"finding":"SLC6A15 knockout mice show attenuated reduction of food intake and lower neuronal activation in the ventromedial hypothalamic nucleus (VMH) in response to intracerebroventricular leucine, demonstrating that SLC6A15 mediates leucine's anorexigenic effect in the brain.","method":"Slc6a15 KO mice with leucine injection, food intake measurement, and c-Fos immunohistochemistry in VMH","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — KO with defined physiological phenotype and neuroanatomical readout, replicated in two papers","pmids":["23505546","24023709"],"is_preprint":false},{"year":2013,"finding":"SLC6A15 protein (B0AT2) is localized predominantly to neurons (including GABAergic neurons and spinal cord motor neurons), with additional expression in astrocytes near ventricles and in choroid plexus epithelial cells (co-localizing with cytokeratin and diazepam binding inhibitor).","method":"Immunohistochemistry and in situ hybridization on mouse CNS tissue; co-localization with cell-type markers","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 — direct localization by IHC with cell-type marker co-localization, single lab","pmids":["23505546"],"is_preprint":false},{"year":2015,"finding":"Loss of SLC6A15 in mice reduces hippocampal tissue levels of proline and other neutral amino acids, decreases overall tissue glutamate and glutamine, yet increases basal extracellular glutamate tone; conversely, hippocampal SLC6A15 overexpression increases glutamate/glutamine tissue concentrations, linking SLC6A15 transport activity to glutamatergic neurochemistry.","method":"Slc6a15 KO mice and virus-mediated hippocampal overexpression with HPLC/NMR neurochemistry and in vivo microdialysis","journal":"Journal of psychiatric research","confidence":"High","confidence_rationale":"Tier 2 — bidirectional genetic manipulation (KO and OE) with quantitative neurochemical readouts in two directions","pmids":["26228428"],"is_preprint":false},{"year":2015,"finding":"SLC6A15 overexpression in the hippocampus increases anxiety-like behavior basally, while knockout reduces anxiety and depressive-like behavior after chronic social stress; GluR1 (AMPA receptor subunit) expression in the dentate gyrus is regulated by Slc6a15, suggesting glutamatergic modulation as a downstream mechanism.","method":"Slc6a15 KO mice and virus-mediated hippocampal overexpression with behavioral testing and Western blot for GluR1/GluR2/NR1","journal":"Stress (Amsterdam, Netherlands)","confidence":"Medium","confidence_rationale":"Tier 2 — bidirectional manipulation with behavioral and molecular endpoints; single lab","pmids":["26585320"],"is_preprint":false},{"year":2013,"finding":"Two rare non-synonymous coding variants in SLC6A15 significantly increase maximal 3H-proline uptake compared to wild-type sequence, demonstrating that specific amino acid changes alter transporter activity.","method":"Cellular uptake assay with 3H-proline in cells expressing variant SLC6A15 constructs","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1 — functional mutagenesis in cellular uptake assay; single lab, two variants identified","pmids":["23874702"],"is_preprint":false},{"year":2017,"finding":"Selective reduction of Slc6a15 in nucleus accumbens D2-medium spiny neurons (using Cre-inducible virus with D2-Cre or A2A-Cre mice) causes enhanced susceptibility to subthreshold social defeat stress, while restoration of Slc6a15 expression in D2-neurons prevents social avoidance after chronic social defeat stress, placing SLC6A15 in NAc D2-neurons as a regulator of stress susceptibility.","method":"Cre-inducible viral knockdown/overexpression in D2-Cre and A2A-Cre mice; social defeat stress paradigm with social interaction readout","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — cell-type-specific bidirectional manipulation with defined behavioral phenotype; multiple Cre lines used as controls","pmids":["28576941"],"is_preprint":false},{"year":2020,"finding":"Loss of SLC6A15 in primary hippocampal neurons reduces glutamate release probability at glutamatergic synapses, increases mitochondrial function, elevates GSH/GSSG redox ratio, and improves neurite outgrowth, demonstrating that SLC6A15 controls neutral amino acid concentrations that affect mitochondrial activity, synaptic function, and neuronal structure.","method":"Slc6a15-KO hippocampal neurons with proteomics, electrophysiology (release probability), Seahorse mitochondrial assay, glutathione assay, and neurite morphometry","journal":"The European journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods in KO neurons; single lab","pmids":["33007132"],"is_preprint":false},{"year":2025,"finding":"SLC6A15 (B0AT2) transports phenylalanine into melanocytes, and its knockdown reduces intracellular phenylalanine levels, decreases melanin synthesis, downregulates MITF, TYR, and DCT expression, and abrogates UVB-induced pigmentation increase; UVB exposure transcriptionally upregulates SLC6A15.","method":"siRNA knockdown in MNT1 cells and primary melanocytes; Fontana-Masson staining; tyrosinase activity assay; intracellular phenylalanine measurement; RT-qPCR","journal":"Journal of photochemistry and photobiology. B, Biology","confidence":"Medium","confidence_rationale":"Tier 2 — KD with multiple functional readouts in two cell systems; single lab","pmids":["41352278"],"is_preprint":false},{"year":2025,"finding":"First selective inhibitors of B0AT2/SLC6A15 were identified by HTS of 200,000 compounds using a 3H-proline uptake assay; a 1,5-benzodiazepine series inhibits SLC6A15 with IC50 ~250 nM in SLC6A15-overexpressing HEK293 cells and primary neurons, with no detectable inhibition of SERT, DAT, GAT1, or NTT4/SLC6A17; inhibitor treatment dose-dependently stimulates neurite outgrowth in primary neurons.","method":"High-throughput 3H-proline uptake assay; selectivity counter-screens vs. related SLC6 transporters; neurite outgrowth assay in primary hippocampal neurons","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro assay with selectivity panel and cellular validation; preprint, not yet peer-reviewed","pmids":["bio_10.1101_2025.03.25.645215"],"is_preprint":true},{"year":2000,"finding":"Human SLC6A15 (v7-3) encodes a protein with 12 predicted transmembrane domains, intracellular N- and C-terminal domains, large extracellular loops between TM3-4 and TM7-8, and N-linked glycosylation sites; when expressed with an epitope tag, v7-3 localizes to the cell surface, in contrast to the related NTT5 which is predominantly intracellular.","method":"Epitope-tagged transient transfection and subcellular localization by immunofluorescence","journal":"Genomics","confidence":"Low","confidence_rationale":"Tier 3 — single localization experiment without functional consequence measurement","pmids":["11112352"],"is_preprint":false}],"current_model":"SLC6A15 (B0AT2) is a neuronal plasma-membrane, sodium-dependent neutral amino acid transporter with selectivity for branched-chain amino acids (leucine, isoleucine, valine), methionine, proline, and phenylalanine; PKC activation reduces its surface expression; in the brain it supplies neutral amino acids that regulate intracellular glutamate/glutamine pools and extracellular glutamate tone, modulates GluR1 expression, and in nucleus accumbens D2-neurons controls stress susceptibility; in melanocytes it transports phenylalanine to support melanogenesis; selective small-molecule inhibitors have been identified that block proline transport with ~250 nM potency and stimulate neurite outgrowth."},"narrative":{"teleology":[{"year":2000,"claim":"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","pmids":["11112352"],"confidence":"Low","gaps":["No transport activity measured; surface localization based on single tagged construct without endogenous validation","Glycosylation sites predicted but functional significance untested"]},{"year":2005,"claim":"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","pmids":["16226721"],"confidence":"High","gaps":["Structural basis for substrate selectivity unknown","PKC-mediated internalization pathway not delineated"]},{"year":2007,"claim":"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","pmids":["17931606"],"confidence":"High","gaps":["Residual uptake indicates redundant transporters not identified","Regional heterogeneity of contribution not mapped"]},{"year":2013,"claim":"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","pmids":["23505546","24023709","23874702"],"confidence":"High","gaps":["Downstream signaling from leucine sensing in VMH not characterized","Coding variants not tested in vivo"]},{"year":2015,"claim":"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","pmids":["26228428","26585320"],"confidence":"High","gaps":["Mechanism connecting neutral amino acid import to glutamate pool regulation not fully delineated","GluR1 regulation could be indirect"]},{"year":2017,"claim":"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","pmids":["28576941"],"confidence":"High","gaps":["Amino acid changes in D2-MSNs upon manipulation not measured","Whether glutamatergic mechanism generalizes from hippocampus to NAc untested"]},{"year":2020,"claim":"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","pmids":["33007132"],"confidence":"Medium","gaps":["Causal chain from amino acid depletion to mitochondrial and redox changes not resolved","In vivo relevance of neurite outgrowth phenotype unclear"]},{"year":2025,"claim":"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","pmids":["41352278"],"confidence":"Medium","gaps":["Whether phenylalanine effect is direct or via tyrosine conversion not distinguished","In vivo pigmentation phenotype in Slc6a15 KO mice not reported"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Low","gaps":["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)"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,1,4,9]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,11]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,1,4,9]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[4,5,7,8]}],"complexes":[],"partners":["GRIA1"],"other_free_text":[]},"mechanistic_narrative":"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]."},"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":166,"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 brain.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23505546","citation_count":22,"is_preprint":false},{"pmid":"26228428","id":"PMC_26228428","title":"The amino acid transporter SLC6A15 is a regulator of hippocampal neurochemistry and behavior.","date":"2015","source":"Journal of psychiatric research","url":"https://pubmed.ncbi.nlm.nih.gov/26228428","citation_count":22,"is_preprint":false},{"pmid":"26585320","id":"PMC_26585320","title":"SLC6A15, a novel stress vulnerability candidate, modulates anxiety and depressive-like behavior: involvement of the glutamatergic system.","date":"2015","source":"Stress (Amsterdam, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/26585320","citation_count":21,"is_preprint":false},{"pmid":"31344373","id":"PMC_31344373","title":"Edaravone presents antidepressant-like activity in corticosterone model of depression in mice with possible role of Fkbp5, Comt, Adora1 and Slc6a15 genes.","date":"2019","source":"Toxicology and applied pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/31344373","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":"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":"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":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":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},{"pmid":null,"id":"bio_10.1101_2024.06.17.599325","title":"The UPR<sup>ER</sup>governs the cell-specific response of human dopaminergic neurons to mitochondrial stress","date":"2024-06-17","source":"bioRxiv","url":"https://doi.org/10.1101/2024.06.17.599325","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15578,"output_tokens":2979,"usd":0.04571},"stage2":{"model":"claude-opus-4-6","input_tokens":6333,"output_tokens":2070,"usd":0.125122},"total_usd":0.170832,"stage1_batch_id":"msgbatch_011rkcQdVV1RaFq9XhcG6df6","stage2_batch_id":"msgbatch_01RzgrJafdF4EWHhj5mNi6dh","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"SLC6A15 (SBAT1) encodes a Na+-coupled transporter with strong preference for branched-chain amino acids (leucine, isoleucine, valine) and methionine (K0.5 80-160 µM), excluding aromatic or charged amino acids, β-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 expression system with radiolabeled substrate uptake assays and PKC activation experiments\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted transport in Xenopus oocytes with substrate specificity, kinetics, pH, temperature, and PKC regulation characterized\",\n      \"pmids\": [\"16226721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Deletion of SLC6A15 (v7-3) in mice causes 15% and 40% reductions in sodium-dependent proline and leucine uptake into cortical synaptosomes, respectively, establishing SLC6A15 as a contributor to synaptosomal neutral amino acid transport in vivo.\",\n      \"method\": \"V7-3 knockout mice with synaptosomal amino acid uptake assays\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with direct biochemical readout in native tissue; reductions quantified for two substrates\",\n      \"pmids\": [\"17931606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SLC6A15 knockout mice show attenuated reduction of food intake and lower neuronal activation in the ventromedial hypothalamic nucleus (VMH) in response to intracerebroventricular leucine, demonstrating that SLC6A15 mediates leucine's anorexigenic effect in the brain.\",\n      \"method\": \"Slc6a15 KO mice with leucine injection, food intake measurement, and c-Fos immunohistochemistry in VMH\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO with defined physiological phenotype and neuroanatomical readout, replicated in two papers\",\n      \"pmids\": [\"23505546\", \"24023709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SLC6A15 protein (B0AT2) is localized predominantly to neurons (including GABAergic neurons and spinal cord motor neurons), with additional expression in astrocytes near ventricles and in choroid plexus epithelial cells (co-localizing with cytokeratin and diazepam binding inhibitor).\",\n      \"method\": \"Immunohistochemistry and in situ hybridization on mouse CNS tissue; co-localization with cell-type markers\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — direct localization by IHC with cell-type marker co-localization, single lab\",\n      \"pmids\": [\"23505546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Loss of SLC6A15 in mice reduces hippocampal tissue levels of proline and other neutral amino acids, decreases overall tissue glutamate and glutamine, yet increases basal extracellular glutamate tone; conversely, hippocampal SLC6A15 overexpression increases glutamate/glutamine tissue concentrations, linking SLC6A15 transport activity to glutamatergic neurochemistry.\",\n      \"method\": \"Slc6a15 KO mice and virus-mediated hippocampal overexpression with HPLC/NMR neurochemistry and in vivo microdialysis\",\n      \"journal\": \"Journal of psychiatric research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — bidirectional genetic manipulation (KO and OE) with quantitative neurochemical readouts in two directions\",\n      \"pmids\": [\"26228428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SLC6A15 overexpression in the hippocampus increases anxiety-like behavior basally, while knockout reduces anxiety and depressive-like behavior after chronic social stress; GluR1 (AMPA receptor subunit) expression in the dentate gyrus is regulated by Slc6a15, suggesting glutamatergic modulation as a downstream mechanism.\",\n      \"method\": \"Slc6a15 KO mice and virus-mediated hippocampal overexpression with behavioral testing and Western blot for GluR1/GluR2/NR1\",\n      \"journal\": \"Stress (Amsterdam, Netherlands)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — bidirectional manipulation with behavioral and molecular endpoints; single lab\",\n      \"pmids\": [\"26585320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Two rare non-synonymous coding variants in SLC6A15 significantly increase maximal 3H-proline uptake compared to wild-type sequence, demonstrating that specific amino acid changes alter transporter activity.\",\n      \"method\": \"Cellular uptake assay with 3H-proline in cells expressing variant SLC6A15 constructs\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — functional mutagenesis in cellular uptake assay; single lab, two variants identified\",\n      \"pmids\": [\"23874702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Selective reduction of Slc6a15 in nucleus accumbens D2-medium spiny neurons (using Cre-inducible virus with D2-Cre or A2A-Cre mice) causes enhanced susceptibility to subthreshold social defeat stress, while restoration of Slc6a15 expression in D2-neurons prevents social avoidance after chronic social defeat stress, placing SLC6A15 in NAc D2-neurons as a regulator of stress susceptibility.\",\n      \"method\": \"Cre-inducible viral knockdown/overexpression in D2-Cre and A2A-Cre mice; social defeat stress paradigm with social interaction readout\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific bidirectional manipulation with defined behavioral phenotype; multiple Cre lines used as controls\",\n      \"pmids\": [\"28576941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Loss of SLC6A15 in primary hippocampal neurons reduces glutamate release probability at glutamatergic synapses, increases mitochondrial function, elevates GSH/GSSG redox ratio, and improves neurite outgrowth, demonstrating that SLC6A15 controls neutral amino acid concentrations that affect mitochondrial activity, synaptic function, and neuronal structure.\",\n      \"method\": \"Slc6a15-KO hippocampal neurons with proteomics, electrophysiology (release probability), Seahorse mitochondrial assay, glutathione assay, and neurite morphometry\",\n      \"journal\": \"The European journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in KO neurons; single lab\",\n      \"pmids\": [\"33007132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SLC6A15 (B0AT2) transports phenylalanine into melanocytes, and its knockdown reduces intracellular phenylalanine levels, decreases melanin synthesis, downregulates MITF, TYR, and DCT expression, and abrogates UVB-induced pigmentation increase; UVB exposure transcriptionally upregulates SLC6A15.\",\n      \"method\": \"siRNA knockdown in MNT1 cells and primary melanocytes; Fontana-Masson staining; tyrosinase activity assay; intracellular phenylalanine measurement; RT-qPCR\",\n      \"journal\": \"Journal of photochemistry and photobiology. B, Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD with multiple functional readouts in two cell systems; single lab\",\n      \"pmids\": [\"41352278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"First selective inhibitors of B0AT2/SLC6A15 were identified by HTS of 200,000 compounds using a 3H-proline uptake assay; a 1,5-benzodiazepine series inhibits SLC6A15 with IC50 ~250 nM in SLC6A15-overexpressing HEK293 cells and primary neurons, with no detectable inhibition of SERT, DAT, GAT1, or NTT4/SLC6A17; inhibitor treatment dose-dependently stimulates neurite outgrowth in primary neurons.\",\n      \"method\": \"High-throughput 3H-proline uptake assay; selectivity counter-screens vs. related SLC6 transporters; neurite outgrowth assay in primary hippocampal neurons\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro assay with selectivity panel and cellular validation; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.03.25.645215\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Human SLC6A15 (v7-3) encodes a protein with 12 predicted transmembrane domains, intracellular N- and C-terminal domains, large extracellular loops between TM3-4 and TM7-8, and N-linked glycosylation sites; when expressed with an epitope tag, v7-3 localizes to the cell surface, in contrast to the related NTT5 which is predominantly intracellular.\",\n      \"method\": \"Epitope-tagged transient transfection and subcellular localization by immunofluorescence\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single localization experiment without functional consequence measurement\",\n      \"pmids\": [\"11112352\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLC6A15 (B0AT2) is a neuronal plasma-membrane, sodium-dependent neutral amino acid transporter with selectivity for branched-chain amino acids (leucine, isoleucine, valine), methionine, proline, and phenylalanine; PKC activation reduces its surface expression; in the brain it supplies neutral amino acids that regulate intracellular glutamate/glutamine pools and extracellular glutamate tone, modulates GluR1 expression, and in nucleus accumbens D2-neurons controls stress susceptibility; in melanocytes it transports phenylalanine to support melanogenesis; selective small-molecule inhibitors have been identified that block proline transport with ~250 nM potency and stimulate neurite outgrowth.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"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].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"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.\",\n      \"evidence\": \"Epitope-tagged expression with immunofluorescence in transfected cells\",\n      \"pmids\": [\"11112352\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No transport activity measured; surface localization based on single tagged construct without endogenous validation\", \"Glycosylation sites predicted but functional significance untested\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"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.\",\n      \"evidence\": \"Radiolabeled uptake in Xenopus oocytes with kinetic, pH, temperature, and PKC analyses\",\n      \"pmids\": [\"16226721\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for substrate selectivity unknown\", \"PKC-mediated internalization pathway not delineated\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"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.\",\n      \"evidence\": \"Slc6a15 KO mice with synaptosomal radiolabeled amino acid uptake\",\n      \"pmids\": [\"17931606\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Residual uptake indicates redundant transporters not identified\", \"Regional heterogeneity of contribution not mapped\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"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.\",\n      \"evidence\": \"KO mice with ICV leucine injection, food intake, c-Fos IHC; cellular 3H-proline uptake with variant constructs\",\n      \"pmids\": [\"23505546\", \"24023709\", \"23874702\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling from leucine sensing in VMH not characterized\", \"Coding variants not tested in vivo\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"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.\",\n      \"evidence\": \"Slc6a15 KO and viral overexpression with HPLC, NMR, microdialysis, behavioral tests, and Western blot\",\n      \"pmids\": [\"26228428\", \"26585320\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism connecting neutral amino acid import to glutamate pool regulation not fully delineated\", \"GluR1 regulation could be indirect\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"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.\",\n      \"evidence\": \"Cre-inducible viral KD/OE in D2-Cre and A2A-Cre mice with social defeat paradigm\",\n      \"pmids\": [\"28576941\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Amino acid changes in D2-MSNs upon manipulation not measured\", \"Whether glutamatergic mechanism generalizes from hippocampus to NAc untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"KO hippocampal neurons with electrophysiology, Seahorse assay, glutathione quantification, and morphometry\",\n      \"pmids\": [\"33007132\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal chain from amino acid depletion to mitochondrial and redox changes not resolved\", \"In vivo relevance of neurite outgrowth phenotype unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"evidence\": \"siRNA KD in MNT1 cells and primary melanocytes with melanin, phenylalanine, and gene expression assays\",\n      \"pmids\": [\"41352278\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether phenylalanine effect is direct or via tyrosine conversion not distinguished\", \"In vivo pigmentation phenotype in Slc6a15 KO mice not reported\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"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)\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 1, 4, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 1, 4, 9]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [4, 5, 7, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"GRIA1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}