{"gene":"SLC18B1","run_date":"2026-06-10T07:46:32","timeline":{"discoveries":[{"year":2014,"finding":"Purified human SLC18B1 protein reconstituted in proteoliposomes actively transports spermine and spermidine via H+ exchange (antiport), driven by an electrochemical H+ gradient. SLC18B1 is localized to vesicles in astrocytes, and gene knockdown decreased both SLC18B1 protein and spermine/spermidine contents in astrocytes, establishing SLC18B1 as a vesicular polyamine transporter (VPAT).","method":"Proteoliposome reconstitution with purified human SLC18B1; in vitro transport assay; immunolocalization to vesicles in astrocytes; siRNA knockdown with polyamine content measurement","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro reconstitution with purified protein, transport assay, loss-of-function knockdown with biochemical readout, all in a single focused study","pmids":["25355561"],"is_preprint":false},{"year":2020,"finding":"SLC18B1 (VPAT) transports both monoamines and polyamines (spermidine, spermine) using the electrochemical H+ gradient established by vacuolar H+-ATPase (V-ATPase) as driving force. SLC18B1 gene knockdown abolished polyamine exocytosis from mast cells, which in turn affected histamine secretion, placing VPAT upstream of histamine release.","method":"Proteoliposome transport assay; siRNA knockdown in mast cells; polyamine exocytosis measurement; histamine secretion assay","journal":"Biochimica et biophysica acta. Biomembranes","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro reconstitution replicated plus cell-based knockdown with defined downstream secretion phenotype","pmids":["32004521"],"is_preprint":false},{"year":2019,"finding":"Slc18b1 knockout mice show significantly reduced polyamine content (~20% decrease) in the brain, impaired short- and long-term memory (novel object recognition, radial arm maze, self-administration), altered expression of genes involved in long-term potentiation, calcium signalling, and synaptic function, and partial resistance to diazepam, indicating that VPAT is functionally required for maintaining brain polyamine levels and normal GABAergic/glutamatergic signalling.","method":"Slc18b1 knockout mouse model; polyamine content measurement in brain; behavioral tests (novel object recognition, radial arm maze, cocaine self-administration); brain RNA-seq; diazepam locomotor assay","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with multiple orthogonal behavioral and biochemical phenotypes, replicated across several paradigms","pmids":["31800589"],"is_preprint":false},{"year":2024,"finding":"SLC18B1 (VPAT) is expressed in MEG-01 megakaryoblastic cells and platelets. VPAT-mediated vesicular polyamine release from MEG-01 cells is temperature-dependent, Ca2+-dependent, and sensitive to bafilomycin A1 (V-ATPase inhibitor), reserpine, VPAT inhibitors, and VPAT RNA interference, establishing that polyamine secretion from these cells occurs via VPAT-dependent vesicular exocytosis. Platelets also express VPAT and release spermidine upon A23187 and thrombin stimulation.","method":"RT-PCR, western blotting, immunohistochemistry for VPAT expression; A23187/thrombin stimulation assay; pharmacological inhibition (bafilomycin A1, reserpine, VPAT inhibitors); siRNA knockdown; polyamine secretion measurement","journal":"Biochimica et biophysica acta. General subjects","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pharmacological and genetic perturbations in cell-based system, single lab","pmids":["38527572"],"is_preprint":false},{"year":2009,"finding":"C6ORF192 (SLC18B1) was identified as a novel solute carrier forming a unique evolutionary branch most closely related to SLC16, SLC17, and SLC18 families within the Major Facilitator Superfamily. It lacks key transmembrane domain motifs shared by those families. Expression profiling (qRT-PCR and in situ hybridization) detected the transcript in multiple CNS regions and peripheral tissues.","method":"Phylogenetic/evolutionary analysis; quantitative RT-PCR; in situ hybridization","journal":"Journal of molecular neuroscience : MN","confidence":"Low","confidence_rationale":"Tier 3–4 / Weak — expression profiling and bioinformatics; no functional transport or biochemical assay performed","pmids":["19697161"],"is_preprint":false}],"current_model":"SLC18B1 encodes the vesicular polyamine transporter (VPAT), a Major Facilitator Superfamily H+/polyamine antiporter that uses the V-ATPase-generated electrochemical H+ gradient to concentrate spermine and spermidine (and monoamines) into secretory vesicles in neurons, astrocytes, mast cells, megakaryoblasts, and platelets, thereby enabling Ca2+-dependent vesicular exocytosis of polyamines; loss of VPAT in mice reduces brain polyamine content and impairs memory and GABAergic/glutamatergic signalling."},"narrative":{"mechanistic_narrative":"SLC18B1 encodes the vesicular polyamine transporter (VPAT), which loads polyamines into secretory vesicles to enable their regulated exocytosis across multiple cell types [PMID:25355561, PMID:31800589]. Purified human SLC18B1 reconstituted into proteoliposomes actively transports spermine and spermidine by H+ antiport, driven by an electrochemical H+ gradient, and the protein localizes to vesicles in astrocytes where its knockdown lowers cellular polyamine content [PMID:25355561]. VPAT also handles monoamines and depends on the V-ATPase-generated H+ gradient; in mast cells it operates upstream of histamine release, with its knockdown abolishing polyamine exocytosis [PMID:32004521]. Vesicular, Ca2+-dependent polyamine secretion via VPAT is similarly demonstrated in megakaryoblastic MEG-01 cells and platelets, where release is sensitive to bafilomycin A1 (V-ATPase inhibition), reserpine, and VPAT inhibitors [PMID:38527572]. In vivo, Slc18b1 knockout mice show reduced brain polyamine content, impaired short- and long-term memory, altered expression of LTP/calcium-signalling/synaptic genes, and partial diazepam resistance, establishing VPAT as required for normal brain polyamine homeostasis and GABAergic/glutamatergic signalling [PMID:31800589].","teleology":[{"year":2009,"claim":"Established SLC18B1 (C6ORF192) as a distinct solute carrier within the Major Facilitator Superfamily and mapped its tissue expression, framing it as an orphan transporter candidate before any substrate was known.","evidence":"Phylogenetic analysis, qRT-PCR, and in situ hybridization across CNS and peripheral tissues","pmids":["19697161"],"confidence":"Low","gaps":["No functional transport or biochemical assay performed","Substrate identity entirely unresolved at this stage","Subcellular localization not determined"]},{"year":2014,"claim":"Resolved the orphan status by showing purified SLC18B1 directly transports spermine and spermidine via H+ antiport, defining it as the vesicular polyamine transporter (VPAT).","evidence":"Proteoliposome reconstitution with purified human protein, in vitro transport assay, vesicular immunolocalization in astrocytes, and siRNA knockdown with polyamine readout","pmids":["25355561"],"confidence":"High","gaps":["Physiological role beyond astrocytes not addressed","Coupling stoichiometry and structural basis of antiport not defined"]},{"year":2019,"claim":"Demonstrated that VPAT is required in vivo for brain polyamine homeostasis and normal cognition, linking vesicular polyamine handling to memory and inhibitory/excitatory neurotransmission.","evidence":"Slc18b1 knockout mouse with brain polyamine measurement, multiple behavioral paradigms, brain RNA-seq, and diazepam locomotor assay","pmids":["31800589"],"confidence":"High","gaps":["Cell-type origin of the behavioral phenotypes not dissected","Mechanistic link between reduced polyamines and altered GABAergic/glutamatergic genes not established","No human disease association tested"]},{"year":2020,"claim":"Broadened substrate scope to include monoamines and placed VPAT upstream of histamine release in mast cells, connecting polyamine transport to immune secretory output.","evidence":"Proteoliposome transport assay plus siRNA knockdown in mast cells with polyamine exocytosis and histamine secretion measurement","pmids":["32004521"],"confidence":"High","gaps":["Mechanism by which polyamine exocytosis controls histamine release not defined","Relative physiological contribution of monoamine vs polyamine transport unclear"]},{"year":2024,"claim":"Extended VPAT-dependent vesicular polyamine secretion to megakaryoblasts and platelets, showing it is Ca2+- and V-ATPase-dependent in hemostatic cell types.","evidence":"Expression profiling, agonist (A23187/thrombin) stimulation, pharmacological inhibition (bafilomycin A1, reserpine, VPAT inhibitors), and siRNA knockdown in MEG-01 cells and platelets","pmids":["38527572"],"confidence":"Medium","gaps":["Single-lab cell-based evidence without in vivo confirmation","Functional consequence of platelet polyamine release not established"]},{"year":null,"claim":"How VPAT substrate selectivity, transport stoichiometry, and structural mechanism are determined, and whether SLC18B1 variants cause human disease, remain open.","evidence":"Not addressed in the available corpus","pmids":[],"confidence":"Low","gaps":["No structural model of the transporter","No human Mendelian disease link tested in the timeline","Regulation of VPAT expression and vesicular targeting uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[1,3]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6NT16","full_name":"MFS-type transporter SLC18B1","aliases":["Solute carrier family 18 member B1","Vesicular polyamine transporter","VPAT"],"length_aa":456,"mass_kda":48.9,"function":"Proton-coupled polyamine antiporter involved in the translocation of polyamines from cytosol into secretory vesicles prior to their release via exocytosis. Uses the electrochemical proton gradient generated by a V-type proton-pumping ATPase to couple the efflux of protons with the uptake of a polyamine molecule (PubMed:25355561). Facilitates vesicular storage of spermine and spermidine in astrocytes with an impact on glutamatergic neuronal transmission and memory formation (By similarity) (PubMed:25355561). Upon antigen stimulation, regulates polyamine accumulation and release in mast cell secretory granules, which in turn potentiates mast cell degranulation and histamine secretion (By similarity)","subcellular_location":"Cytoplasmic vesicle, secretory vesicle membrane; Cytoplasmic vesicle, secretory vesicle, synaptic vesicle membrane","url":"https://www.uniprot.org/uniprotkb/Q6NT16/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SLC18B1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000146409","cell_line_id":"CID001315","localizations":[{"compartment":"vesicles","grade":3}],"interactors":[{"gene":"LAMP1","stoichiometry":10.0},{"gene":"LAMTOR2","stoichiometry":0.2},{"gene":"USP10","stoichiometry":0.2},{"gene":"BACH1","stoichiometry":0.2},{"gene":"LAMTOR5","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001315","total_profiled":1310},"omim":[{"mim_id":"613361","title":"SOLUTE CARRIER FAMILY 18, MEMBER B1; SLC18B1","url":"https://www.omim.org/entry/613361"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SLC18B1"},"hgnc":{"alias_symbol":["dJ55C23.6"],"prev_symbol":["C6orf192"]},"alphafold":{"accession":"Q6NT16","domains":[{"cath_id":"1.20.1250.20","chopping":"32-219","consensus_level":"medium","plddt":90.0396,"start":32,"end":219},{"cath_id":"1.20.1250.20","chopping":"223-437","consensus_level":"medium","plddt":87.2113,"start":223,"end":437}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6NT16","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6NT16-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6NT16-F1-predicted_aligned_error_v6.png","plddt_mean":84.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLC18B1","jax_strain_url":"https://www.jax.org/strain/search?query=SLC18B1"},"sequence":{"accession":"Q6NT16","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6NT16.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6NT16/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6NT16"}},"corpus_meta":[{"pmid":"25355561","id":"PMC_25355561","title":"Identification of a mammalian vesicular polyamine transporter.","date":"2014","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/25355561","citation_count":82,"is_preprint":false},{"pmid":"23506877","id":"PMC_23506877","title":"SLC18: Vesicular neurotransmitter transporters for monoamines and acetylcholine.","date":"2013","source":"Molecular aspects of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/23506877","citation_count":82,"is_preprint":false},{"pmid":"32004521","id":"PMC_32004521","title":"Vesicular polyamine transporter as a novel player in amine-mediated chemical transmission.","date":"2020","source":"Biochimica et biophysica acta. Biomembranes","url":"https://pubmed.ncbi.nlm.nih.gov/32004521","citation_count":35,"is_preprint":false},{"pmid":"31800589","id":"PMC_31800589","title":"The polyamine transporter Slc18b1(VPAT) is important for both short and long time memory and for regulation of polyamine content in the brain.","date":"2019","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31800589","citation_count":27,"is_preprint":false},{"pmid":"19697161","id":"PMC_19697161","title":"C6ORF192 forms a unique evolutionary branch among solute carriers (SLC16, SLC17, and SLC18) and is abundantly expressed in several brain regions.","date":"2009","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/19697161","citation_count":14,"is_preprint":false},{"pmid":"36008447","id":"PMC_36008447","title":"A systematic exploration reveals the potential of spermidine for hypopigmentation treatment through the stabilization of melanogenesis-associated proteins.","date":"2022","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/36008447","citation_count":11,"is_preprint":false},{"pmid":"37481717","id":"PMC_37481717","title":"Genetic pathways regulating the longitudinal acquisition of cocaine self-administration in a panel of inbred and recombinant inbred mice.","date":"2023","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/37481717","citation_count":11,"is_preprint":false},{"pmid":"29885947","id":"PMC_29885947","title":"A transcriptomic signature predicting septic outcome in patients undergoing autologous stem cell transplantation.","date":"2018","source":"Experimental hematology","url":"https://pubmed.ncbi.nlm.nih.gov/29885947","citation_count":7,"is_preprint":false},{"pmid":"38527572","id":"PMC_38527572","title":"Polyamine release and vesicular polyamine transporter expression in megakaryoblastic cells and platelets.","date":"2024","source":"Biochimica et biophysica acta. General subjects","url":"https://pubmed.ncbi.nlm.nih.gov/38527572","citation_count":5,"is_preprint":false},{"pmid":"39703124","id":"PMC_39703124","title":"Investigating the common genetic architecture and causality of metabolic disorders with neurodegenerative diseases.","date":"2024","source":"Diabetes, obesity & metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/39703124","citation_count":5,"is_preprint":false},{"pmid":"39130372","id":"PMC_39130372","title":"Involvement of mammalian SoLute Carriers (SLC) in the traffic of polyamines.","date":"2024","source":"Frontiers in molecular biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/39130372","citation_count":5,"is_preprint":false},{"pmid":"39379401","id":"PMC_39379401","title":"Polyamine impact on physiology of early stages of reef-building corals-insights from rearing experiments and RNA-Seq analysis.","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/39379401","citation_count":1,"is_preprint":false},{"pmid":"41806308","id":"PMC_41806308","title":"Genome-Wide Association Study Reveals Insect Genetics and Microbial Symbiont Effects on Susceptibility of Diaphorina citri to the Citrus Greening Pathogen, Candidatus Liberibacter Asiaticus.","date":"2026","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/41806308","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7576,"output_tokens":1520,"usd":0.022764,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8265,"output_tokens":2180,"usd":0.047912,"stage2_stop_reason":"end_turn"},"total_usd":0.070676,"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\": 2014,\n      \"finding\": \"Purified human SLC18B1 protein reconstituted in proteoliposomes actively transports spermine and spermidine via H+ exchange (antiport), driven by an electrochemical H+ gradient. SLC18B1 is localized to vesicles in astrocytes, and gene knockdown decreased both SLC18B1 protein and spermine/spermidine contents in astrocytes, establishing SLC18B1 as a vesicular polyamine transporter (VPAT).\",\n      \"method\": \"Proteoliposome reconstitution with purified human SLC18B1; in vitro transport assay; immunolocalization to vesicles in astrocytes; siRNA knockdown with polyamine content measurement\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro reconstitution with purified protein, transport assay, loss-of-function knockdown with biochemical readout, all in a single focused study\",\n      \"pmids\": [\"25355561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SLC18B1 (VPAT) transports both monoamines and polyamines (spermidine, spermine) using the electrochemical H+ gradient established by vacuolar H+-ATPase (V-ATPase) as driving force. SLC18B1 gene knockdown abolished polyamine exocytosis from mast cells, which in turn affected histamine secretion, placing VPAT upstream of histamine release.\",\n      \"method\": \"Proteoliposome transport assay; siRNA knockdown in mast cells; polyamine exocytosis measurement; histamine secretion assay\",\n      \"journal\": \"Biochimica et biophysica acta. Biomembranes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro reconstitution replicated plus cell-based knockdown with defined downstream secretion phenotype\",\n      \"pmids\": [\"32004521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Slc18b1 knockout mice show significantly reduced polyamine content (~20% decrease) in the brain, impaired short- and long-term memory (novel object recognition, radial arm maze, self-administration), altered expression of genes involved in long-term potentiation, calcium signalling, and synaptic function, and partial resistance to diazepam, indicating that VPAT is functionally required for maintaining brain polyamine levels and normal GABAergic/glutamatergic signalling.\",\n      \"method\": \"Slc18b1 knockout mouse model; polyamine content measurement in brain; behavioral tests (novel object recognition, radial arm maze, cocaine self-administration); brain RNA-seq; diazepam locomotor assay\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with multiple orthogonal behavioral and biochemical phenotypes, replicated across several paradigms\",\n      \"pmids\": [\"31800589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SLC18B1 (VPAT) is expressed in MEG-01 megakaryoblastic cells and platelets. VPAT-mediated vesicular polyamine release from MEG-01 cells is temperature-dependent, Ca2+-dependent, and sensitive to bafilomycin A1 (V-ATPase inhibitor), reserpine, VPAT inhibitors, and VPAT RNA interference, establishing that polyamine secretion from these cells occurs via VPAT-dependent vesicular exocytosis. Platelets also express VPAT and release spermidine upon A23187 and thrombin stimulation.\",\n      \"method\": \"RT-PCR, western blotting, immunohistochemistry for VPAT expression; A23187/thrombin stimulation assay; pharmacological inhibition (bafilomycin A1, reserpine, VPAT inhibitors); siRNA knockdown; polyamine secretion measurement\",\n      \"journal\": \"Biochimica et biophysica acta. General subjects\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacological and genetic perturbations in cell-based system, single lab\",\n      \"pmids\": [\"38527572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"C6ORF192 (SLC18B1) was identified as a novel solute carrier forming a unique evolutionary branch most closely related to SLC16, SLC17, and SLC18 families within the Major Facilitator Superfamily. It lacks key transmembrane domain motifs shared by those families. Expression profiling (qRT-PCR and in situ hybridization) detected the transcript in multiple CNS regions and peripheral tissues.\",\n      \"method\": \"Phylogenetic/evolutionary analysis; quantitative RT-PCR; in situ hybridization\",\n      \"journal\": \"Journal of molecular neuroscience : MN\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3–4 / Weak — expression profiling and bioinformatics; no functional transport or biochemical assay performed\",\n      \"pmids\": [\"19697161\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLC18B1 encodes the vesicular polyamine transporter (VPAT), a Major Facilitator Superfamily H+/polyamine antiporter that uses the V-ATPase-generated electrochemical H+ gradient to concentrate spermine and spermidine (and monoamines) into secretory vesicles in neurons, astrocytes, mast cells, megakaryoblasts, and platelets, thereby enabling Ca2+-dependent vesicular exocytosis of polyamines; loss of VPAT in mice reduces brain polyamine content and impairs memory and GABAergic/glutamatergic signalling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SLC18B1 encodes the vesicular polyamine transporter (VPAT), which loads polyamines into secretory vesicles to enable their regulated exocytosis across multiple cell types [#0, #2]. Purified human SLC18B1 reconstituted into proteoliposomes actively transports spermine and spermidine by H+ antiport, driven by an electrochemical H+ gradient, and the protein localizes to vesicles in astrocytes where its knockdown lowers cellular polyamine content [#0]. VPAT also handles monoamines and depends on the V-ATPase-generated H+ gradient; in mast cells it operates upstream of histamine release, with its knockdown abolishing polyamine exocytosis [#1]. Vesicular, Ca2+-dependent polyamine secretion via VPAT is similarly demonstrated in megakaryoblastic MEG-01 cells and platelets, where release is sensitive to bafilomycin A1 (V-ATPase inhibition), reserpine, and VPAT inhibitors [#3]. In vivo, Slc18b1 knockout mice show reduced brain polyamine content, impaired short- and long-term memory, altered expression of LTP/calcium-signalling/synaptic genes, and partial diazepam resistance, establishing VPAT as required for normal brain polyamine homeostasis and GABAergic/glutamatergic signalling [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established SLC18B1 (C6ORF192) as a distinct solute carrier within the Major Facilitator Superfamily and mapped its tissue expression, framing it as an orphan transporter candidate before any substrate was known.\",\n      \"evidence\": \"Phylogenetic analysis, qRT-PCR, and in situ hybridization across CNS and peripheral tissues\",\n      \"pmids\": [\"19697161\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No functional transport or biochemical assay performed\",\n        \"Substrate identity entirely unresolved at this stage\",\n        \"Subcellular localization not determined\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved the orphan status by showing purified SLC18B1 directly transports spermine and spermidine via H+ antiport, defining it as the vesicular polyamine transporter (VPAT).\",\n      \"evidence\": \"Proteoliposome reconstitution with purified human protein, in vitro transport assay, vesicular immunolocalization in astrocytes, and siRNA knockdown with polyamine readout\",\n      \"pmids\": [\"25355561\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Physiological role beyond astrocytes not addressed\",\n        \"Coupling stoichiometry and structural basis of antiport not defined\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated that VPAT is required in vivo for brain polyamine homeostasis and normal cognition, linking vesicular polyamine handling to memory and inhibitory/excitatory neurotransmission.\",\n      \"evidence\": \"Slc18b1 knockout mouse with brain polyamine measurement, multiple behavioral paradigms, brain RNA-seq, and diazepam locomotor assay\",\n      \"pmids\": [\"31800589\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Cell-type origin of the behavioral phenotypes not dissected\",\n        \"Mechanistic link between reduced polyamines and altered GABAergic/glutamatergic genes not established\",\n        \"No human disease association tested\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Broadened substrate scope to include monoamines and placed VPAT upstream of histamine release in mast cells, connecting polyamine transport to immune secretory output.\",\n      \"evidence\": \"Proteoliposome transport assay plus siRNA knockdown in mast cells with polyamine exocytosis and histamine secretion measurement\",\n      \"pmids\": [\"32004521\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which polyamine exocytosis controls histamine release not defined\",\n        \"Relative physiological contribution of monoamine vs polyamine transport unclear\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended VPAT-dependent vesicular polyamine secretion to megakaryoblasts and platelets, showing it is Ca2+- and V-ATPase-dependent in hemostatic cell types.\",\n      \"evidence\": \"Expression profiling, agonist (A23187/thrombin) stimulation, pharmacological inhibition (bafilomycin A1, reserpine, VPAT inhibitors), and siRNA knockdown in MEG-01 cells and platelets\",\n      \"pmids\": [\"38527572\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab cell-based evidence without in vivo confirmation\",\n        \"Functional consequence of platelet polyamine release not established\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How VPAT substrate selectivity, transport stoichiometry, and structural mechanism are determined, and whether SLC18B1 variants cause human disease, remain open.\",\n      \"evidence\": \"Not addressed in the available corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of the transporter\",\n        \"No human Mendelian disease link tested in the timeline\",\n        \"Regulation of VPAT expression and vesicular targeting uncharacterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}