{"gene":"HTR3B","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":1999,"finding":"The 5-HT3B subunit (HTR3B) assembles with the 5-HT3A subunit to form heteromeric 5-HT3AB receptors with a large single-channel conductance (16 pS), low calcium permeability, and a current-voltage relationship resembling native neuronal 5-HT3 channels, in contrast to homomeric 5-HT3A receptors (sub-picosiemens conductance). The M2 region of 5-HT3B lacks structural features known to promote conductance in related receptors.","method":"Recombinant heterologous expression of 5-HT3A and 5-HT3B subunits, single-channel patch-clamp electrophysiology, ion permeability measurements","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — original reconstitution with single-channel electrophysiology, foundational paper with 465 citations replicated across multiple subsequent studies","pmids":["9950429"],"is_preprint":false},{"year":2003,"finding":"Co-expression of the 5-HT3B subunit with 5-HT3A in HEK293 cells reduces 5-HT sensitivity (EC50 shifts from 3 µM to 25 µM, Hill coefficient from 1.8 to 0.9), markedly alters receptor desensitization kinetics, eliminates agonist-induced open-channel block seen in homomeric receptors, and accelerates recovery from desensitization in heteromeric 5-HT3AB receptors.","method":"Whole-cell patch-clamp recordings in HEK293 cells expressing homomeric 5-HT3A or heteromeric 5-HT3AB receptors; kinetic modeling","journal":"Biophysical journal","confidence":"High","confidence_rationale":"Tier 1 — direct electrophysiological characterization with kinetic modeling, multiple biophysical parameters measured","pmids":["12609874"],"is_preprint":false},{"year":2003,"finding":"The 5-HT3B subunit confers 100-fold reduced sensitivity to picrotoxin inhibition when co-expressed with 5-HT3A, identifying picrotoxin as a pharmacological probe to distinguish homomeric 5-HT3A from heteromeric 5-HT3A/3B receptors.","method":"Whole-cell patch-clamp recordings in cells expressing homomeric mouse 5-HT3A or heteromeric 5-HT3A/3B receptors","journal":"Brain research. Molecular brain research","confidence":"High","confidence_rationale":"Tier 1 — direct electrophysiological assay with quantitative comparison between receptor compositions","pmids":["14625088"],"is_preprint":false},{"year":2003,"finding":"Introduction of recombinant 5-HT3B subunits into mouse neuroblastoma NB41A3 cells (which endogenously express 5-HT3A) shifts receptors from homomeric to heteromeric, reducing 5-HT potency, altering current kinetics, and abolishing 5-HT-induced Ca2+ increases, consistent with conversion of high-Ca2+-permeability homomeric 5-HT3A to low-Ca2+-permeability heteromeric 5-HT3AB receptors.","method":"Transient transfection of 5-HT3B into NB41A3 neuroblastoma cells; Ca2+ imaging; whole-cell patch-clamp electrophysiology; RT-PCR","journal":"Neuropharmacology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (electrophysiology, Ca2+ imaging, RT-PCR) in native neuronal cell line","pmids":["12623220"],"is_preprint":false},{"year":2006,"finding":"Two alternative promoters control tissue-specific expression of different HTR3B transcripts: one active in the intestine (corresponding to published genome annotation) and one active in the brain (~4000 bp downstream), generating brain-specific transcripts with an upstream-extended exon 2 and a new potential translational start site, suggesting different 5-HT3B isoforms in peripheral vs. central nervous system.","method":"Transcription start site analysis, transcript-specific RT-PCR, luciferase reporter gene (functional promoter) assays in intestinal and brain tissue","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 — multiple methods (TSS mapping, RT-PCR, reporter assay) from a single lab","pmids":["17010535"],"is_preprint":false},{"year":2006,"finding":"5-HT3A and 5-HT3B subunit immunoreactivity was identified in pyramidal neurons of human hippocampal CA2/CA3 fields and hilar neurons, with both subunit proteins co-expressed in the same regions, indicating capacity to form heteromeric receptors in human brain.","method":"SDS-PAGE/Western blotting with selective polyclonal antibodies, immunohistochemistry, RT-PCR on human hippocampal tissue","journal":"Neuropharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple detection methods (WB, IHC, PCR) for protein and transcript localization in human tissue","pmids":["17327132"],"is_preprint":false},{"year":2001,"finding":"The 5-HT3B subunit protein is expressed in interneurons of the rat hippocampus, as detected by a selective polyclonal antibody (AP86/3) in immunohistochemical studies.","method":"Generation of subunit-selective polyclonal antibody; Western blot on recombinant cell lines; immunohistochemistry on rat hippocampal sections","journal":"Neuropharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — antibody validated on recombinant systems before use in native tissue","pmids":["11747906"],"is_preprint":false},{"year":2006,"finding":"5-HT3B subunits do not reach the plasma membrane in the absence of 5-HT3A subunits, demonstrating that surface trafficking of 5-HT3B requires co-assembly with 5-HT3A.","method":"Immunocytochemistry using a validated anti-5-HT3B polyclonal antibody (pAb77) on transfected HEK293 cells expressing 5-HT3B alone or with 5-HT3A","journal":"BMC neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization experiment with functional implication, antibody validated by WB","pmids":["16571125"],"is_preprint":false},{"year":2008,"finding":"The naturally occurring 5-HT3B variant Y129S (rs1176744) dramatically augments 5-HT3AB receptor signaling: 5-HT3AB(Y129S) receptors display 20-fold slower deactivation, 10-fold slower desensitization, and 7-fold increased mean single-channel open time compared to wild-type 5-HT3AB receptors, substantially increasing maximal responses to serotonin.","method":"Fluorescence-based cellular Ca2+ assays; whole-cell and single-channel patch-clamp electrophysiology in HEK293 cells expressing 5-HT3A and 5-HT3B(Y129S)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — multiple orthogonal electrophysiological methods including single-channel recordings, quantitative kinetic analysis","pmids":["18184810"],"is_preprint":false},{"year":2008,"finding":"Co-expression of 5-HT3A and 5-HT3B subunits produces a receptor with constitutive (agonist-independent) channel opening. Additionally, subunit composition changes ligand properties: 5-methoxyindole is a partial agonist at homomeric 5-HT3A but becomes a protean agonist (acting as both agonist and inverse agonist) at heteromeric 5-HT3AB receptors; 5-hydroxyindole positively modulates ligand-gated active (AR*) conformation but negatively modulates the spontaneously active (R*) conformation of 5-HT3AB.","method":"Whole-cell patch-clamp electrophysiology in HEK293 cells expressing 5-HT3A and 5-HT3B; two-state allosteric model analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — direct electrophysiological recordings with mechanistic modeling, multiple ligands tested","pmids":["18187416"],"is_preprint":false},{"year":2008,"finding":"Naturally occurring HTR3B variants differentially affect heteromeric 5-HT3AB receptor function: p.Y129S and p.S156R increase 5-HT maximum responses; p.V183I decreases surface expression; p.I143T markedly reduces cell surface expression of both 5-HT3B and 5-HT3A subunits and reduces current density ~3-fold while preserving macroscopic kinetics.","method":"Aequorin bioluminescence Ca2+ influx assay; [3H]GR65630 radioligand binding; ELISA for surface expression; immunocytochemistry; whole-cell patch-clamp electrophysiology in HEK293 cells","journal":"Pharmacogenetics and genomics / Pharmacogenetics and genomics","confidence":"High","confidence_rationale":"Tier 1 — multiple orthogonal methods (radioligand binding, Ca2+ assay, ELISA, electrophysiology) across two independent studies (PMIDs 18698232 and 19008750)","pmids":["18698232","19008750"],"is_preprint":false},{"year":2011,"finding":"The human 5-HT3B subunit is N-glycosylated at five consensus sites (N31, N75, N117, N147, N182); disruption of each site individually reduces molecular weight (~2–4 kDa per site) and reduces cell membrane expression of the subunit when co-expressed with 5-HT3A, establishing that N-glycosylation is required for proper trafficking of 5-HT3B to the plasma membrane.","method":"Tunicamycin treatment; site-directed mutagenesis of N-glycosylation sites (N→S substitutions); SDS-PAGE/Western blot; immunocytochemistry in HEK293 cells stably expressing 5-HT3A","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis of each glycosylation site combined with biochemical and imaging readouts, clear structure-function relationship established","pmids":["21138434"],"is_preprint":false},{"year":2008,"finding":"The -100_-102delAAG deletion in the HTR3B promoter region increases HTR3B promoter activity in vitro by 25–43% compared to the insertion allele, with differential binding of nuclear proteins to the polymorphic region, providing a molecular mechanism for previously reported disease associations of this variant.","method":"Electrophoretic mobility shift assay (EMSA); luciferase reporter gene assays in PC-12 and HEK293 cells; deletion mapping","journal":"Pharmacogenetics and genomics","confidence":"Medium","confidence_rationale":"Tier 2 — two orthogonal methods (EMSA and reporter assay) from a single lab, replicated in two cell lines","pmids":["18300944"],"is_preprint":false}],"current_model":"HTR3B (5-HT3B) is an obligate auxiliary subunit that co-assembles with the 5-HT3A subunit to form heteromeric pentameric ligand-gated ion channels (5-HT3AB receptors); incorporation of 5-HT3B dramatically increases single-channel conductance to ~16 pS, reduces calcium permeability and 5-HT potency, alters desensitization/deactivation kinetics, confers constitutive channel opening, and changes ligand pharmacology — with 5-HT3B requiring N-glycosylation and co-assembly with 5-HT3A for plasma membrane trafficking, and naturally occurring variants (e.g., Y129S, I143T) quantitatively modulating receptor surface expression and gating properties."},"narrative":{"teleology":[{"year":1999,"claim":"Identification of HTR3B as a heteromeric partner of 5-HT3A resolved the long-standing discrepancy between the sub-picosiemens conductance of recombinant homomeric 5-HT3A receptors and the ~16 pS conductance of native neuronal 5-HT3 channels.","evidence":"Reconstitution of heteromeric 5-HT3AB receptors in heterologous cells with single-channel patch-clamp electrophysiology","pmids":["9950429"],"confidence":"High","gaps":["Subunit stoichiometry within the pentamer was not determined","The structural basis for the conductance increase remained unknown given the 5-HT3B M2 region lacks features associated with high conductance","Whether 5-HT3B is expressed at the protein level in native neurons was unconfirmed"]},{"year":2001,"claim":"Detection of 5-HT3B protein in rat hippocampal interneurons established that the subunit is expressed in native brain tissue, supporting the physiological relevance of heteromeric 5-HT3AB receptors in the CNS.","evidence":"Subunit-selective antibody immunohistochemistry on rat hippocampal sections","pmids":["11747906"],"confidence":"Medium","gaps":["Antibody specificity was validated on recombinant lines but not with knockout controls","Co-localization with 5-HT3A at the single-cell level was not demonstrated","Expression in other brain regions was not surveyed"]},{"year":2003,"claim":"Detailed biophysical characterization showed that 5-HT3B incorporation shifts 5-HT EC50, Hill coefficient, desensitization kinetics, recovery kinetics, calcium permeability, and picrotoxin sensitivity, establishing that the B subunit is a major determinant of channel pharmacology and gating.","evidence":"Whole-cell patch-clamp and Ca2+ imaging in HEK293 cells and NB41A3 neuroblastoma cells comparing homomeric 5-HT3A with heteromeric 5-HT3AB","pmids":["12609874","14625088","12623220"],"confidence":"High","gaps":["Which structural domains of 5-HT3B mediate specific kinetic changes was unknown","Stoichiometry and arrangement of A and B subunits in the pentamer remained undetermined"]},{"year":2006,"claim":"Discovery that 5-HT3B cannot traffic to the plasma membrane without 5-HT3A, combined with identification of tissue-specific alternative promoters, revealed that 5-HT3B is an obligate auxiliary subunit whose expression is independently regulated in brain versus intestine.","evidence":"Immunocytochemistry in transfected HEK293 cells; transcript-specific RT-PCR and luciferase reporter assays across brain and intestinal tissue","pmids":["16571125","17010535","17327132"],"confidence":"Medium","gaps":["The trafficking signal that retains 5-HT3B intracellularly in the absence of 5-HT3A was not identified","Whether alternative promoter usage generates functionally distinct 5-HT3B isoforms at the protein level was not tested","Surface trafficking dependence demonstrated only in HEK293 cells, not in neurons"]},{"year":2008,"claim":"Functional analysis of naturally occurring HTR3B variants revealed that coding polymorphisms (Y129S, I143T, S156R, V183I) modulate receptor gating kinetics and surface expression, establishing HTR3B as a pharmacogenomic determinant of 5-HT3 receptor function, while a promoter indel variant alters transcriptional output.","evidence":"Single-channel and whole-cell electrophysiology, radioligand binding, ELISA surface expression, Ca2+ assays, and luciferase reporter assays in HEK293 cells","pmids":["18184810","18698232","19008750","18300944"],"confidence":"High","gaps":["Whether these variants alter receptor function in native neurons or in vivo was not tested","Structural mechanism by which Y129S slows deactivation 20-fold was not resolved","The transcription factors differentially binding the promoter indel were not identified"]},{"year":2008,"claim":"Demonstration of constitutive (agonist-independent) channel opening in heteromeric 5-HT3AB receptors, and identification of protean agonist behavior at these receptors, revealed that 5-HT3B shifts the allosteric equilibrium of the channel toward spontaneous activity.","evidence":"Whole-cell patch-clamp with allosteric model fitting in HEK293 cells expressing 5-HT3AB","pmids":["18187416"],"confidence":"High","gaps":["The structural basis for the shift in basal equilibrium toward the open state was not identified","Whether constitutive activity occurs in native heteromeric receptors in neurons was not tested"]},{"year":2011,"claim":"Mapping of five N-glycosylation sites on 5-HT3B and demonstration that each contributes to membrane trafficking established post-translational modification as a critical quality-control mechanism for heteromeric receptor biogenesis.","evidence":"Site-directed mutagenesis of each N-glycosylation site, SDS-PAGE, immunocytochemistry in HEK293 cells stably expressing 5-HT3A","pmids":["21138434"],"confidence":"High","gaps":["Whether glycosylation affects receptor gating or pharmacology beyond trafficking was not assessed","The ER quality-control checkpoint(s) sensing under-glycosylated 5-HT3B were not identified"]},{"year":null,"claim":"The subunit stoichiometry and arrangement within the heteromeric pentamer, the structural basis for the conductance increase, and the in vivo consequences of 5-HT3B variants on serotonergic signaling remain to be established by structural and genetic approaches.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structure of the heteromeric 5-HT3AB receptor has been reported in this timeline","Subunit stoichiometry (e.g., 2A:3B vs. 3A:2B) is unresolved","In vivo phenotypes of HTR3B loss-of-function or variant alleles in animal models are lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,1,9]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[7,11]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,5,6]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,9]}],"complexes":["5-HT3AB heteromeric receptor"],"partners":["HTR3A"],"other_free_text":[]},"mechanistic_narrative":"HTR3B encodes the 5-HT3B subunit of the serotonin type 3 receptor, a pentameric ligand-gated ion channel that functions as an obligate heteromeric partner of the 5-HT3A subunit to recapitulate native neuronal 5-HT3 receptor properties. Co-assembly of 5-HT3B with 5-HT3A increases single-channel conductance to ~16 pS, reduces calcium permeability, lowers 5-HT potency, alters desensitization and deactivation kinetics, confers constitutive (agonist-independent) channel opening, and changes the pharmacological profile of modulators including picrotoxin and indole compounds [PMID:9950429, PMID:12609874, PMID:18187416, PMID:14625088]. 5-HT3B requires N-glycosylation at five extracellular sites and co-expression with 5-HT3A for trafficking to the plasma membrane, and naturally occurring coding variants (Y129S, I143T) quantitatively alter receptor surface expression and gating kinetics [PMID:21138434, PMID:18184810, PMID:18698232, PMID:16571125]. The subunit is expressed in hippocampal neurons and intestinal tissue under control of alternative tissue-specific promoters [PMID:11747906, PMID:17327132, PMID:17010535]."},"prefetch_data":{"uniprot":{"accession":"O95264","full_name":"5-hydroxytryptamine receptor 3B","aliases":["Serotonin receptor 3B"],"length_aa":441,"mass_kda":50.3,"function":"Forms serotonin (5-hydroxytryptamine/5-HT3)-activated cation-selective channel complexes, which when activated cause fast, depolarizing responses in neurons","subcellular_location":"Postsynaptic cell membrane; Cell membrane","url":"https://www.uniprot.org/uniprotkb/O95264/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HTR3B","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/HTR3B","total_profiled":1310},"omim":[{"mim_id":"610123","title":"5-@HYDROXYTRYPTAMINE RECEPTOR 3E; HTR3E","url":"https://www.omim.org/entry/610123"},{"mim_id":"610122","title":"5-@HYDROXYTRYPTAMINE RECEPTOR 3D; HTR3D","url":"https://www.omim.org/entry/610122"},{"mim_id":"610121","title":"5-@HYDROXYTRYPTAMINE RECEPTOR 3C; HTR3C","url":"https://www.omim.org/entry/610121"},{"mim_id":"604654","title":"5-@HYDROXYTRYPTAMINE RECEPTOR 3B; HTR3B","url":"https://www.omim.org/entry/604654"},{"mim_id":"182139","title":"5-@HYDROXYTRYPTAMINE RECEPTOR 3A; HTR3A","url":"https://www.omim.org/entry/182139"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in single","driving_tissues":[{"tissue":"brain","ntpm":3.9}],"url":"https://www.proteinatlas.org/search/HTR3B"},"hgnc":{"alias_symbol":["5-HT3B"],"prev_symbol":[]},"alphafold":{"accession":"O95264","domains":[{"cath_id":"2.70.170.10","chopping":"34-238","consensus_level":"high","plddt":92.182,"start":34,"end":238},{"cath_id":"1.20.58.390","chopping":"240-330_397-441","consensus_level":"medium","plddt":86.366,"start":240,"end":441}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O95264","model_url":"https://alphafold.ebi.ac.uk/files/AF-O95264-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O95264-F1-predicted_aligned_error_v6.png","plddt_mean":81.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HTR3B","jax_strain_url":"https://www.jax.org/strain/search?query=HTR3B"},"sequence":{"accession":"O95264","fasta_url":"https://rest.uniprot.org/uniprotkb/O95264.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O95264/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O95264"}},"corpus_meta":[{"pmid":"9950429","id":"PMC_9950429","title":"The 5-HT3B subunit is a major determinant of serotonin-receptor function.","date":"1999","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/9950429","citation_count":465,"is_preprint":false},{"pmid":"16487942","id":"PMC_16487942","title":"Distinguishable haplotype blocks in the HTR3A and HTR3B region in the Japanese reveal evidence of association of HTR3B with female major depression.","date":"2006","source":"Biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/16487942","citation_count":73,"is_preprint":false},{"pmid":"12609874","id":"PMC_12609874","title":"Co-expression of the 5-HT3B serotonin receptor subunit alters the biophysics of the 5-HT3 receptor.","date":"2003","source":"Biophysical journal","url":"https://pubmed.ncbi.nlm.nih.gov/12609874","citation_count":67,"is_preprint":false},{"pmid":"18184810","id":"PMC_18184810","title":"High-frequency HTR3B variant associated with major depression dramatically augments the signaling of the human 5-HT3AB receptor.","date":"2008","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/18184810","citation_count":65,"is_preprint":false},{"pmid":"19713259","id":"PMC_19713259","title":"Do variations in the 5-HT3A and 5-HT3B serotonin receptor genes (HTR3A and HTR3B) influence the occurrence of postoperative vomiting?","date":"2009","source":"Anesthesia and analgesia","url":"https://pubmed.ncbi.nlm.nih.gov/19713259","citation_count":52,"is_preprint":false},{"pmid":"17010535","id":"PMC_17010535","title":"Tissue-specific alternative promoters of the serotonin receptor gene HTR3B in human brain and intestine.","date":"2006","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/17010535","citation_count":50,"is_preprint":false},{"pmid":"15389765","id":"PMC_15389765","title":"Investigation of the human serotonin receptor gene HTR3B in bipolar affective and schizophrenic patients.","date":"2004","source":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15389765","citation_count":46,"is_preprint":false},{"pmid":"14625088","id":"PMC_14625088","title":"The 5-HT3B subunit confers reduced sensitivity to picrotoxin when co-expressed with the 5-HT3A receptor.","date":"2003","source":"Brain research. Molecular brain research","url":"https://pubmed.ncbi.nlm.nih.gov/14625088","citation_count":39,"is_preprint":false},{"pmid":"15293096","id":"PMC_15293096","title":"Mutational analysis of serotonin receptor genes: HTR3A and HTR3B in fibromyalgia patients.","date":"2004","source":"Clinical rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/15293096","citation_count":38,"is_preprint":false},{"pmid":"12363396","id":"PMC_12363396","title":"Novel mutations in 5-HT3A and 5-HT3B receptor genes not associated with clozapine response.","date":"2002","source":"Schizophrenia research","url":"https://pubmed.ncbi.nlm.nih.gov/12363396","citation_count":37,"is_preprint":false},{"pmid":"18698232","id":"PMC_18698232","title":"Naturally occurring variants in the HTR3B gene significantly alter properties of human heteromeric 5-hydroxytryptamine-3A/B receptors.","date":"2008","source":"Pharmacogenetics and genomics","url":"https://pubmed.ncbi.nlm.nih.gov/18698232","citation_count":35,"is_preprint":false},{"pmid":"12623220","id":"PMC_12623220","title":"Introduction of the 5-HT3B subunit alters the functional properties of 5-HT3 receptors native to neuroblastoma cells.","date":"2003","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/12623220","citation_count":34,"is_preprint":false},{"pmid":"19185213","id":"PMC_19185213","title":"HTR3B is associated with alcoholism with antisocial behavior and alpha EEG power--an intermediate phenotype for alcoholism and co-morbid behaviors.","date":"2009","source":"Alcohol (Fayetteville, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/19185213","citation_count":34,"is_preprint":false},{"pmid":"18187416","id":"PMC_18187416","title":"The 5-HT3B subunit confers spontaneous channel opening and altered ligand properties of the 5-HT3 receptor.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18187416","citation_count":32,"is_preprint":false},{"pmid":"21840870","id":"PMC_21840870","title":"Association of ABCB1, 5-HT3B receptor and CYP2D6 genetic polymorphisms with ondansetron and metoclopramide antiemetic response in Indonesian cancer patients treated with highly emetogenic chemotherapy.","date":"2011","source":"Japanese journal of clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/21840870","citation_count":30,"is_preprint":false},{"pmid":"17327132","id":"PMC_17327132","title":"Identification of 5-HT3A and 5-HT3B receptor subunits in human hippocampus.","date":"2007","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/17327132","citation_count":28,"is_preprint":false},{"pmid":"19794330","id":"PMC_19794330","title":"Influence of 5-HT3 receptor subunit genes HTR3A, HTR3B, HTR3C, HTR3D and HTR3E on treatment response to antipsychotics in schizophrenia.","date":"2009","source":"Pharmacogenetics and genomics","url":"https://pubmed.ncbi.nlm.nih.gov/19794330","citation_count":28,"is_preprint":false},{"pmid":"26256989","id":"PMC_26256989","title":"Association of 5-HT3B Receptor Gene Polymorphisms with the Efficacy of Ondansetron for Postoperative Nausea and Vomiting.","date":"2015","source":"Yonsei medical journal","url":"https://pubmed.ncbi.nlm.nih.gov/26256989","citation_count":25,"is_preprint":false},{"pmid":"16571125","id":"PMC_16571125","title":"Detection of human and rodent 5-HT3B receptor subunits by anti-peptide polyclonal antibodies.","date":"2006","source":"BMC neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/16571125","citation_count":22,"is_preprint":false},{"pmid":"11747906","id":"PMC_11747906","title":"Generation of a selective 5-HT3B subunit-recognising polyclonal antibody; identification of immunoreactive cells in rat hippocampus.","date":"2001","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/11747906","citation_count":22,"is_preprint":false},{"pmid":"23464988","id":"PMC_23464988","title":"Polymorphisms of the HTR3B gene are associated with post-surgery emesis in a Chinese Han population.","date":"2013","source":"Journal of clinical pharmacy and therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/23464988","citation_count":18,"is_preprint":false},{"pmid":"18300944","id":"PMC_18300944","title":"Functional characterization of a -100_-102delAAG deletion-insertion polymorphism in the promoter region of the HTR3B gene.","date":"2008","source":"Pharmacogenetics and genomics","url":"https://pubmed.ncbi.nlm.nih.gov/18300944","citation_count":17,"is_preprint":false},{"pmid":"16314763","id":"PMC_16314763","title":"Serotonin receptor genes HTR3A and HTR3B are not involved in Gilles de la Tourette syndrome.","date":"2005","source":"Psychiatric genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16314763","citation_count":16,"is_preprint":false},{"pmid":"18807291","id":"PMC_18807291","title":"An association between serotonin receptor 3B gene (HTR3B) and treatment-resistant schizophrenia (TRS) in a Japanese population.","date":"2008","source":"Nagoya journal of medical science","url":"https://pubmed.ncbi.nlm.nih.gov/18807291","citation_count":15,"is_preprint":false},{"pmid":"21138434","id":"PMC_21138434","title":"The identification of N-glycosylated residues of the human 5-HT3B receptor subunit: importance for cell membrane expression.","date":"2011","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21138434","citation_count":12,"is_preprint":false},{"pmid":"19008750","id":"PMC_19008750","title":"Characterization of the effects of four HTR3B polymorphisms on human 5-HT3AB receptor expression and signalling.","date":"2008","source":"Pharmacogenetics and genomics","url":"https://pubmed.ncbi.nlm.nih.gov/19008750","citation_count":11,"is_preprint":false},{"pmid":"27488933","id":"PMC_27488933","title":"Effect of the allelic variants of ABCB1, CYP2D6 and HTR3B on response of ramosetron to prevent chemotherapy-induced nausea and vomiting in Korean cancer patients.","date":"2016","source":"Asia-Pacific journal of clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/27488933","citation_count":7,"is_preprint":false},{"pmid":"34948773","id":"PMC_34948773","title":"The Predictive Role of ADRA2A rs1800544 and HTR3B rs3758987 Polymorphisms in Motion Sickness Susceptibility.","date":"2021","source":"International journal of environmental research and public health","url":"https://pubmed.ncbi.nlm.nih.gov/34948773","citation_count":4,"is_preprint":false},{"pmid":"27706728","id":"PMC_27706728","title":"Associations of serotonin receptor gene HTR3A, HTR3B, and HTR3A haplotypes with bipolar disorder in Chinese patients.","date":"2016","source":"Genetics and molecular research : GMR","url":"https://pubmed.ncbi.nlm.nih.gov/27706728","citation_count":4,"is_preprint":false},{"pmid":"36849934","id":"PMC_36849934","title":"Association of HTR3B gene polymorphisms with depression and its executive dysfunction: a case-control study.","date":"2023","source":"BMC psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/36849934","citation_count":1,"is_preprint":false},{"pmid":"29885172","id":"PMC_29885172","title":"Association of anti-emetic efficacy of Ondansetron with 18792A>G polymorphism in a drug target gene 5-HT3B in Pakistani population.","date":"2018","source":"JPMA. The Journal of the Pakistan Medical Association","url":"https://pubmed.ncbi.nlm.nih.gov/29885172","citation_count":1,"is_preprint":false},{"pmid":"40249884","id":"PMC_40249884","title":"Personalized Prophylactic Antiemetic Regimens for Control of Chemotherapy-Induced Nausea and Vomiting by Pharmacogenetic Analysis of Three Receptor Genes: HTR3A, HTR3B, TACR1.","date":"2025","source":"JCO precision oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40249884","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.12.29.24319754","title":"Personalized prophylactic antiemetic regimens for the control of chemotherapy-induced nausea and vomiting by pharmacogenetic analysis of three receptors genes:<i>HTR3A, HTR3B, TACR1</i>","date":"2024-12-30","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.29.24319754","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":19166,"output_tokens":3483,"usd":0.054871},"stage2":{"model":"claude-opus-4-6","input_tokens":6865,"output_tokens":2408,"usd":0.141788},"total_usd":0.196659,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"The 5-HT3B subunit (HTR3B) assembles with the 5-HT3A subunit to form heteromeric 5-HT3AB receptors with a large single-channel conductance (16 pS), low calcium permeability, and a current-voltage relationship resembling native neuronal 5-HT3 channels, in contrast to homomeric 5-HT3A receptors (sub-picosiemens conductance). The M2 region of 5-HT3B lacks structural features known to promote conductance in related receptors.\",\n      \"method\": \"Recombinant heterologous expression of 5-HT3A and 5-HT3B subunits, single-channel patch-clamp electrophysiology, ion permeability measurements\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — original reconstitution with single-channel electrophysiology, foundational paper with 465 citations replicated across multiple subsequent studies\",\n      \"pmids\": [\"9950429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Co-expression of the 5-HT3B subunit with 5-HT3A in HEK293 cells reduces 5-HT sensitivity (EC50 shifts from 3 µM to 25 µM, Hill coefficient from 1.8 to 0.9), markedly alters receptor desensitization kinetics, eliminates agonist-induced open-channel block seen in homomeric receptors, and accelerates recovery from desensitization in heteromeric 5-HT3AB receptors.\",\n      \"method\": \"Whole-cell patch-clamp recordings in HEK293 cells expressing homomeric 5-HT3A or heteromeric 5-HT3AB receptors; kinetic modeling\",\n      \"journal\": \"Biophysical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct electrophysiological characterization with kinetic modeling, multiple biophysical parameters measured\",\n      \"pmids\": [\"12609874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The 5-HT3B subunit confers 100-fold reduced sensitivity to picrotoxin inhibition when co-expressed with 5-HT3A, identifying picrotoxin as a pharmacological probe to distinguish homomeric 5-HT3A from heteromeric 5-HT3A/3B receptors.\",\n      \"method\": \"Whole-cell patch-clamp recordings in cells expressing homomeric mouse 5-HT3A or heteromeric 5-HT3A/3B receptors\",\n      \"journal\": \"Brain research. Molecular brain research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct electrophysiological assay with quantitative comparison between receptor compositions\",\n      \"pmids\": [\"14625088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Introduction of recombinant 5-HT3B subunits into mouse neuroblastoma NB41A3 cells (which endogenously express 5-HT3A) shifts receptors from homomeric to heteromeric, reducing 5-HT potency, altering current kinetics, and abolishing 5-HT-induced Ca2+ increases, consistent with conversion of high-Ca2+-permeability homomeric 5-HT3A to low-Ca2+-permeability heteromeric 5-HT3AB receptors.\",\n      \"method\": \"Transient transfection of 5-HT3B into NB41A3 neuroblastoma cells; Ca2+ imaging; whole-cell patch-clamp electrophysiology; RT-PCR\",\n      \"journal\": \"Neuropharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (electrophysiology, Ca2+ imaging, RT-PCR) in native neuronal cell line\",\n      \"pmids\": [\"12623220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Two alternative promoters control tissue-specific expression of different HTR3B transcripts: one active in the intestine (corresponding to published genome annotation) and one active in the brain (~4000 bp downstream), generating brain-specific transcripts with an upstream-extended exon 2 and a new potential translational start site, suggesting different 5-HT3B isoforms in peripheral vs. central nervous system.\",\n      \"method\": \"Transcription start site analysis, transcript-specific RT-PCR, luciferase reporter gene (functional promoter) assays in intestinal and brain tissue\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods (TSS mapping, RT-PCR, reporter assay) from a single lab\",\n      \"pmids\": [\"17010535\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"5-HT3A and 5-HT3B subunit immunoreactivity was identified in pyramidal neurons of human hippocampal CA2/CA3 fields and hilar neurons, with both subunit proteins co-expressed in the same regions, indicating capacity to form heteromeric receptors in human brain.\",\n      \"method\": \"SDS-PAGE/Western blotting with selective polyclonal antibodies, immunohistochemistry, RT-PCR on human hippocampal tissue\",\n      \"journal\": \"Neuropharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple detection methods (WB, IHC, PCR) for protein and transcript localization in human tissue\",\n      \"pmids\": [\"17327132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The 5-HT3B subunit protein is expressed in interneurons of the rat hippocampus, as detected by a selective polyclonal antibody (AP86/3) in immunohistochemical studies.\",\n      \"method\": \"Generation of subunit-selective polyclonal antibody; Western blot on recombinant cell lines; immunohistochemistry on rat hippocampal sections\",\n      \"journal\": \"Neuropharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — antibody validated on recombinant systems before use in native tissue\",\n      \"pmids\": [\"11747906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"5-HT3B subunits do not reach the plasma membrane in the absence of 5-HT3A subunits, demonstrating that surface trafficking of 5-HT3B requires co-assembly with 5-HT3A.\",\n      \"method\": \"Immunocytochemistry using a validated anti-5-HT3B polyclonal antibody (pAb77) on transfected HEK293 cells expressing 5-HT3B alone or with 5-HT3A\",\n      \"journal\": \"BMC neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment with functional implication, antibody validated by WB\",\n      \"pmids\": [\"16571125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The naturally occurring 5-HT3B variant Y129S (rs1176744) dramatically augments 5-HT3AB receptor signaling: 5-HT3AB(Y129S) receptors display 20-fold slower deactivation, 10-fold slower desensitization, and 7-fold increased mean single-channel open time compared to wild-type 5-HT3AB receptors, substantially increasing maximal responses to serotonin.\",\n      \"method\": \"Fluorescence-based cellular Ca2+ assays; whole-cell and single-channel patch-clamp electrophysiology in HEK293 cells expressing 5-HT3A and 5-HT3B(Y129S)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple orthogonal electrophysiological methods including single-channel recordings, quantitative kinetic analysis\",\n      \"pmids\": [\"18184810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Co-expression of 5-HT3A and 5-HT3B subunits produces a receptor with constitutive (agonist-independent) channel opening. Additionally, subunit composition changes ligand properties: 5-methoxyindole is a partial agonist at homomeric 5-HT3A but becomes a protean agonist (acting as both agonist and inverse agonist) at heteromeric 5-HT3AB receptors; 5-hydroxyindole positively modulates ligand-gated active (AR*) conformation but negatively modulates the spontaneously active (R*) conformation of 5-HT3AB.\",\n      \"method\": \"Whole-cell patch-clamp electrophysiology in HEK293 cells expressing 5-HT3A and 5-HT3B; two-state allosteric model analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct electrophysiological recordings with mechanistic modeling, multiple ligands tested\",\n      \"pmids\": [\"18187416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Naturally occurring HTR3B variants differentially affect heteromeric 5-HT3AB receptor function: p.Y129S and p.S156R increase 5-HT maximum responses; p.V183I decreases surface expression; p.I143T markedly reduces cell surface expression of both 5-HT3B and 5-HT3A subunits and reduces current density ~3-fold while preserving macroscopic kinetics.\",\n      \"method\": \"Aequorin bioluminescence Ca2+ influx assay; [3H]GR65630 radioligand binding; ELISA for surface expression; immunocytochemistry; whole-cell patch-clamp electrophysiology in HEK293 cells\",\n      \"journal\": \"Pharmacogenetics and genomics / Pharmacogenetics and genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple orthogonal methods (radioligand binding, Ca2+ assay, ELISA, electrophysiology) across two independent studies (PMIDs 18698232 and 19008750)\",\n      \"pmids\": [\"18698232\", \"19008750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The human 5-HT3B subunit is N-glycosylated at five consensus sites (N31, N75, N117, N147, N182); disruption of each site individually reduces molecular weight (~2–4 kDa per site) and reduces cell membrane expression of the subunit when co-expressed with 5-HT3A, establishing that N-glycosylation is required for proper trafficking of 5-HT3B to the plasma membrane.\",\n      \"method\": \"Tunicamycin treatment; site-directed mutagenesis of N-glycosylation sites (N→S substitutions); SDS-PAGE/Western blot; immunocytochemistry in HEK293 cells stably expressing 5-HT3A\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis of each glycosylation site combined with biochemical and imaging readouts, clear structure-function relationship established\",\n      \"pmids\": [\"21138434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The -100_-102delAAG deletion in the HTR3B promoter region increases HTR3B promoter activity in vitro by 25–43% compared to the insertion allele, with differential binding of nuclear proteins to the polymorphic region, providing a molecular mechanism for previously reported disease associations of this variant.\",\n      \"method\": \"Electrophoretic mobility shift assay (EMSA); luciferase reporter gene assays in PC-12 and HEK293 cells; deletion mapping\",\n      \"journal\": \"Pharmacogenetics and genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — two orthogonal methods (EMSA and reporter assay) from a single lab, replicated in two cell lines\",\n      \"pmids\": [\"18300944\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HTR3B (5-HT3B) is an obligate auxiliary subunit that co-assembles with the 5-HT3A subunit to form heteromeric pentameric ligand-gated ion channels (5-HT3AB receptors); incorporation of 5-HT3B dramatically increases single-channel conductance to ~16 pS, reduces calcium permeability and 5-HT potency, alters desensitization/deactivation kinetics, confers constitutive channel opening, and changes ligand pharmacology — with 5-HT3B requiring N-glycosylation and co-assembly with 5-HT3A for plasma membrane trafficking, and naturally occurring variants (e.g., Y129S, I143T) quantitatively modulating receptor surface expression and gating properties.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"HTR3B encodes the 5-HT3B subunit of the serotonin type 3 receptor, a pentameric ligand-gated ion channel that functions as an obligate heteromeric partner of the 5-HT3A subunit to recapitulate native neuronal 5-HT3 receptor properties. Co-assembly of 5-HT3B with 5-HT3A increases single-channel conductance to ~16 pS, reduces calcium permeability, lowers 5-HT potency, alters desensitization and deactivation kinetics, confers constitutive (agonist-independent) channel opening, and changes the pharmacological profile of modulators including picrotoxin and indole compounds [PMID:9950429, PMID:12609874, PMID:18187416, PMID:14625088]. 5-HT3B requires N-glycosylation at five extracellular sites and co-expression with 5-HT3A for trafficking to the plasma membrane, and naturally occurring coding variants (Y129S, I143T) quantitatively alter receptor surface expression and gating kinetics [PMID:21138434, PMID:18184810, PMID:18698232, PMID:16571125]. The subunit is expressed in hippocampal neurons and intestinal tissue under control of alternative tissue-specific promoters [PMID:11747906, PMID:17327132, PMID:17010535].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Identification of HTR3B as a heteromeric partner of 5-HT3A resolved the long-standing discrepancy between the sub-picosiemens conductance of recombinant homomeric 5-HT3A receptors and the ~16 pS conductance of native neuronal 5-HT3 channels.\",\n      \"evidence\": \"Reconstitution of heteromeric 5-HT3AB receptors in heterologous cells with single-channel patch-clamp electrophysiology\",\n      \"pmids\": [\"9950429\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Subunit stoichiometry within the pentamer was not determined\",\n        \"The structural basis for the conductance increase remained unknown given the 5-HT3B M2 region lacks features associated with high conductance\",\n        \"Whether 5-HT3B is expressed at the protein level in native neurons was unconfirmed\"\n      ]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Detection of 5-HT3B protein in rat hippocampal interneurons established that the subunit is expressed in native brain tissue, supporting the physiological relevance of heteromeric 5-HT3AB receptors in the CNS.\",\n      \"evidence\": \"Subunit-selective antibody immunohistochemistry on rat hippocampal sections\",\n      \"pmids\": [\"11747906\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Antibody specificity was validated on recombinant lines but not with knockout controls\",\n        \"Co-localization with 5-HT3A at the single-cell level was not demonstrated\",\n        \"Expression in other brain regions was not surveyed\"\n      ]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Detailed biophysical characterization showed that 5-HT3B incorporation shifts 5-HT EC50, Hill coefficient, desensitization kinetics, recovery kinetics, calcium permeability, and picrotoxin sensitivity, establishing that the B subunit is a major determinant of channel pharmacology and gating.\",\n      \"evidence\": \"Whole-cell patch-clamp and Ca2+ imaging in HEK293 cells and NB41A3 neuroblastoma cells comparing homomeric 5-HT3A with heteromeric 5-HT3AB\",\n      \"pmids\": [\"12609874\", \"14625088\", \"12623220\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Which structural domains of 5-HT3B mediate specific kinetic changes was unknown\",\n        \"Stoichiometry and arrangement of A and B subunits in the pentamer remained undetermined\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Discovery that 5-HT3B cannot traffic to the plasma membrane without 5-HT3A, combined with identification of tissue-specific alternative promoters, revealed that 5-HT3B is an obligate auxiliary subunit whose expression is independently regulated in brain versus intestine.\",\n      \"evidence\": \"Immunocytochemistry in transfected HEK293 cells; transcript-specific RT-PCR and luciferase reporter assays across brain and intestinal tissue\",\n      \"pmids\": [\"16571125\", \"17010535\", \"17327132\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The trafficking signal that retains 5-HT3B intracellularly in the absence of 5-HT3A was not identified\",\n        \"Whether alternative promoter usage generates functionally distinct 5-HT3B isoforms at the protein level was not tested\",\n        \"Surface trafficking dependence demonstrated only in HEK293 cells, not in neurons\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Functional analysis of naturally occurring HTR3B variants revealed that coding polymorphisms (Y129S, I143T, S156R, V183I) modulate receptor gating kinetics and surface expression, establishing HTR3B as a pharmacogenomic determinant of 5-HT3 receptor function, while a promoter indel variant alters transcriptional output.\",\n      \"evidence\": \"Single-channel and whole-cell electrophysiology, radioligand binding, ELISA surface expression, Ca2+ assays, and luciferase reporter assays in HEK293 cells\",\n      \"pmids\": [\"18184810\", \"18698232\", \"19008750\", \"18300944\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether these variants alter receptor function in native neurons or in vivo was not tested\",\n        \"Structural mechanism by which Y129S slows deactivation 20-fold was not resolved\",\n        \"The transcription factors differentially binding the promoter indel were not identified\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstration of constitutive (agonist-independent) channel opening in heteromeric 5-HT3AB receptors, and identification of protean agonist behavior at these receptors, revealed that 5-HT3B shifts the allosteric equilibrium of the channel toward spontaneous activity.\",\n      \"evidence\": \"Whole-cell patch-clamp with allosteric model fitting in HEK293 cells expressing 5-HT3AB\",\n      \"pmids\": [\"18187416\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The structural basis for the shift in basal equilibrium toward the open state was not identified\",\n        \"Whether constitutive activity occurs in native heteromeric receptors in neurons was not tested\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Mapping of five N-glycosylation sites on 5-HT3B and demonstration that each contributes to membrane trafficking established post-translational modification as a critical quality-control mechanism for heteromeric receptor biogenesis.\",\n      \"evidence\": \"Site-directed mutagenesis of each N-glycosylation site, SDS-PAGE, immunocytochemistry in HEK293 cells stably expressing 5-HT3A\",\n      \"pmids\": [\"21138434\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether glycosylation affects receptor gating or pharmacology beyond trafficking was not assessed\",\n        \"The ER quality-control checkpoint(s) sensing under-glycosylated 5-HT3B were not identified\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The subunit stoichiometry and arrangement within the heteromeric pentamer, the structural basis for the conductance increase, and the in vivo consequences of 5-HT3B variants on serotonergic signaling remain to be established by structural and genetic approaches.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No high-resolution structure of the heteromeric 5-HT3AB receptor has been reported in this timeline\",\n        \"Subunit stoichiometry (e.g., 2A:3B vs. 3A:2B) is unresolved\",\n        \"In vivo phenotypes of HTR3B loss-of-function or variant alleles in animal models are lacking\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 1, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [7, 11]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 5, 6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 9]}\n    ],\n    \"complexes\": [\n      \"5-HT3AB heteromeric receptor\"\n    ],\n    \"partners\": [\n      \"HTR3A\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}