Affinage

HTR3B

5-hydroxytryptamine receptor 3B · UniProt O95264

Length
441 aa
Mass
50.3 kDa
Annotated
2026-06-10
32 papers in source corpus 13 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HTR3B encodes the 5-HT3B subunit, an accessory component of serotonin-gated cation channels that does not function autonomously but co-assembles with the 5-HT3A subunit to build heteromeric pentameric ligand-gated ion channels with biophysical properties matching native neuronal 5-HT3 receptors (PMID:9950429). Incorporation of 5-HT3B confers a large single-channel conductance (~16 pS versus sub-picosiemen homomeric channels) by an indirect mechanism, since its M2 region lacks the structural features that promote conductance in related receptors, together with reduced calcium permeability (PMID:9950429). The subunit reshapes receptor gating: it lowers serotonin sensitivity, abolishes the open-channel-block mode of desensitization seen in homomeric receptors, accelerates recovery from desensitization, and endows the channel with constitutive, agonist-independent opening (PMID:12609874, PMID:18187416). 5-HT3B also reduces sensitivity to the channel blocker picrotoxin, providing a pharmacological signature of heteromeric assembly (PMID:14625088). The subunit cannot reach the plasma membrane on its own and depends strictly on co-expression with 5-HT3A for surface trafficking (PMID:16571125), a process that further requires N-glycosylation at five consensus sites (N31, N75, N117, N147, N182) (PMID:21138434). 5-HT3A and 5-HT3B are co-expressed in human hippocampal neurons, supporting heteromeric receptor formation in human brain (PMID:17327132). Coding and regulatory variation in HTR3B alters receptor behavior: the Y129S variant (rs1176744) dramatically slows deactivation and desensitization, prolongs single-channel open time, and increases maximal serotonin responses (PMID:18184810, PMID:18698232), other variants such as I143T and V183I reduce surface expression (PMID:18698232, PMID:19008750), and a promoter -100_-102delAAG deletion increases transcriptional activity through differential recruitment of nuclear proteins (PMID:18300944).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 1999 High

    Established that the orphan 5-HT3B subunit is functionally meaningful by showing it confers native-like high conductance only when co-assembled with 5-HT3A, defining its role as a heteromeric channel-shaping subunit.

    Evidence Recombinant co-expression with single-channel electrophysiology and pharmacological profiling

    PMID:9950429

    Open questions at the time
    • Indirect mechanism of conductance enhancement not structurally resolved
    • Subunit stoichiometry of the heteromer not defined
    • No evidence whether 5-HT3B forms functional channels with subunits other than 5-HT3A
  2. 2003 High

    Resolved how 5-HT3B reshapes channel gating, showing it lowers serotonin sensitivity, eliminates the open-channel-block desensitization mode, and speeds recovery, distinguishing heteromeric from homomeric kinetics.

    Evidence Whole-cell patch-clamp with kinetic modeling in HEK293 cells; conversion of native neuroblastoma receptors by transfection; picrotoxin pharmacology

    PMID:12609874 PMID:12623220 PMID:14625088

    Open questions at the time
    • Kinetic measurements from single labs in heterologous systems
    • Loss of calcium signaling implications for downstream physiology not addressed
    • Structural basis of altered desensitization unknown
  3. 2006 Medium

    Explained why 5-HT3B is non-functional alone by demonstrating its surface delivery depends on 5-HT3A, and revealed tissue-specific regulation through dual alternative promoters generating distinct transcripts in gut versus brain.

    Evidence Immunocytochemistry and Western blot with a novel anti-5-HT3B antibody; transcription start site mapping, transcript-specific RT-PCR, and luciferase promoter assays

    PMID:16571125 PMID:17010535

    Open questions at the time
    • Molecular trafficking determinants requiring 5-HT3A not mapped
    • Predicted tissue-specific protein isoforms not biochemically confirmed
    • Functional consequences of brain-specific N-terminal isoform untested
  4. 2007 Medium

    Provided anatomical support for native heteromeric receptors by showing 5-HT3A and 5-HT3B proteins co-localize in human hippocampal neurons.

    Evidence Western blot, immunohistochemistry with selective antibodies, and PCR on human hippocampal tissue

    PMID:17327132

    Open questions at the time
    • Co-expression in same cells inferred but direct heteromer assembly in tissue not demonstrated
    • Limited to hippocampus; broader CNS distribution not addressed
  5. 2008 Medium

    Demonstrated that 5-HT3B endows the receptor with constitutive opening and converts ligand pharmacology, establishing the subunit as a determinant of agonist-independent activity and allosteric ligand behavior.

    Evidence Whole-cell patch-clamp in HEK293 cells with multiple indole ligands

    PMID:18187416

    Open questions at the time
    • Single method type, single lab
    • Physiological relevance of constitutive activity in vivo unknown
    • Structural states (R*/AR*) inferred from kinetics, not resolved structurally
  6. 2008 High

    Mapped functional impact of HTR3B coding and promoter variants, showing distinct mechanisms by which natural variation alters receptor gating, surface expression, and transcription.

    Evidence Patch-clamp and single-channel recordings for Y129S; aequorin Ca2+ influx, radioligand binding, ELISA/immunocytochemistry for variant surface expression; EMSA and luciferase reporter assays for the promoter deletion

    PMID:18184810 PMID:18300944 PMID:18698232 PMID:19008750

    Open questions at the time
    • Nuclear proteins binding the promoter polymorphism not identified
    • In vivo phenotypic consequences of variants not established
    • No direct clinical or disease causation demonstrated in these studies
  7. 2011 High

    Defined the post-translational requirement for surface delivery by showing N-glycosylation at all five consensus sites is needed for efficient 5-HT3B membrane trafficking.

    Evidence Tunicamycin treatment, site-directed mutagenesis of each glycosylation site, Western blot and immunocytochemistry in HEK293 cells stably expressing 5-HT3A

    PMID:21138434

    Open questions at the time
    • Whether glycosylation affects channel gating beyond trafficking not tested
    • Enzymatic machinery and glycan structures not characterized

Open questions

Synthesis pass · forward-looking unresolved questions
  • The physiological and behavioral roles of 5-HT3B-containing receptors in vivo, and whether HTR3B variants drive specific clinical phenotypes, remain unresolved.
  • No in vivo or genetic model linking HTR3B function to organismal physiology in the corpus
  • No high-resolution structure of the heteromeric channel
  • No direct disease-causation evidence in the timeline

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-112316 Neuronal System 2
Partners
HTR3A
Complex memberships
5-HT3A/5-HT3B heteromeric receptor

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 The 5-HT3B subunit assembles with 5-HT3A subunits to form heteromeric receptors with a large single-channel conductance (16 pS), low calcium permeability, and a current-voltage relationship resembling native neuronal 5-HT3 channels. Homomeric 5-HT3A receptors have sub-picosiemen conductance. The M2 region of 5-HT3B lacks structural features known to promote conductance in related receptors, indicating an indirect mechanism of conductance enhancement. Recombinant co-expression of 5-HT3A and 5-HT3B subunits, single-channel electrophysiology, pharmacological profiling Nature High 9950429
2003 Co-expression of 5-HT3B 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 desensitization kinetics (homomeric receptors desensitize via agonist-induced open-channel block whereas heteromeric receptors do not), and accelerates recovery from desensitization. Whole-cell patch-clamp recordings in HEK293 cells expressing homomeric 5-HT3A or heteromeric 5-HT3AB receptors; kinetic modeling Biophysical journal High 12609874
2003 Picrotoxin inhibits homomeric 5-HT3A receptors with ~100-fold higher potency than heteromeric 5-HT3A/3B receptors, demonstrating that the 5-HT3B subunit confers reduced sensitivity to this channel blocker and providing a pharmacological tool to distinguish the two receptor isoforms. Whole-cell patch-clamp recordings in cells expressing homomeric mouse 5-HT3A or heteromeric 5-HT3A/3B receptors Brain research. Molecular brain research Medium 14625088
2003 Transient transfection of recombinant 5-HT3B subunit into NB41A3 neuroblastoma cells (which endogenously express mainly homomeric 5-HT3A receptors) converts native receptors to heteromeric 5-HT3AB receptors, reducing 5-HT potency, altering current kinetics, and abolishing the 5-HT-induced intracellular Ca2+ rise. RT-PCR for subunit expression, calcium imaging, whole-cell patch-clamp, transient transfection Neuropharmacology Medium 12623220
2006 5-HT3B subunit protein is absent from the plasma membrane when expressed alone but reaches the cell surface when co-expressed with the 5-HT3A subunit, establishing that 5-HT3A is required for 5-HT3B membrane trafficking. Immunocytochemistry using a novel anti-5-HT3B polyclonal antibody (pAb77) in transfected HEK cells; Western blot BMC neuroscience Medium 16571125
2006 Two alternative promoters control tissue-specific expression of different HTR3B transcripts: intestinal transcripts initiate upstream (matching genome annotation), while brain transcripts initiate ~4 kb downstream, lacking the first coding exon but containing an upstream-extended exon 2 with a new potential translational start site, implying tissue-specific 5-HT3B isoforms. Transcription start site analyses, transcript-specific RT-PCR, reporter gene (luciferase) promoter assays Gene Medium 17010535
2007 5-HT3A and 5-HT3B subunit proteins are co-expressed in human hippocampal pyramidal neurones (CA2, CA3) and large hilar neurones (CA4), as established by subunit-selective polyclonal antibodies and PCR, indicating the capacity to form heteromeric 5-HT3A/3B receptors in human brain. SDS-PAGE/Western blotting, immunohistochemistry with selective polyclonal antibodies, and PCR on human hippocampal tissue Neuropharmacology Medium 17327132
2008 The naturally occurring variant Y129S in the 5-HT3B subunit (HTR3B rs1176744) dramatically augments 5-HT3AB receptor signaling: deactivation kinetics are 20-fold slower, desensitization 10-fold slower, mean single-channel open time 7-fold longer, and maximal response to serotonin is substantially increased compared to wild-type. Fluorescence-based cellular assays, whole-cell patch-clamp electrophysiology, single-channel recordings in cells expressing 5-HT3AB(Y129S) vs. WT receptors Proceedings of the National Academy of Sciences of the United States of America High 18184810
2008 Co-expression of 5-HT3A and 5-HT3B subunits confers constitutive (agonist-independent) channel opening on the heteromeric 5-HT3AB receptor. The 5-HT3B subunit also alters ligand properties: 5-methoxyindole, a partial agonist at 5-HT3A, becomes a protean agonist (acting as both agonist and inverse agonist) at 5-HT3AB, and 5-hydroxyindole acts as a negative allosteric modulator of the spontaneously active R* conformation but a positive modulator of the ligand-bound AR* conformation. Whole-cell patch-clamp electrophysiology in HEK293 cells co-expressing 5-HT3A and 5-HT3B The Journal of biological chemistry Medium 18187416
2008 The HTR3B variant V183I decreases surface expression of heteromeric 5-HT3A/B receptors, while Y129S and S156R increase maximal 5-HT responses without substantially altering surface expression levels, as established by Ca2+ influx (aequorin) and radioligand binding ([3H]GR65630) assays. Aequorin-based Ca2+ influx assay, radioligand binding with [3H]GR65630, transient transfection in HEK293 cells Pharmacogenetics and genomics Medium 18698232
2008 The HTR3B variant I143T markedly reduces cell surface expression of both 5-HT3B and 5-HT3A subunits and produces 3-fold lower current densities with otherwise similar macroscopic kinetics; variants S156R, V183I, and A223T do not significantly alter 5-HT3AB receptor expression or signaling. ELISA and immunocytochemistry for surface expression, whole-cell patch-clamp electrophysiology, membrane potential fluorescence assay in HEK cells Pharmacogenetics and genomics Medium 19008750
2008 The -100_-102delAAG deletion in the HTR3B promoter region increases promoter activity by 25-43% compared to the insertion allele, and differential binding of nuclear proteins to the polymorphic DNA region was detected (stronger binding to insertion allele), establishing a functional molecular mechanism for this polymorphism. Electrophoretic mobility shift assay (EMSA), luciferase reporter gene assay in PC-12 and HEK293 cells with native HTR3B promoter and tandem triplication constructs Pharmacogenetics and genomics Medium 18300944
2011 The 5-HT3B subunit is N-glycosylated at five consensus sites (N31, N75, N117, N147, N182); disruption of each site individually reduces the molecular weight of the subunit by ~2-4 kDa and decreases cell membrane expression of the 5-HT3B subunit when co-expressed with 5-HT3A, establishing that N-glycosylation at all five sites is required for efficient surface trafficking. Tunicamycin treatment, site-directed mutagenesis (N→S at each glycosylation site), immunocytochemistry, SDS-PAGE/Western blot in HEK293 cells stably expressing 5-HT3A Journal of neurochemistry High 21138434

Source papers

Stage 0 corpus · 32 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 The 5-HT3B subunit is a major determinant of serotonin-receptor function. Nature 465 9950429
2006 Distinguishable haplotype blocks in the HTR3A and HTR3B region in the Japanese reveal evidence of association of HTR3B with female major depression. Biological psychiatry 73 16487942
2003 Co-expression of the 5-HT3B serotonin receptor subunit alters the biophysics of the 5-HT3 receptor. Biophysical journal 68 12609874
2008 High-frequency HTR3B variant associated with major depression dramatically augments the signaling of the human 5-HT3AB receptor. Proceedings of the National Academy of Sciences of the United States of America 67 18184810
2009 Do variations in the 5-HT3A and 5-HT3B serotonin receptor genes (HTR3A and HTR3B) influence the occurrence of postoperative vomiting? Anesthesia and analgesia 52 19713259
2006 Tissue-specific alternative promoters of the serotonin receptor gene HTR3B in human brain and intestine. Gene 50 17010535
2004 Investigation of the human serotonin receptor gene HTR3B in bipolar affective and schizophrenic patients. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 46 15389765
2003 The 5-HT3B subunit confers reduced sensitivity to picrotoxin when co-expressed with the 5-HT3A receptor. Brain research. Molecular brain research 39 14625088
2004 Mutational analysis of serotonin receptor genes: HTR3A and HTR3B in fibromyalgia patients. Clinical rheumatology 38 15293096
2002 Novel mutations in 5-HT3A and 5-HT3B receptor genes not associated with clozapine response. Schizophrenia research 37 12363396
2008 Naturally occurring variants in the HTR3B gene significantly alter properties of human heteromeric 5-hydroxytryptamine-3A/B receptors. Pharmacogenetics and genomics 35 18698232
2009 HTR3B is associated with alcoholism with antisocial behavior and alpha EEG power--an intermediate phenotype for alcoholism and co-morbid behaviors. Alcohol (Fayetteville, N.Y.) 34 19185213
2003 Introduction of the 5-HT3B subunit alters the functional properties of 5-HT3 receptors native to neuroblastoma cells. Neuropharmacology 34 12623220
2008 The 5-HT3B subunit confers spontaneous channel opening and altered ligand properties of the 5-HT3 receptor. The Journal of biological chemistry 32 18187416
2011 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. Japanese journal of clinical oncology 30 21840870
2009 Influence of 5-HT3 receptor subunit genes HTR3A, HTR3B, HTR3C, HTR3D and HTR3E on treatment response to antipsychotics in schizophrenia. Pharmacogenetics and genomics 28 19794330
2007 Identification of 5-HT3A and 5-HT3B receptor subunits in human hippocampus. Neuropharmacology 28 17327132
2015 Association of 5-HT3B Receptor Gene Polymorphisms with the Efficacy of Ondansetron for Postoperative Nausea and Vomiting. Yonsei medical journal 25 26256989
2006 Detection of human and rodent 5-HT3B receptor subunits by anti-peptide polyclonal antibodies. BMC neuroscience 22 16571125
2001 Generation of a selective 5-HT3B subunit-recognising polyclonal antibody; identification of immunoreactive cells in rat hippocampus. Neuropharmacology 22 11747906
2013 Polymorphisms of the HTR3B gene are associated with post-surgery emesis in a Chinese Han population. Journal of clinical pharmacy and therapeutics 18 23464988
2008 Functional characterization of a -100_-102delAAG deletion-insertion polymorphism in the promoter region of the HTR3B gene. Pharmacogenetics and genomics 17 18300944
2005 Serotonin receptor genes HTR3A and HTR3B are not involved in Gilles de la Tourette syndrome. Psychiatric genetics 16 16314763
2008 An association between serotonin receptor 3B gene (HTR3B) and treatment-resistant schizophrenia (TRS) in a Japanese population. Nagoya journal of medical science 15 18807291
2011 The identification of N-glycosylated residues of the human 5-HT3B receptor subunit: importance for cell membrane expression. Journal of neurochemistry 12 21138434
2008 Characterization of the effects of four HTR3B polymorphisms on human 5-HT3AB receptor expression and signalling. Pharmacogenetics and genomics 11 19008750
2016 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. Asia-Pacific journal of clinical oncology 7 27488933
2021 The Predictive Role of ADRA2A rs1800544 and HTR3B rs3758987 Polymorphisms in Motion Sickness Susceptibility. International journal of environmental research and public health 5 34948773
2016 Associations of serotonin receptor gene HTR3A, HTR3B, and HTR3A haplotypes with bipolar disorder in Chinese patients. Genetics and molecular research : GMR 4 27706728
2023 Association of HTR3B gene polymorphisms with depression and its executive dysfunction: a case-control study. BMC psychiatry 1 36849934
2018 Association of anti-emetic efficacy of Ondansetron with 18792A>G polymorphism in a drug target gene 5-HT3B in Pakistani population. JPMA. The Journal of the Pakistan Medical Association 1 29885172
2025 Personalized Prophylactic Antiemetic Regimens for Control of Chemotherapy-Induced Nausea and Vomiting by Pharmacogenetic Analysis of Three Receptor Genes: HTR3A, HTR3B, TACR1. JCO precision oncology 0 40249884

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