Affinage

HTR3B

5-hydroxytryptamine receptor 3B · UniProt O95264

Length
441 aa
Mass
50.3 kDa
Annotated
2026-04-28
32 papers in source corpus 14 papers cited in narrative 13 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

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

    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

    PMID:9950429

    Open questions at the time
    • 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
  2. 2001 Medium

    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

    PMID:11747906

    Open questions at the time
    • 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
  3. 2003 High

    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

    PMID:12609874 PMID:12623220 PMID:14625088

    Open questions at the time
    • 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
  4. 2006 Medium

    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

    PMID:16571125 PMID:17010535 PMID:17327132

    Open questions at the time
    • 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
  5. 2008 High

    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

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

    Open questions at the time
    • 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
  6. 2008 High

    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

    PMID:18187416

    Open questions at the time
    • 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
  7. 2011 High

    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

    PMID:21138434

    Open questions at the time
    • 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

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 3
Localization
GO:0005886 plasma membrane 2 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3
Partners
HTR3A
Complex memberships
5-HT3AB 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 (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. Recombinant heterologous expression of 5-HT3A and 5-HT3B subunits, single-channel patch-clamp electrophysiology, ion permeability measurements Nature High 9950429
2003 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. Whole-cell patch-clamp recordings in HEK293 cells expressing homomeric 5-HT3A or heteromeric 5-HT3AB receptors; kinetic modeling Biophysical journal High 12609874
2003 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. Whole-cell patch-clamp recordings in cells expressing homomeric mouse 5-HT3A or heteromeric 5-HT3A/3B receptors Brain research. Molecular brain research High 14625088
2003 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. Transient transfection of 5-HT3B into NB41A3 neuroblastoma cells; Ca2+ imaging; whole-cell patch-clamp electrophysiology; RT-PCR Neuropharmacology High 12623220
2006 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. Transcription start site analysis, transcript-specific RT-PCR, luciferase reporter gene (functional promoter) assays in intestinal and brain tissue Gene Medium 17010535
2006 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. SDS-PAGE/Western blotting with selective polyclonal antibodies, immunohistochemistry, RT-PCR on human hippocampal tissue Neuropharmacology Medium 17327132
2001 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. Generation of subunit-selective polyclonal antibody; Western blot on recombinant cell lines; immunohistochemistry on rat hippocampal sections Neuropharmacology Medium 11747906
2006 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. Immunocytochemistry using a validated anti-5-HT3B polyclonal antibody (pAb77) on transfected HEK293 cells expressing 5-HT3B alone or with 5-HT3A BMC neuroscience Medium 16571125
2008 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. Fluorescence-based cellular Ca2+ assays; whole-cell and single-channel patch-clamp electrophysiology in HEK293 cells expressing 5-HT3A and 5-HT3B(Y129S) 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 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. Whole-cell patch-clamp electrophysiology in HEK293 cells expressing 5-HT3A and 5-HT3B; two-state allosteric model analysis The Journal of biological chemistry High 18187416
2008 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. Aequorin bioluminescence Ca2+ influx assay; [3H]GR65630 radioligand binding; ELISA for surface expression; immunocytochemistry; whole-cell patch-clamp electrophysiology in HEK293 cells Pharmacogenetics and genomics / Pharmacogenetics and genomics High 18698232 19008750
2011 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. 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 of neurochemistry High 21138434
2008 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. Electrophoretic mobility shift assay (EMSA); luciferase reporter gene assays in PC-12 and HEK293 cells; deletion mapping Pharmacogenetics and genomics Medium 18300944

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 67 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 65 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 4 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