Affinage

HTR3A

5-hydroxytryptamine receptor 3A · UniProt P46098

Length
478 aa
Mass
55.3 kDa
Annotated
2026-06-10
100 papers in source corpus 41 papers cited in narrative 41 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HTR3A encodes the obligatory subunit of the homomeric 5-HT3A receptor, a pentameric serotonin-gated cation channel that requires the concerted binding of at least three serotonin molecules to open with high peak open probability (PMID:11533135). Agonist recognition occurs in the extracellular domain through a cation-π interaction between serotonin and Trp183 in loop B, energetically coupled to a hydrogen-bond network involving E129 and D124 in loop A that operates as a single functional unit and discriminates among agonists (PMID:12162741, PMID:23077719); loop C residues (I228, D229) further confer agonist-specific engagement (PMID:15966738). Binding is mechanically relayed to the pore: the pre-TM1 residue R222 couples agonist occupancy to gating (PMID:12970351), while the TM2-TM3 linker residue D298 and the M2-M3 proline P303 set gating kinetics and extracellular Ca2+ modulation (PMID:16096341, PMID:19457066), and the M2 residue L293 mediates allosteric potentiation (PMID:18436267). Single-channel conductance and Ca2+ permeability are rate-limited not at the membrane but at peripheral charges—extracellular vestibule aspartates D113/D127 and the cytoplasmic portal arginines R436/R440 of the MA helix (PMID:21454663, PMID:17200121, PMID:24030822)—while desensitization is governed by the M2 4'-lysine, the cytoplasmic R427, and the length/composition of the M3-M4 intracellular loop (PMID:10639097, PMID:16754678, PMID:22539982). Receptor biogenesis and surface delivery depend on N-linked glycosylation at N109/N174/N190, on the extreme C-terminus (A455), and is enhanced by the ER chaperone RIC-3, which binds the subunit directly (PMID:15264219, PMID:18786552, PMID:20522555). In the brain the receptor is expressed in GABAergic interneurons of limbic and cortical regions (PMID:28276429), where it is required for fear extinction, NMDA-dependent hippocampal LTD with AMPAR internalization, and proper excitatory/inhibitory balance, such that its loss elevates NMDAR-driven interneuron excitability and produces autistic-like behavior reversible by memantine (PMID:24344177, PMID:25130560, PMID:34646371). HTR3A transcription and mRNA stability are epigenetically controlled—repressed by SETDB1-mediated H3K9 methylation through an endogenous retroviral enhancer (PMID:36335068) and stabilized after nerve injury by ALKBH5-mediated m6A demethylation that blocks YTHDF2-driven decay to promote neuropathic pain (PMID:38285939).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2000 High

    Establishing which residues set desensitization addressed how the channel terminates its response; the M2 4'-lysine was shown to shape desensitization kinetics without lining the conducting pore.

    Evidence Site-directed mutagenesis with whole-cell patch clamp and fluctuation analysis in HEK293 cells

    PMID:10639097

    Open questions at the time
    • Did not resolve the structural pathway linking 4'-lysine to the desensitized state
    • Conductance was unaffected, leaving the conductance determinants unidentified
  2. 2001 High

    Defining the activation stoichiometry answered how many agonist molecules are needed to open the channel, showing ≥3 serotonin molecules with high open probability.

    Evidence Voltage clamp with rapid agonist application and macroscopic state-model fitting in HEK293 cells

    PMID:11533135

    Open questions at the time
    • Single-channel transitions not directly resolved here
    • Did not map binding sites to specific residues
  3. 2002 High

    Locating the agonist-binding site answered where serotonin docks, identifying a cation-π interaction with Trp183 worth ~4 kcal/mol.

    Evidence Unnatural amino acid mutagenesis with electrophysiology in Xenopus oocytes

    PMID:12162741

    Open questions at the time
    • Did not establish coupling to gating
    • Single binding-site residue, not the full network
  4. 2003 High

    Linking binding to gating addressed how occupancy is transduced to channel opening, identifying pre-TM1 R222 as a binding-gating coupling element.

    Evidence Mutagenesis with whole-cell patch clamp and kinetic analysis in HEK293 cells

    PMID:12970351

    Open questions at the time
    • Structural basis of coupling not resolved
    • Interaction partners of R222 not identified
  5. 2004 High

    Multiple studies dissected biogenesis, pore architecture, splice diversity, and trafficking: glycosylation sites required for assembly and surface targeting, a narrow cytoplasmic selectivity filter maintained during gating, alternatively spliced isoforms that modify function, and predominant surface expression in neurons.

    Evidence Glycosylation-site mutagenesis with Ca2+ influx and binding assays; cysteine-scanning with Cd2+ probing; cloning and patch clamp of splice variants; YFP imaging with electrophysiology

    PMID:11111833 PMID:15009132 PMID:15131114 PMID:15264219

    Open questions at the time
    • Trafficking machinery beyond glycosylation not defined
    • Physiological role of splice isoforms in vivo unknown
  6. 2004 Medium

    Cellular and subcellular localization studies addressed where the receptor acts, placing it in GABAergic interneurons co-expressing CB1 and at both pre- and postsynaptic profiles.

    Evidence Electron microscopic immunocytochemistry and double in situ hybridization with GABA immunohistochemistry in rat brain

    PMID:14648680 PMID:15527741

    Open questions at the time
    • Single-method, single-lab localization without functional manipulation
    • Functional consequence of presynaptic localization not tested
  7. 2005 High

    Mapping the gating-pore interface answered how the TM2-TM3 region and loop C contribute to gating and Ca2+ modulation, identifying D298 and loop C residues with agonist-specific roles.

    Evidence Charge-altering and conventional mutagenesis with patch clamp, radioligand binding, and docking

    PMID:15966738 PMID:16096341

    Open questions at the time
    • Coupling mechanism between binding site and TM2-TM3 not structurally resolved
  8. 2006 High

    Defining cytoplasmic desensitization and conductance elements and antagonist binding addressed how the large cytoplasmic domain and binding loops shape function: R427 governs desensitization, MA-helix R436 rate-limits conductance, and granisetron engages loop B/E residues.

    Evidence Deletion and SCAM/MTS mutagenesis with single-channel recording; homology modeling with radioligand binding

    PMID:16430206 PMID:16754678 PMID:17200121

    Open questions at the time
    • Did not resolve full set of portal residues
    • Structural model of cytoplasmic portals inferred, not solved
  9. 2007 High

    Naturally occurring HTR3A SNPs and dopamine pharmacology addressed how genetic variation and alternative agonists affect the receptor, revealing trafficking-impairing variants and a slow-opening low-efficacy dopamine response.

    Evidence Ca2+ influx, binding, and surface-expression assays for SNP variants; rapid-exchange electrophysiology with kinetic modeling

    PMID:17496724 PMID:18045909

    Open questions at the time
    • In vivo phenotypic consequence of SNPs not established
    • Physiological relevance of dopamine agonism unclear
  10. 2008 High

    Identifying allosteric and C-terminal determinants answered how 5-HI potentiation and folding/assembly are controlled, implicating M2 L293 and the C-terminal A455.

    Evidence Mutagenesis with patch clamp in two cell systems; C-terminal deletion with binding/expression assays and temperature rescue

    PMID:18436267 PMID:18786552

    Open questions at the time
    • Mechanism of C-terminal stabilization of folding not defined
  11. 2010 High

    Identifying a chaperone addressed how surface receptor density is set, showing RIC-3 binds the subunit and enhances homomeric surface expression from the ER.

    Evidence Co-immunoprecipitation, ER co-localization, flow cytometry, binding, and Ca2+ influx assays in HEK293 cells

    PMID:20522555

    Open questions at the time
    • Structural basis of RIC-3 binding not defined
    • Whether RIC-3 acts on assembly versus export not fully resolved
  12. 2013 High

    Systematic MA-helix scanning answered which cytoplasmic portal residues set conductance, mapping positions 435, 436, 439, and 440 as major determinants.

    Evidence Alanine/arginine scanning with SCAM and single-channel recording

    PMID:24030822

    Open questions at the time
    • Functional map relied on homology models, not an experimental structure
  13. 2014 High

    Single-channel dissection of partial agonism answered why some ligands are weak agonists, showing tryptamine reduces priming whereas 2-Me-5HT's low efficacy is channel block.

    Evidence Single-channel recording in high-conductance mutants with activation-scheme modeling and docking

    PMID:25505338

    Open questions at the time
    • Generalizability of priming model to other partial agonists untested
  14. 2014 Medium

    Loss-of-function studies established the receptor's synaptic role, showing it is required for fear extinction and for NMDAR-dependent LTD with AMPAR internalization.

    Evidence Htr3a knockout mice with fear paradigms and hippocampal slice electrophysiology/internalization assays

    PMID:24344177 PMID:25130560

    Open questions at the time
    • Single-lab behavioral readouts
    • Cellular circuit linking the receptor to LTD not fully resolved
  15. 2021 High

    Defining the circuit consequence of HTR3A loss answered how the receptor maintains E/I balance, placing it upstream of NMDAR levels in PV+ interneurons with autistic-like behavior rescued by memantine.

    Evidence TALEN Htr3a KO mice with behavior, transcriptomics, cell-type-specific electrophysiology, and pharmacological rescue

    PMID:34646371

    Open questions at the time
    • Molecular link between HTR3A and NMDAR upregulation not defined
    • Relevance to human autism not established
  16. 2024 High

    Epigenetic and post-transcriptional control studies answered how HTR3A expression is regulated, identifying SETDB1/H3K9-RMER21B repression and an ALKBH5-m6A-YTHDF2 axis stabilizing Htr3a mRNA to drive neuropathic pain; methylation/acetylation changes link ethanol exposure to expression.

    Evidence Conditional Setdb1 KO with epigenomics and 3C; nerve-injury model with m6A-seq, RIP, electrophysiology and genetic rescue; promoter methylation/ChIP with mRNA quantification

    PMID:11505217 PMID:22834954 PMID:25722691 PMID:36335068 PMID:38285939

    Open questions at the time
    • Whether these regulatory axes converge in the same neurons unknown
    • Causal contribution to human disease not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the extracellular binding-site network mechanically couples to the cytoplasmic portals to set both gating and conductance in a single experimentally resolved structure remains unresolved.
  • No experimental full-length structure cited in the corpus
  • Integration of binding, gating, conductance, and desensitization determinants into one mechanistic model incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Localization
GO:0005886 plasma membrane 3 GO:0005783 endoplasmic reticulum 2
Pathway
R-HSA-112316 Neuronal System 4 R-HSA-382551 Transport of small molecules 3
Partners
HTR3BRIC-3
Complex memberships
heteromeric 5-HT3A/5-HT3B receptorhomomeric 5-HT3A receptor

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 A cation-π interaction between serotonin and Trp183 (loop B) of the 5-HT3A receptor was identified as critical for ligand binding, with an energetic contribution of ~4 kcal/mol, precisely locating the agonist-binding site. Unnatural amino acid mutagenesis with heterologous expression in Xenopus oocytes; electrophysiology Biochemistry High 12162741
2003 Arginine 222 in the pre-transmembrane domain 1 (pre-TM1) of the 5-HT3A receptor links agonist binding to channel gating; R222A mutation increased agonist potency and efficacy, accelerated activation and desensitization kinetics, and converted a weak partial agonist/antagonist into a potent agonist. Site-directed mutagenesis, whole-cell patch clamp in HEK293 cells, kinetic analysis The Journal of biological chemistry High 12970351
2006 Arginine 427 in the large cytoplasmic domain (LCD) of the 5-HT3A receptor contributes to receptor desensitization through electrostatic interactions with neighboring residues; deletion or point mutation of R427 slowed desensitization kinetics proportional to the polarity of the substituted residue, without altering single-channel conductance. Sequential deletion mutagenesis and site-directed mutagenesis, whole-cell patch clamp, single-channel recording in HEK293 cells The Journal of biological chemistry High 16754678
2000 The 4′-lysine residue in the putative channel-lining M2 domain of the 5-HT3A receptor affects desensitization kinetics but is unlikely to be exposed to the channel lumen; mutations at this position slowed desensitization (rank: Arg > Gly > Ser > Gln) without altering single-channel conductance (~390 fS). Site-directed mutagenesis, whole-cell patch clamp, fluctuation analysis in HEK293 cells The Journal of physiology High 10639097
2001 Homomeric 5-HT3A receptors require binding of at least three serotonin molecules to open and possess peak open probability >0.8; open probability varies with the number of bound agonist molecules, with reduced open probability for fully liganded receptors. Whole-cell and excised patch voltage clamp with rapid agonist application, macroscopic current modeling in HEK293 cells The Journal of physiology High 11533135
2004 N-linked glycosylation at three sites (N109, N174, N190) in the extracellular N-terminus of the murine 5-HT3A receptor is required for receptor maturation and function: N109 is necessary for receptor assembly, while N174 and N190 are important for plasma membrane targeting and ligand binding; all three sites are necessary for 5-HT3A-mediated Ca2+ influx. Site-directed mutagenesis, tunicamycin treatment, radioligand binding, Ca2+ influx assay, plasma membrane expression analysis in transfected cells Journal of neuroscience research High 15264219
2010 RIC-3 directly interacts with 5-HT3A subunits and functions as a chaperone that preferentially enhances surface expression of homomeric 5-HT3A receptors; co-localization occurs in the endoplasmic reticulum, and RIC-3 increases Bmax (surface receptor density) without altering the 5-HT concentration-response relationship. Co-immunoprecipitation, immunocytochemistry (ER co-localization), flow cytometry (surface expression), Ca2+ influx assay, radioligand binding in HEK293 cells The Journal of biological chemistry High 20522555
2007 Arg436 within the cytoplasmic portals (MA helix) of the 5-HT3A receptor acts as a rate-limiting determinant of single-channel conductance; dynamic modification of the charge at this residue via MTS reagents on substituted Cys436 reversibly modulates conductance, consistent with ion passage through cytoplasmic portals. Cysteine substitution mutagenesis, substituted cysteine accessibility method (SCAM) with MTS reagents, single-channel recording in outside-out patches The Journal of biological chemistry High 17200121
2013 Mutagenic scanning of the MA helix of the human 5-HT3A receptor identified residues at positions 435, 436, 439, and 440 as major determinants of single-channel conductance, providing a functional map of the cytoplasmic portals consistent with structural homology models. Alanine- and arginine-scanning mutagenesis, substituted cysteine accessibility method, single-channel recording The Journal of biological chemistry High 24030822
2011 Two anionic residues in the extracellular vestibule of the 5-HT3A receptor, Asp113 and Asp127, markedly influence single-channel conductance, Ca2+ permeability (PCa/PCs), and suppression of conductance by extracellular Ca2+; charge neutralization or reversal at these positions strongly reduces inward conductance and Ca2+ selectivity. Site-directed mutagenesis, single-channel recording in outside-out patches, bi-ionic permeability measurements in high-conductance mutant 5-HT3A(QDA) receptors The Journal of biological chemistry High 21454663
2005 Aspartate 298 (D298) in the TM2-TM3 extracellular loop of the mouse 5-HT3A receptor contributes to channel gating kinetics and extracellular Ca2+ modulation; charge-neutralizing (D→A) or charge-reversing (D→R) mutations reduce 5-HT potency, accelerate desensitization and deactivation, reduce partial agonist efficacy, and abolish Ca2+ modulation; charge-conserving D→E mutation preserves wild-type properties. Site-directed mutagenesis, whole-cell patch clamp with fast agonist application, Ca2+ modulation experiments in HEK293 cells The Journal of physiology High 16096341
2005 Loop C residues F226, I228, D229, and Y234 in the murine 5-HT3A receptor contribute to ligand binding and/or gating; I228 and D229 are specifically required for 5-HT (but not mCPBG) interactions, revealing differential ligand engagement with loop C; mutations at F226, I228, and Y234 alter relative agonist efficacies. Site-directed mutagenesis, radioligand binding, two-electrode voltage clamp, immunofluorescence, ligand docking modeling Biochemistry High 15966738
2006 Granisetron binding to the 5-HT3A receptor involves loop B residues (H185, D189) and loop E residues (Y143, Y153); H185A mutation abolished granisetron binding and D189A reduced affinity 22-fold, while Y143F and Y153F decreased affinity equivalently to alanine substitutions, indicating the OH groups of these tyrosines are important. Homology modeling, site-directed mutagenesis, radioligand binding in Xenopus oocytes/HEK cells Biochemistry High 16430206
2006 Ginsenoside Rg3 inhibits 5-HT3A receptor channel activity through interactions with residues V291, F292, and I295 in the TM2 gating pore; mutations at these positions attenuated or abolished Rg3-induced inhibition, and Rg3 acts at a site distinct from the TMB-8 and diltiazem open-channel blocker sites. Site-directed mutagenesis of TM2, two-electrode voltage clamp in Xenopus oocytes expressing wild-type or mutant receptors, occlusion experiments Neuropharmacology High 17257631
2008 L293 (L15′) in the second transmembrane domain (TM2) of the 5-HT3A receptor is a molecular determinant of allosteric modulation by 5-hydroxyindole (5-HI); L293C and L293S mutations abolished 5-HI potentiation and converted 5-HI to a partial agonist, while L293S enhanced dopamine efficacy; other TM2 mutations (D298A, T284F) did not alter 5-HI modulation. Site-directed mutagenesis, whole-cell patch clamp in neuroblastoma and HEK293 cells expressing native or recombinant 5-HT3A receptors Neuropharmacology High 18436267
2012 A coupled array of noncovalent interactions governs 5-HT3A receptor activation: a cation-π interaction at W183 (loop B), a hydrogen bond at E129 (loop A), and backbone hydrogen bonds mediated by D124 (loop A) are tightly coupled and function as a unit; agonist mCPBG shows no cation-π interaction at W183 and extreme sensitivity to E129 positioning, revealing agonist-specific differences in binding-site interactions. Mutant cycle analysis using conventional and unnatural amino acid mutagenesis with two-electrode voltage clamp in Xenopus oocytes ACS chemical neuroscience High 23077719
2004 The S2′C substitution in the cytoplasmic selectivity filter of the 5-HT3A receptor showed high-affinity Cd2+ inhibition in both open and closed states, indicating that the cytoplasmic selectivity filter maintains a narrow pore during channel gating with minimal structural rearrangement. Systematic cysteine substitution scanning of M1-M2 loop and M2 domain, Cd2+ inhibition in outside-out and whole-cell patches, voltage-dependent recovery experiments The Journal of biological chemistry High 15131114
2009 Hydrophobic photoaffinity labeling with [125I]TID identified Ser451 in the M4 transmembrane segment of the 5-HT3A receptor as exposed to lipid at the lipid-protein interface, with ~60% of photolabel incorporated into the M4-containing fragment and ~40% into the M1-M3 fragment. Affinity purification of alphaBgTx-tagged 5-HT3A receptors, hydrophobic photoaffinity labeling ([125I]TID), proteolytic mapping, sequencing Biochemistry High 19715355
2004 V13′S mutation in the M2 channel-lining domain of the 5-HT3A receptor renders the channel 70-fold more sensitive to serotonin and produces constitutive activity when co-expressed with 5-HT3B subunit, causing excitotoxic neuronal cell death in the urinary bladder and functional bladder deficits in vivo. Targeted exon replacement knock-in mouse model, whole-cell electrophysiology in sympathetic ganglion cells, bladder functional assays, immunohistochemistry The Journal of neuroscience High 15201326
2000 Human 5-HT3A receptor has two alternatively spliced isoforms (short/truncated h5-HT3AT, 238 aa with single TM domain; long h5-HT3AL with 32 additional aa in M2-M3 extracellular loop); neither forms functional homomeric receptors alone, but co-expression with 5-HT3A modifies function: h5-HT3AT slows desensitization and increases cation flux, while h5-HT3AL reduces cation flux. Molecular cloning and sequencing, heterologous expression in HEK293 cells, patch clamp electrophysiology Naunyn-Schmiedeberg's archives of pharmacology High 11111833
2007 Naturally occurring SNPs A33T, S253N, and M257I in the human 5-HT3A receptor reduce 5-HT-induced maximal responses to 3-64% of wild-type; A33T, M257I, and R344H reduce surface expression 2-4-fold without altering total expression levels, indicating impaired receptor biogenesis/trafficking; co-expression with wild-type 5-HT3A or 5-HT3B cannot rescue these defects. Fluorescence-based Ca2+ influx assay, radioligand binding ([3H]GR65630), flow cytometry for surface expression in transfected HEK cells Pharmacogenetics and genomics High 17496724
2004 5-HT3A subunit is localized to axonal profiles (presynaptic vesicle membranes and extrasynaptic plasma membranes), somatodendritic profiles (near excitatory-type synapses), and glial processes in the rat medial NTS, indicating roles in both presynaptic modulation of transmitter release and postsynaptic signaling. Electron microscopic immunocytochemistry with anti-5-HT3A antibody and anti-SERT antibody in rat brain sections Brain research Medium 15527741
2004 YFP-tagged 5-HT3A receptor is targeted to the plasma membrane and dendritic spines of hippocampal neurons and to micropodia of HEK293 cells, with predominant surface expression; this contrasts with predominantly intracellular retention of alpha3beta4-nAChRs, and the surface targeting correlates with large serotonin-evoked currents. Fluorescent protein tagging (YFP), live fluorescence microscopy, extracellular probe labeling, whole-cell voltage clamp in HEK293 cells and primary hippocampal neurons The European journal of neuroscience Medium 15009132
2012 The M3-M4 intracellular loop of the 5-HT3A receptor is not required for receptor assembly or function but its length and amino acid composition influence channel expression and desensitization rate; replacing the 115-residue loop with 3 or 5 alanines dramatically accelerated desensitization (>10-fold), while 2, 4, 6, or 7 alanines preserved near-wild-type desensitization. Loop replacement mutagenesis, two-electrode voltage clamp in Xenopus oocytes PloS one Medium 22539982
2008 The C-terminal residue (Ala455) of the human 5-HT3A subunit is critical for receptor folding, assembly, and plasma membrane expression; deletion of the three C-terminal residues (Gln453-Tyr454-Ala455) prevents specific radioligand binding and membrane expression, while ΔAla455 alone reduces both; growth at 27°C partially rescues these defects, suggesting the C-terminus stabilizes subunit folding. C-terminal deletion and point mutagenesis, radioligand binding, cell membrane expression assays in HEK293 cells at 27°C and 37°C Neuropharmacology Medium 18786552
2003 The 5-HT3B subunit confers reduced sensitivity to picrotoxin (100-fold reduction in inhibitory effect) when co-expressed with 5-HT3A, establishing picrotoxin as a selective probe that can distinguish homomeric 5-HT3A from heteromeric 5-HT3A/3B receptors. Whole-cell patch clamp recordings comparing homomeric mouse 5-HT3A vs. heteromeric 5-HT3A/3B receptors Brain research. Molecular brain research Medium 14625088
2007 Dopamine acts as a low-efficacy agonist at human 5-HT3A receptors with kinetics distinct from serotonin: dopamine activation rates are concentration-independent, deactivation is faster than desensitization (opposite to serotonin), and recovery from desensitization is faster and non-sigmoidal; an allosteric kinetic model indicates these differences arise from much slower rates of channel opening and faster dissociation from open/desensitized states for dopamine. Rapid solution exchange electrophysiology, whole-cell patch clamp in HEK293 cells, kinetic modeling The Journal of neuroscience High 18045909
2014 Partial agonism of tryptamine at 5-HT3A receptors results from reduced priming (fewer/slower transitions through preopen closed states) rather than reduced channel blockade; 2-Me-5HT is not a genuine partial agonist because priming is intact and low apparent efficacy is primarily due to channel blockade within the activating concentration range. Single-channel recording using high-conductance 5-HT3A mutant receptors, full activation scheme modeling, molecular docking The Journal of neuroscience High 25505338
2013 Deletion of the 5-HT3A receptor (Htr3a KO) in mice abolishes fear extinction for both contextual and tone-cued fear without affecting fear acquisition or retention, establishing the 5-HT3A receptor as essential for fear extinction. Htr3a knockout mouse model, fear conditioning and extinction paradigms Learning & memory Medium 24344177
2014 5-HT3A receptor deletion in mice abolishes NMDA receptor-dependent long-term depression (LTD) induced by low-frequency stimulation in hippocampal CA1 and inhibits AMPA receptor internalization, without affecting mGluR-dependent LTD, basal AMPAR surface levels, synapse number, or spine morphology. Htr3a knockout mouse model, hippocampal slice electrophysiology (LFS-LTD), AMPAR internalization assay Neuroscience Medium 25130560
2021 Htr3a knockout mice exhibit autistic-like behaviors, impaired memory, and reduced seizure susceptibility; mechanistically, loss of HTR3A leads to upregulation of NMDAR in parvalbumin-positive interneurons, increased NMDAR-mediated excitability of these interneurons, enhanced GABAergic transmission onto pyramidal neurons, and decreased E/I ratio; NMDAR antagonist memantine rescues both the GABAergic phenotype and autistic-like behaviors. TALEN-generated Htr3a KO mice, behavioral testing, transcriptome sequencing, patch-clamp electrophysiology in pyramidal neurons and PV+ interneurons, immunoblotting, immunofluorescence, immunoprecipitation, qRT-PCR, memantine rescue experiment Theranostics High 34646371
2024 Peripheral nerve injury upregulates ALKBH5 (m6A demethylase) in trigeminal ganglion neurons via a FOXD3-H3K27ac-dependent transcriptional mechanism; ALKBH5 removes m6A from Htr3a mRNA, preventing YTHDF2-mediated degradation and thereby stabilizing Htr3a mRNA, increasing 5-HT3A protein expression and 5-HT3 channel currents to promote neuropathic pain. Nerve injury rat model, ALKBH5 knockdown/overexpression in TG, m6A sequencing, RIP assay, electrophysiology, histone ChIP, behavioral pain assays, 5-HT3A knockdown rescue Proceedings of the National Academy of Sciences of the United States of America High 38285939
2012 Ethanol consumption in mice induces tissue-specific DNA methylation changes at the Htr3a promoter; in the dorsomedial striatum, ethanol drinking reduces CpG methylation at the Htr3a promoter and increases Htr3a mRNA expression (1.43-fold), suggesting an inverse correlation between promoter methylation and Htr3a expression. Sequenom MassARRAY methylation quantification of 8-9 CpGs across 9 brain regions and blood, qRT-PCR for Htr3a mRNA in CD-1 mice Alcoholism, clinical and experimental research Medium 22834954
2012 Chronic ethanol exposure in rat prefrontal cortex increases histone H3K9 acetylation at the htr3a promoter region and upregulates htr3a mRNA; histone deacetylase inhibitor sodium butyrate potentiated both effects and enhanced ethanol-induced conditioned place preference. Chromatin immunoprecipitation (ChIP) for H3K9ac at htr3a promoter, qRT-PCR for htr3a mRNA, conditioned place preference behavioral assay in rats Neural regeneration research Medium 25722691
2022 SETDB1 (histone H3K9 methyltransferase) represses Htr3a transcription in embryonic GABAergic interneuron progenitors via the endogenous retroviral enhancer element RMER21B, which forms distal chromatin interaction with the Htr3a promoter; Setdb1 knockout increases Htr3a expression, increases the number and excitability of Htr3a+ cortical interneurons, and causes anxiety/depressive-like behaviors reversible by 5-HT3 receptor antagonist. Conditional Setdb1 knockout mice, RNA-seq, ATAC-seq, ChIP-seq, luciferase assay, chromatin conformation capture (3C), CRISPR/dCas9, in situ hybridization, whole-cell recording, behavioral testing Biological psychiatry High 36335068
2001 A C178T variant in the 5′ UTR upstream open reading frame of HTR3A drives 245% increased luciferase reporter expression compared to wild-type, establishing this polymorphism as a functional variant that increases translational-level gene expression. Luciferase reporter gene assay comparing C178T (Pro16Ser) allele vs. wild-type and compound variant constructs in transfected cells Pharmacogenetics Medium 11505217
2020 HTR3A knockdown in lung adenocarcinoma cells attenuates proliferation by reducing ERK phosphorylation, identifying ERK signaling as a downstream effector of HTR3A in cancer cell proliferation. siRNA knockdown of HTR3A in lung adenocarcinoma cell lines, proliferation assay, Western blot for ERK phosphorylation Cancer science Medium 32736413
2017 5-HT3A receptor is expressed in fetal mouse pelvic ganglia and loss of Htr3a in male mice causes increased urinary voiding frequency, decreased voiding efficiency, and a transient imbalance of autonomic neuronal subtypes in fetal pelvic ganglia; adult Htr3a KO mice show higher density of autonomic and sensory nerve fibers in bladder smooth muscle. Htr3a KO mouse model, anesthetized cystometry, immunohistochemistry for autonomic neuron markers (TH, ChAT) in pelvic ganglia and bladder Frontiers in neuroscience Medium 29311772
2017 5-HT3AR is expressed in GABAergic interneurons containing somatostatin or calretinin in the mouse brain, with strong expression in olfactory bulb, cerebral cortex, hippocampus, and amygdala, and no expression in cerebellum; confirmed by double-immunostaining with neural markers in 5-HT3AR-GFP transgenic mice. Immunofluorescent staining of 5-HT3AR-GFP transgenic mice, double-immunostaining with GAD67, somatostatin, calretinin markers Scientific reports Medium 28276429
2009 Proline P303 in the M2-M3 linker of human 5-HT3A receptor is important for receptor function but trans-cis isomerization at this position is not required for channel gating; P303H and P303W mutations do not abolish agonist-mediated currents but accelerate desensitization 10-fold and alter Ca2+ dependence. Site-directed mutagenesis (natural amino acids), two-electrode voltage clamp in Xenopus oocytes, Ca2+ concentration-response experiments Journal of neurochemistry Medium 19457066
2004 5-HT3A and CB1 cannabinoid receptors are co-expressed in GABAergic interneurons throughout the rat telencephalon (cortex, hippocampus, amygdala), with 37-53% of 5-HT3A-expressing neurons co-expressing CB1; this co-expression pattern was confirmed by combining double in situ hybridization with GABA immunohistochemistry. Double in situ hybridization, combination of in situ hybridization and immunohistochemistry for GABA in rat brain sections The Journal of comparative neurology Medium 14648680

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Cation-pi interactions in ligand recognition by serotonergic (5-HT3A) and nicotinic acetylcholine receptors: the anomalous binding properties of nicotine. Biochemistry 230 12162741
2002 Direct inhibition by cannabinoids of human 5-HT3A receptors: probable involvement of an allosteric modulatory site. British journal of pharmacology 161 12381672
2007 Mechanical, thermal and formalin-induced nociception is differentially altered in 5-HT1A-/-, 5-HT1B-/-, 5-HT2A-/-, 5-HT3A-/- and 5-HTT-/- knock-out male mice. Pain 124 17250964
2001 Association between the 5' UTR variant C178T of the serotonin receptor gene HTR3A and bipolar affective disorder. Pharmacogenetics 100 11505217
2003 Targeted gene deletion of the 5-HT3A receptor subunit produces an anxiolytic phenotype in mice. European journal of pharmacology 85 12568911
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
2001 Pharmacological comparison of human homomeric 5-HT3A receptors versus heteromeric 5-HT3A/3B receptors. Neuropharmacology 71 11489465
2011 The HTR3A polymorphism c. -42C>T is associated with amygdala responsiveness in patients with irritable bowel syndrome. Gastroenterology 68 21420406
2005 A variant C178T in the regulatory region of the serotonin receptor gene HTR3A modulates neural activation in the human amygdala. The Journal of neuroscience : the official journal of the Society for Neuroscience 66 16000636
2003 A polymorphism in the serotonin receptor 3A (HTR3A) gene and its association with harm avoidance in women. Archives of general psychiatry 66 14557147
2004 Expression of 5-HT3A receptors in cells of the immune system. Scandinavian journal of rheumatology. Supplement 65 15515405
2017 Building a 5-HT3A Receptor Expression Map in the Mouse Brain. Scientific reports 64 28276429
2008 Serotonin type 3 receptor genes: HTR3A, B, C, D, E. Pharmacogenomics 64 18466097
2013 Serotonin homeostasis and serotonin receptors as actors of cortical construction: special attention to the 5-HT3A and 5-HT6 receptor subtypes. Frontiers in cellular neuroscience 63 23801939
2010 Impact of the HTR3A gene with early life trauma on emotional brain networks and depressed mood. Depression and anxiety 62 20694966
2004 Investigation of the association between 5-HT3A receptor gene polymorphisms and efficiency of antiemetic treatment with 5-HT3 receptor antagonists. Pharmacogenetics 56 15115912
2001 Serotonin receptor gene HTR3A variants in schizophrenic and bipolar affective patients. Pharmacogenetics 55 11207027
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
2003 Arginine 222 in the pre-transmembrane domain 1 of 5-HT3A receptors links agonist binding to channel gating. The Journal of biological chemistry 50 12970351
1995 Embryonic expression of the 5-HT3 receptor subunit, 5-HT3R-A, in the rat: an in situ hybridization study. Molecular and cellular neurosciences 49 7551565
2000 Modified 5-HT3A receptor function by co-expression of alternatively spliced human 5-HT3A receptor isoforms. Naunyn-Schmiedeberg's archives of pharmacology 46 11111833
2001 Open probability of homomeric murine 5-HT3A serotonin receptors depends on subunit occupancy. The Journal of physiology 43 11533135
2004 Cannabinoid CB1 receptor and serotonin 3 receptor subunit A (5-HT3A) are co-expressed in GABA neurons in the rat telencephalon. The Journal of comparative neurology 39 14648680
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
2007 Differential effects of serotonin and dopamine on human 5-HT3A receptor kinetics: interpretation within an allosteric kinetic model. The Journal of neuroscience : the official journal of the Society for Neuroscience 38 18045909
2004 Mutational analysis of serotonin receptor genes: HTR3A and HTR3B in fibromyalgia patients. Clinical rheumatology 38 15293096
2003 Effects of ginsenoside Rg2 on the 5-HT3A receptor-mediated ion current in Xenopus oocytes. Molecules and cells 38 12661769
2013 The 5-HT3A receptor is essential for fear extinction. Learning & memory (Cold Spring Harbor, N.Y.) 37 24344177
2002 Novel mutations in 5-HT3A and 5-HT3B receptor genes not associated with clozapine response. Schizophrenia research 37 12363396
2007 Naturally occurring variations in the human 5-HT3A gene profoundly impact 5-HT3 receptor function and expression. Pharmacogenetics and genomics 36 17496724
2013 Discriminating between 5-HT₃A and 5-HT₃AB receptors. British journal of pharmacology 34 23489111
2006 An interaction involving an arginine residue in the cytoplasmic domain of the 5-HT3A receptor contributes to receptor desensitization mechanism. The Journal of biological chemistry 33 16754678
2021 linc01305 promotes metastasis and proliferation of esophageal squamous cell carcinoma through interacting with IGF2BP2 and IGF2BP3 to stabilize HTR3A mRNA. The international journal of biochemistry & cell biology 32 34022433
2012 Altered dendritic complexity affects firing properties of cortical layer 2/3 pyramidal neurons in mice lacking the 5-HT3A receptor. Journal of neurophysiology 32 22696545
2004 5-HT3A receptor subunits in the rat medial nucleus of the solitary tract: subcellular distribution and relation to the serotonin transporter. Brain research 32 15527741
2005 Molecular properties important for inhaled anesthetic action on human 5-HT3A receptors. Anesthesia and analgesia 31 15920198
2003 Characterisation of axon terminals in the rat dorsal horn that are immunoreactive for serotonin 5-HT3A receptor subunits. Experimental brain research 31 12592509
2000 The 4'lysine in the putative channel lining domain affects desensitization but not the single-channel conductance of recombinant homomeric 5-HT3A receptors. The Journal of physiology 31 10639097
2010 RIC-3 exclusively enhances the surface expression of human homomeric 5-hydroxytryptamine type 3A (5-HT3A) receptors despite direct interactions with 5-HT3A, -C, -D, and -E subunits. The Journal of biological chemistry 30 20522555
2008 Relationship between three serotonin receptor subtypes (HTR3A, HTR2A and HTR4) and treatment-resistant schizophrenia in the Japanese population. Neuroscience letters 30 18359159
2021 Upregulated NMDAR-mediated GABAergic transmission underlies autistic-like deficits in Htr3a knockout mice. Theranostics 29 34646371
2007 Anandamide inhibition of 5-HT3A receptors varies with receptor density and desensitization. Molecular pharmacology 29 17993512
2006 Interactions of granisetron with an agonist-free 5-HT3A receptor model. Biochemistry 29 16430206
2017 Response of Htr3a knockout mice to antidepressant treatment and chronic stress. British journal of pharmacology 28 28493335
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
2008 Association between a polymorphism of the HTR3A gene and therapeutic response to risperidone treatment in drug-naive Chinese schizophrenia patients. Pharmacogenetics and genomics 27 18622264
2012 Ethanol-induced Htr3a promoter methylation changes in mouse blood and brain. Alcoholism, clinical and experimental research 25 22834954
2009 Isomerization of the proline in the M2-M3 linker is not required for activation of the human 5-HT3A receptor. Journal of neurochemistry 25 19457066
2008 Molecular actions of propofol on human 5-HT3A receptors: enhancement as well as inhibition by closely related phenol derivatives. Anesthesia and analgesia 25 18292429
2006 Identification of ginsenoside interaction sites in 5-HT3A receptors. Neuropharmacology 25 17257631
2000 Recombinant human 5-HT3A receptors in outside-out patches of HEK 293 cells: basic properties and barbiturate effects. Naunyn-Schmiedeberg's archives of pharmacology 25 10997728
2013 Agonists and antagonists induce different palonosetron dissociation rates in 5-HT₃A and 5-HT₃AB receptors. Neuropharmacology 24 23747573
2011 Fragment library screening reveals remarkable similarities between the G protein-coupled receptor histamine H₄ and the ion channel serotonin 5-HT₃A. Bioorganic & medicinal chemistry letters 24 21782429
2007 Dynamic modification of a mutant cytoplasmic cysteine residue modulates the conductance of the human 5-HT3A receptor. The Journal of biological chemistry 24 17200121
2004 Uropathic observations in mice expressing a constitutively active point mutation in the 5-HT3A receptor subunit. The Journal of neuroscience : the official journal of the Society for Neuroscience 24 15201326
2012 Outcome definitions and clinical predictors influence pharmacogenetic associations between HTR3A gene polymorphisms and response to clozapine in patients with schizophrenia. Psychopharmacology 23 22700043
2012 Length and amino acid sequence of peptides substituted for the 5-HT3A receptor M3M4 loop may affect channel expression and desensitization. PloS one 22 22539982
2006 Effects of tramadol and O-demethyl-tramadol on human 5-HT reuptake carriers and human 5-HT3A receptors: a possible mechanism for tramadol-induced early emesis. European journal of pharmacology 22 16427041
2004 Three putative N-glycosylation sites within the murine 5-HT3A receptor sequence affect plasma membrane targeting, ligand binding, and calcium influx in heterologous mammalian cells. Journal of neuroscience research 22 15264219
1995 Detection of 5-HT3R-A, a 5-HT3 receptor subunit, in submucosal and myenteric ganglia of rat small intestine using in situ hybridization. Neuroscience letters 22 7739810
2015 Pathways and Barriers for Ion Translocation through the 5-HT3A Receptor Channel. PloS one 21 26465896
2008 Importance of the C-terminus of the human 5-HT3A receptor subunit. Neuropharmacology 21 18786552
2020 HTR3A is correlated with unfavorable histology and promotes proliferation through ERK phosphorylation in lung adenocarcinoma. Cancer science 20 32736413
2015 Identification of Glycyrrhiza as the rikkunshito constituent with the highest antagonistic potential on heterologously expressed 5-HT3A receptors due to the action of flavonoids. Frontiers in pharmacology 20 26191003
2012 VUF10166, a novel compound with differing activities at 5-HT₃A and 5-HT₃AB receptors. The Journal of pharmacology and experimental therapeutics 20 22306960
2010 Importance of M2-M3 loop in governing properties of genistein at the α7 nicotinic acetylcholine receptor inferred from α7/5-HT3A chimera. European journal of pharmacology 20 20816816
2005 The loop C region of the murine 5-HT3A receptor contributes to the differential actions of 5-hydroxytryptamine and m-chlorophenylbiguanide. Biochemistry 20 15966738
2005 Role of aspartate 298 in mouse 5-HT3A receptor gating and modulation by extracellular Ca2+. The Journal of physiology 20 16096341
2024 FOXD3-mediated transactivation of ALKBH5 promotes neuropathic pain via m6A-dependent stabilization of 5-HT3A mRNA in sensory neurons. Proceedings of the National Academy of Sciences of the United States of America 19 38285939
2023 Torreya grandis Kernel Oil Alleviates Loperamide-Induced Slow Transit Constipation via Up-Regulating the Colonic Expressions of Occludin/Claudin-1/ZO-1 and 5-HT3R/5-HT4R in BALB/c Mice. Molecular nutrition & food research 19 38152983
2011 Rings of charge within the extracellular vestibule influence ion permeation of the 5-HT3A receptor. The Journal of biological chemistry 19 21454663
2004 Distinct subcellular targeting of fluorescent nicotinic alpha 3 beta 4 and serotoninergic 5-HT3A receptors in hippocampal neurons. The European journal of neuroscience 19 15009132
2004 Minimal structural rearrangement of the cytoplasmic pore during activation of the 5-HT3A receptor. The Journal of biological chemistry 19 15131114
2016 The Human Serotonin Type 3 Receptor Gene (HTR3A-E) Allelic Variant Database. Human mutation 17 27763704
2004 Differential effect of ginsenoside metabolites on the 5-HT3A receptor-mediated ion current in Xenopus oocytes. Molecules and cells 17 15055527
2017 Serotonin Receptor 5-HT3A Affects Development of Bladder Innervation and Urinary Bladder Function. Frontiers in neuroscience 16 29311772
2014 Unraveling mechanisms underlying partial agonism in 5-HT3A receptors. The Journal of neuroscience : the official journal of the Society for Neuroscience 16 25505338
2005 Serotonin receptor genes HTR3A and HTR3B are not involved in Gilles de la Tourette syndrome. Psychiatric genetics 16 16314763
2004 Pharmacological and electrophysiological properties of the naturally occurring Pro391Arg variant of the human 5-HT3A receptor. Pharmacogenetics 16 15167704
2021 Polymorphisms in the HTR2A and HTR3A Genes Contribute to Pain in TMD Myalgia. Frontiers in oral health 15 35047998
2019 Xiaoerfupi alleviates the symptoms of functional dyspepsia by regulating the HTR3A and c-FOS. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 15 31546083
2015 Influence of the 5-HT3A Receptor Gene Polymorphism and Childhood Sexual Trauma on Central Serotonin Activity. PloS one 15 26701104
2014 Sequence variants of the HTR3A gene contribute to the genetic prediction of postoperative nausea in Taiwan. Journal of human genetics 15 25339231
2008 The effects of fentanyl-like opioids and hydromorphone on human 5-HT3A receptors. Anesthesia and analgesia 15 18635474
2006 The effects of morphine on human 5-HT3A receptors. Anesthesia and analgesia 15 16931691
2002 Functional group interactions of a 5-HT3R antagonist. BMC biochemistry 15 12079499
2016 Kampo Medicine: Evaluation of the Pharmacological Activity of 121 Herbal Drugs on GABAA and 5-HT3A Receptors. Frontiers in pharmacology 14 27524967
2008 The L293 residue in transmembrane domain 2 of the 5-HT3A receptor is a molecular determinant of allosteric modulation by 5-hydroxyindole. Neuropharmacology 14 18436267
2013 Mutagenic analysis of the intracellular portals of the human 5-HT3A receptor. The Journal of biological chemistry 13 24030822
2012 A coupled array of noncovalent interactions impacts the function of the 5-HT3A serotonin receptor in an agonist-specific way. ACS chemical neuroscience 13 23077719
2000 Exon-intron organization of the human 5-HT3A receptor gene. Neuropharmacology 13 10670426
2015 Association of genetic polymorphisms in HTR3A and HTR3E with diarrhea predominant irritable bowel syndrome. International journal of clinical and experimental medicine 12 26064388
2010 Effects of protostane-type triterpenoids on the 5-HT3A receptor-mediated ion current in Xenopus oocytes. Brain research 12 20307506
2013 A single channel mutation alters agonist efficacy at 5-HT3A and 5-HT3AB receptors. British journal of pharmacology 10 23822584
2022 Histone Methyltransferase SETDB1 Regulates the Development of Cortical Htr3a-Positive Interneurons and Mood Behaviors. Biological psychiatry 9 36335068
2020 5'UTR polymorphism in the serotonergic receptor HTR3A gene is differently associated with striatal Dopamine D2/D3 receptor availability in the right putamen in Fibromyalgia patients and healthy controls-Preliminary evidence. Synapse (New York, N.Y.) 9 31868947
2014 5-HT3A receptors are required in long-term depression and AMPA receptor internalization. Neuroscience 9 25130560
2009 Hydrophobic photolabeling studies identify the lipid-protein interface of the 5-HT3A receptor. Biochemistry 9 19715355
2012 Histone acetylation of the htr3a gene in the prefrontal cortex of Wistar rats regulates ethanol-seeking behavior. Neural regeneration research 8 25722691

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