Affinage

HTR3A

5-hydroxytryptamine receptor 3A · UniProt P46098

Length
478 aa
Mass
55.3 kDa
Annotated
2026-04-28
100 papers in source corpus 42 papers cited in narrative 42 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HTR3A encodes the obligatory 5-HT3A subunit of the serotonin type 3 receptor, a pentameric Cys-loop ligand-gated cation channel that mediates fast excitatory serotonergic neurotransmission and regulates synaptic plasticity, fear memory extinction, cortical circuit development, and autonomic innervation. Agonist recognition requires a cation-π interaction at Trp183 (loop B) coupled to hydrogen bonds from loop A residues E129 and D124, with at least three serotonin molecules needed for channel opening; gating is transduced through pre-TM1 Arg222 and TM2-TM3 linker residue D298, while desensitization is governed by the M2 4′ lysine and cytoplasmic Arg427 (PMID:12162741, PMID:23077719, PMID:11533135, PMID:12970351, PMID:16096341, PMID:10639097, PMID:16754678). Single-channel conductance is rate-limited by arginine residues (Arg436, Arg440) forming electrostatic barriers in the intracellular MA helix portals and by anionic residues (Asp113, Asp127) in the extracellular vestibule, while surface expression depends on RIC-3 chaperone interaction, N-glycosylation at N109/N174/N190, and the C-terminal residue Ala455 (PMID:17200121, PMID:24030822, PMID:21454663, PMID:20522555, PMID:15264219, PMID:18786552). In vivo, 5-HT3A is essential for NMDAR-dependent hippocampal LTD via AMPA receptor internalization, fear extinction, cortical dendritic patterning through Cajal-Retzius cell signaling, excitation/inhibition balance in parvalbumin-positive interneurons, and normal bladder innervation development (PMID:25130560, PMID:24344177, PMID:22696545, PMID:34646371, PMID:29311772).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 2000 High

    Identifying the M2 4′ lysine as a desensitization determinant separable from channel conductance established that gating conformational changes extend beyond the pore-lining face of M2.

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

    PMID:10639097

    Open questions at the time
    • No structural basis for how 4′ position influences desensitization without lining the pore
    • Whether the same residue functions identically in heteromeric 5-HT3A/3B receptors
  2. 2000 High

    Discovery of alternative splice variants (h5-HT3AT and h5-HT3AL) that modulate desensitization and ion flux when co-expressed with 5-HT3A revealed endogenous mechanisms for tuning receptor properties without requiring heteromeric subunit partners.

    Evidence cDNA cloning, HEK293 electrophysiology, RT-PCR confirmation in amygdala/hippocampus

    PMID:11111833

    Open questions at the time
    • Stoichiometry of splice variant incorporation into pentamers unknown
    • In vivo functional significance of splice variants not tested
  3. 2001 High

    Demonstrating that at least three serotonin molecules must bind to open the channel, with concentration-dependent open probability, defined the cooperativity and occupancy requirements for 5-HT3A gating.

    Evidence Rapid agonist application, outside-out patch-clamp, and kinetic modeling in HEK293 cells

    PMID:11533135

    Open questions at the time
    • Which specific binding sites among five subunits are occupied at threshold unknown
    • Whether heteromeric receptors have the same occupancy requirement
  4. 2002 High

    Identification of a cation-π interaction between serotonin and Trp183 (loop B) using unnatural amino acid mutagenesis precisely located the agonist-receptor contact and quantified its ~4 kcal/mol contribution, establishing the primary binding mechanism.

    Evidence Unnatural amino acid incorporation and electrophysiology in Xenopus oocytes

    PMID:12162741

    Open questions at the time
    • Whether the same interaction applies to all five binding sites in the pentamer
    • Structural validation awaited (no crystal/cryo-EM structure at the time)
  5. 2003 High

    Showing that Arg222 in the pre-TM1 region links binding to gating — its mutation increased potency, altered kinetics, and converted an antagonist to agonist — identified a critical transduction element between the extracellular and transmembrane domains.

    Evidence Site-directed mutagenesis and patch-clamp in HEK293 cells

    PMID:12970351

    Open questions at the time
    • The partner residues that Arg222 interacts with during transduction not identified
    • No direct structural evidence for conformational change at this position
  6. 2004 High

    Mapping the M2 pore with systematic SCAM and Cd²⁺ probing in open and closed states revealed that the cytoplasmic selectivity filter maintains a narrow pore in both states, indicating minimal rearrangement at the 2′ and −2′ positions during gating.

    Evidence Cysteine mutagenesis with state-dependent Cd²⁺ accessibility in HEK293 cells

    PMID:15131114

    Open questions at the time
    • Resolution limited to accessibility changes; structural movements below probe size undetectable
    • Whether this holds for heteromeric receptors
  7. 2004 High

    Dissecting N-glycosylation sites showed N109 is required for receptor assembly while N174 and N190 control plasma membrane trafficking and ligand binding, establishing that post-translational modifications at distinct sites play non-redundant roles in receptor biogenesis.

    Evidence Site-directed mutagenesis of each glycosylation site with surface expression, radioligand binding, and Ca²⁺ influx assays

    PMID:15264219

    Open questions at the time
    • Glycan composition at each site not determined
    • Whether glycosylation requirements differ in neurons vs. heterologous cells
  8. 2005 High

    Identification of D298 in the TM2-TM3 linker as a charge-dependent determinant of gating kinetics and Ca²⁺ modulation, together with loop C residue contributions, expanded the map of conformational coupling from the ligand-binding domain to the channel gate.

    Evidence Charge-reversal/neutralization mutagenesis with fast-application patch-clamp (D298); alanine mutagenesis with binding and electrophysiology (loop C) in oocytes and HEK293 cells

    PMID:15966738 PMID:16096341

    Open questions at the time
    • No direct measurement of conformational movements at these positions
    • Interaction partners of D298 within the linker not mapped
  9. 2006 High

    Localization of Arg427 in the large cytoplasmic domain as a desensitization determinant, with polarity-dependent kinetics, extended the desensitization mechanism beyond the transmembrane domain into the intracellular region.

    Evidence Sequential LCD deletion and point mutagenesis with whole-cell patch-clamp in HEK293 cells

    PMID:16754678

    Open questions at the time
    • Structural context of Arg427 within the cytoplasmic domain unknown
    • Whether phosphorylation or protein interactions at this site modulate desensitization in vivo
  10. 2007 High

    Dynamic charge modification at Arg436 and systematic scanning of MA helix residues (435–440) demonstrated that cytoplasmic portals impose a rate-limiting electrostatic barrier to ion permeation, explaining the characteristically low single-channel conductance of homomeric 5-HT3A receptors.

    Evidence SCAM with MTS reagents, alanine/arginine scanning, single-channel electrophysiology in HEK293 cells

    PMID:17200121 PMID:24030822

    Open questions at the time
    • Structural model of portal geometry at atomic resolution not available
    • How heteromeric subunit composition alters portal electrostatics
  11. 2007 High

    Kinetic modeling of serotonin vs. dopamine as high- vs. low-efficacy agonists revealed that partial agonism arises from distinct opening rates and dissociation from open/desensitized states, providing a mechanistic framework for efficacy differences at this receptor.

    Evidence Rapid solution exchange electrophysiology with allosteric kinetic modeling in HEK293 cells

    PMID:18045909

    Open questions at the time
    • Whether the kinetic scheme generalizes to other partial agonists
    • No structural basis for differential state-dependent binding
  12. 2010 High

    Demonstrating that RIC-3 chaperone directly interacts with 5-HT3A (and C/D/E subunits) in the ER and selectively enhances homomeric 5-HT3A surface expression identified an ER-resident quality control step specific to receptor biogenesis.

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

    PMID:20522555

    Open questions at the time
    • Molecular interface between RIC-3 and 5-HT3A not mapped
    • Whether RIC-3 is rate-limiting for 5-HT3A expression in neurons
  13. 2012 High

    Mutant cycle analysis with unnatural amino acids revealed a tightly coupled array — cation-π at W183, hydrogen bonds from E129 and D124 — that functions as a unit for serotonin recognition but not for the partial agonist mCPBG, establishing agonist-specific binding site mechanics.

    Evidence Double mutant cycle analysis with unnatural amino acid mutagenesis in Xenopus oocytes

    PMID:23077719

    Open questions at the time
    • How coupling energetics translate to conformational changes in the binding domain
    • Coupling analysis not extended to other agonists beyond 5-HT and mCPBG
  14. 2012 High

    5-HT3A knockout abolished NMDAR-dependent LTD (but not mGluR-dependent LTD) and blocked activity-dependent AMPA receptor internalization at hippocampal CA1 synapses, establishing a specific role for 5-HT3A in one form of synaptic plasticity.

    Evidence Htr3a KO mice, hippocampal slice LTD protocols, AMPAR internalization assays

    PMID:25130560

    Open questions at the time
    • Cell type (interneuron vs. pyramidal) through which 5-HT3A acts in LTD not determined
    • Signaling intermediates between 5-HT3A activation and AMPAR endocytosis unknown
  15. 2012 High

    Loss of 5-HT3A caused exuberant apical dendritic complexity in cortical L2/3 pyramidal neurons with altered excitability, linking serotonergic input on Cajal-Retzius cells during development to cortical circuit maturation.

    Evidence Htr3a KO mice, morphological reconstruction, whole-cell patch-clamp, computational modeling

    PMID:22696545

    Open questions at the time
    • Molecular signals downstream of 5-HT3A in Cajal-Retzius cells not identified
    • Whether dendritic phenotype is reversible if 5-HT3A is restored postnatally
  16. 2013 High

    Htr3a KO mice showed normal fear acquisition but failed to extinguish contextual and cued fear, dissociating 5-HT3A function specifically to fear extinction circuitry.

    Evidence Fear conditioning and extinction behavioral paradigms in Htr3a KO mice

    PMID:24344177

    Open questions at the time
    • Brain region and cell type mediating the extinction deficit not identified
    • Whether pharmacological 5-HT3 blockade recapitulates the extinction deficit
  17. 2017 High

    5-HT3A loss disrupted bladder innervation development — altering autonomic neuronal subtype balance in fetal pelvic ganglia and increasing fiber density — resulting in voiding dysfunction, establishing a developmental role for 5-HT3A in visceral innervation patterning.

    Evidence Htr3a KO mice, cystometry, immunohistochemistry for neuronal markers across developmental timepoints

    PMID:29311772

    Open questions at the time
    • Mechanism by which 5-HT3A signaling regulates neuronal subtype specification in ganglia unknown
    • Whether human HTR3A variants cause bladder dysfunction
  18. 2021 High

    5-HT3A loss caused NMDAR upregulation specifically in PV+ interneurons, increasing their excitability and GABAergic output onto pyramidal neurons, reducing E/I ratio and producing autistic-like behaviors rescuable by memantine — identifying a cell-type-specific mechanism linking 5-HT3A to E/I balance.

    Evidence TALEN-generated Htr3a KO mice, behavioral testing, patch-clamp in PV+ interneurons, transcriptomics, immunoblotting, memantine rescue

    PMID:34646371

    Open questions at the time
    • How 5-HT3A loss leads to NMDAR transcriptional upregulation in PV+ cells not resolved
    • Whether the E/I imbalance mechanism generalizes to other brain regions
  19. 2024 High

    FOXD3-driven ALKBH5 upregulation erases m6A marks on Htr3a mRNA, preventing YTHDF2-mediated degradation and stabilizing 5-HT3A expression to promote neuropathic pain — revealing an epitranscriptomic regulatory layer controlling HTR3A abundance.

    Evidence Rat trigeminal nerve injury, ALKBH5 manipulation, ChIP-seq, m6A-seq, RIP, patch-clamp, behavioral pain assays

    PMID:38285939

    Open questions at the time
    • Whether m6A regulation of Htr3a occurs in CNS neurons beyond trigeminal ganglia
    • Other m6A reader proteins that may also regulate Htr3a stability

Open questions

Synthesis pass · forward-looking unresolved questions
  • High-resolution structural basis of the full gating cycle (resting → open → desensitized) for homomeric and heteromeric 5-HT3 receptors, the molecular determinants of heteromeric subunit assembly stoichiometry, and the signaling pathways linking 5-HT3A channel activity to AMPAR internalization and fear extinction circuitry remain unresolved.
  • No full gating-cycle cryo-EM structures capturing all functional states in the timeline
  • Intracellular signaling cascade from 5-HT3A to AMPAR endocytosis not identified
  • Cell-type and circuit identity mediating fear extinction role undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 3 GO:0060089 molecular transducer activity 2
Localization
GO:0005886 plasma membrane 3 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-112316 Neuronal System 4 R-HSA-382551 Transport of small molecules 3 R-HSA-162582 Signal Transduction 2
Partners
ALKBH5HTR3BIGF2BP2IGF2BP3RIC3YTHDF2
Complex memberships
5-HT3 receptor (homomeric pentamer)5-HT3A/3B heteromeric receptor

Evidence

Reading pass · 42 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 is required for agonist binding, precisely locating the ligand-binding site. The energetic contribution is approximately 4 kcal/mol. Unnatural amino acid mutagenesis and heterologous expression in Xenopus oocytes (in vitro electrophysiology + mutagenesis) Biochemistry High 12162741
2003 Arginine 222 (Arg-222) in the pre-transmembrane domain 1 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 an antagonist (apomorphine) to a potent agonist. Site-directed mutagenesis and whole-cell patch-clamp electrophysiology in HEK293 cells 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; deletion or point mutation at this position significantly slowed desensitization kinetics, with desensitization rate positively correlated with polarity of the residue at position 427. Sequential LCD deletion and point mutagenesis with whole-cell patch-clamp in HEK293 cells The Journal of biological chemistry High 16754678
2000 The 4′ lysine residue in the M2 channel-lining domain of the 5-HT3A receptor affects desensitization kinetics but does not form part of the channel lining; mutations at this position slow desensitization without altering single-channel conductance. Site-directed mutagenesis, whole-cell patch-clamp, and fluctuation analysis in HEK293 cells The Journal of physiology High 10639097
2001 Homomeric murine 5-HT3A receptors require binding of at least three serotonin molecules to open, and channel open probability varies with the number of bound agonist molecules, with reduced open probability for fully liganded receptors; peak open probability exceeds 0.8. Rapid agonist application, whole-cell and excised outside-out patch clamp, kinetic modeling in HEK293 cells The Journal of physiology High 11533135
2005 The conserved proline P303 in the M2-M3 linker of the human 5-HT3A receptor is important for function (Ca2+ dependence and desensitization rate) but trans-cis isomerization at this proline is not required for agonist-induced channel opening. Natural amino acid mutagenesis of P303 with two-electrode voltage-clamp in Xenopus oocytes Journal of neurochemistry High 19457066
2005 Aspartate 298 (D298) in the TM2-TM3 extracellular loop of the mouse 5-HT3A receptor participates in channel gating kinetics (desensitization, deactivation, partial agonist efficacy) and is crucial for Ca2+ modulation; charge at this residue determines these properties. Site-directed mutagenesis, whole-cell patch-clamp with fast agonist application in HEK293 cells The Journal of physiology High 16096341
2005 Loop C residues F226, I228, D229, and Y234 of the murine 5-HT3A receptor contribute differentially to ligand binding and gating; I228 and D229 are specific for 5-HT versus mCPBG interactions, while F226 and Y234 are important for both agonists. Site-directed mutagenesis, radioligand binding, two-electrode voltage-clamp in Xenopus oocytes, homology modeling Biochemistry High 15966738
2007 Serotonin and dopamine act as high- and low-efficacy agonists, respectively, at human 5-HT3A receptors with distinct kinetic mechanisms: serotonin shows concentration-dependent activation and sigmoidal recovery from desensitization; dopamine shows concentration-independent activation, faster deactivation, and non-sigmoidal recovery, explained by different rates of channel opening and dissociation from open/desensitized states. Rapid solution exchange electrophysiology in HEK293 cells with allosteric kinetic modeling The Journal of neuroscience High 18045909
2007 Dynamic modification of the charge at cytoplasmic residue Arg436 regulates single-channel conductance of the 5-HT3A receptor, consistent with cytoplasmic portals that impose a rate-limiting barrier to ion conduction; negatively charged MTS reagents at this position increased conductance while positively charged reagents decreased it. Cysteine substitution (R436C), MTS reagent modification, outside-out and inside-out patch clamp electrophysiology The Journal of biological chemistry High 17200121
2013 Multiple residues within the MA (membrane-associated) helix intracellular portals of human 5-HT3A (positions 435, 436, 439, 440) markedly influence single-channel conductance; alanine- and arginine-scanning mutagenesis combined with substituted cysteine accessibility method generated a functional map of the cytoplasmic portals. Alanine/arginine-scanning mutagenesis and substituted cysteine accessibility method (SCAM) with single-channel electrophysiology 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 relative to Cs+ (PCa/PCs), and Ca2+-mediated suppression of conductance; D127 mutations had larger effects than D113, and both influenced ion selectivity. Site-directed mutagenesis, single-channel outside-out patch-clamp, permeability ratio measurements in HEK293 cells The Journal of biological chemistry High 21454663
2004 The cytoplasmic pore (selectivity filter) of the 5-HT3A receptor maintains a narrow pore in both open and closed states, indicating minimal structural rearrangement at the 2' and -2' positions during channel gating. Systematic cysteine mutagenesis throughout M1-M2 loop and M2 domain with Cd2+ accessibility probing in open and closed states The Journal of biological chemistry High 15131114
2006 Granisetron interacts with a binding cavity formed by loop B, C, and E residues of the 5-HT3A receptor; H185A mutation abolished granisetron binding and D189A reduced affinity 22-fold; Y143 and Y153 in loop E contribute via their hydroxyl groups. Homology modeling, docking, and alanine mutagenesis with radioligand binding Biochemistry Medium 16430206
2006 Ginsenoside Rg3 inhibits 5-HT3A receptor channel activity through interactions with residues V291, F292, and I295 in the channel gating region of TM2, acting in the open state at sites distinct from those of TMB-8 and diltiazem. TM2 mutagenesis (V291A, F292A, I295A) and two-electrode voltage-clamp in Xenopus oocytes 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 also altering desensitization. Site-directed mutagenesis and whole-cell patch-clamp in HEK293 cells and N1E-115 cells Neuropharmacology High 18436267
2010 RIC-3 chaperone directly interacts with 5-HT3A, -C, -D, and -E subunits (co-localizes in ER) but predominantly enhances surface expression of homomeric 5-HT3A receptors in HEK293 cells without altering 5-HT potency; increased Emax correlates with increased Bmax and surface expression. Co-immunoprecipitation, immunocytochemistry (ER co-localization), flow cytometry for surface expression, Ca2+ influx assays, radioligand binding The Journal of biological chemistry High 20522555
2004 N-glycosylation at three sites of the murine 5-HT3A receptor (N109, N174, N190) plays distinct roles: N109 is necessary for receptor assembly, while N174 and N190 are important for plasma membrane targeting and ligand binding; all three are required for Ca2+ influx. Tunicamycin treatment, site-directed mutagenesis, surface expression assays, radioligand binding, Ca2+ influx assays in transfected cells Journal of neuroscience research High 15264219
2008 The C-terminal residue Ala455 of the human 5-HT3A subunit is critical for receptor folding/maturation and membrane expression; deletion of the three C-terminal residues abolished radioligand binding and membrane expression, and Ala455Leu mutation caused 88% reduction. C-terminal deletion and point mutagenesis, radioligand binding, cell membrane expression assays at 37°C and 27°C Neuropharmacology High 18786552
2004 5-HT3A receptor subunit is localized in axonal (presynaptic), somatodendritic, and glial profiles in the medial nucleus of the solitary tract (mNTS); presynaptically, it associates with synaptic vesicle membranes and extrasynaptic plasma membranes, consistent with modulation of both presynaptic release and postsynaptic responses. Electron microscopic immunocytochemistry with subcellular localization in rat brain tissue Brain research Medium 15527741
2004 Fluorescently tagged YFP-5-HT3A receptor is targeted to plasma membrane, micropodia in HEK293 cells, and dendritic spines in hippocampal neurons, accessible by extracellular probes, in contrast to alpha3beta4-nAChRs which remain predominantly intracellular. Live fluorescence microscopy with YFP-fusion subunit, extracellular fluorescent probe accessibility, whole-cell patch-clamp in HEK293 cells and hippocampal neurons The European journal of neuroscience High 15009132
2000 Alternative splicing of the human 5-HT3A gene produces a short truncated variant (h5-HT3AT, 238 aa, single TM domain) and a long variant (h5-HT3AL, 32 extra aa in M2-M3 extracellular loop); neither forms functional homomeric receptors, but h5-HT3AT slows desensitization and greatly increases cation flux when co-expressed with 5-HT3A, while h5-HT3AL reduces cation flux. CDNA cloning, HEK293 cell transfection, whole-cell patch-clamp electrophysiology, expression in amygdala/hippocampus confirmed by RT-PCR Naunyn-Schmiedeberg's archives of pharmacology High 11111833
2009 The M3M4 intracellular loop of the 5-HT3A receptor is not required for receptor assembly or function; however, loop length and amino acid composition affect channel expression and desensitization rate, suggesting the cytoplasmic ends of M3 and M4 undergo conformational changes during gating/desensitization. M3M4 loop replacement with 1-7 alanine residues, expression in Xenopus oocytes, two-electrode voltage-clamp PloS one High 22539982
2012 Deletion of 5-HT3A receptor gene in mice abolishes NMDAR-dependent long-term depression (LTD) at hippocampal CA1 synapses and inhibits AMPA receptor internalization following low-frequency stimulation, without altering mGluR-dependent LTD, basal AMPAR surface levels, or synaptic structure. 5-HT3AR knockout mice, hippocampal slice electrophysiology (LTD induction by LFS), AMPAR internalization assay Neuroscience High 25130560
2013 The 5-HT3A receptor is essential for fear extinction in mice; Htr3a knockout mice show normal fear acquisition and retention but fail to extinguish contextual and tone-cued fear memory. Htr3a knockout mice, fear conditioning and extinction behavioral paradigms (contextual and cued) Learning & memory High 24344177
2021 Htr3a knockout mice exhibit autistic-like behaviors; mechanistically, loss of 5-HT3A leads to NMDAR upregulation specifically in parvalbumin-positive (PV+) interneurons, increasing NMDAR current and excitability, which enhances GABAergic transmission to pyramidal neurons and decreases the E/I ratio. NMDAR antagonist memantine rescues GABAergic transmission and autistic-like behaviors. TALEN-generated Htr3a KO mice, behavioral tests, patch-clamp electrophysiology, transcriptome sequencing, immunoblotting, immunofluorescence, immunoprecipitation, memantine rescue Theranostics High 34646371
2017 5-HT3A receptor is required for normal bladder innervation development; Htr3a knockout male mice exhibit increased voiding frequency and decreased voiding efficiency. Loss of 5-HT3A causes transient imbalance of autonomic neuronal subtype markers in fetal pelvic ganglia and higher density of autonomic/sensory neuronal fibers in bladder smooth muscle in both fetal and adult mice. Htr3a knockout mice, cystometry, immunohistochemistry for neuronal markers, fiber density quantification Frontiers in neuroscience High 29311772
2004 Constitutively activating V13'S mutation in the M2 domain of the 5-HT3A receptor (valine to serine) renders the receptor 70-fold more sensitive to serotonin and produces constitutive activity when combined with 5-HT3B; homozygous knock-in mice develop urinary bladder dysfunction and die from obstructive uropathy, suggesting persistent 5-HT3A activation causes excitotoxic neuronal death in bladder. Targeted exon replacement knock-in mice (V13'S), whole-cell patch-clamp in sympathetic ganglion cells, cystometry, histological analysis The Journal of neuroscience High 15201326
2002 Cannabinoids (including anandamide) stereoselectively inhibit currents through human 5-HT3A receptors independently of cannabinoid CB1/CB2 receptors, reducing maximum current without changing EC50 of 5-HT, consistent with allosteric modulatory site action; WIN55,212-2 did not displace [3H]-GR65630 from the 5-HT3 binding site. Outside-out patch-clamp in HEK293 cells stably transfected with h5-HT3A, radioligand binding competition assays British journal of pharmacology High 12381672
2007 Anandamide (AEA) inhibits 5-HT3A receptor function by accelerating desensitization in a concentration-dependent manner; the magnitude of inhibition is inversely correlated with surface receptor density and is reduced by agents (5-hydroxyindole, nocodazole) that slow desensitization, indicating desensitization kinetics regulate AEA potency. Two-electrode voltage-clamp in Xenopus oocytes and whole-cell patch-clamp in HEK293 cells; surface expression manipulation with actinomycin D Molecular pharmacology High 17993512
2009 The lipid-protein interface of the 5-HT3A receptor is defined at the M4 transmembrane helix; hydrophobic photolabel [125I]TID labeled Ser451 within M4, equivalent to the lipid-exposed face of Torpedo nAChR alpha1M4, establishing the lipid-facing surface of the 5-HT3A receptor. Purification of alphaBgTx-tagged 5-HT3A receptor, hydrophobic photoaffinity labeling with [125I]TID, peptide mapping Biochemistry High 19715355
2001 The 5-HT3B subunit, when co-expressed with 5-HT3A, alters predominantly biophysical rather than pharmacological properties of the 5-HT3 receptor; homomeric 5-HT3A and heteromeric 5-HT3A/3B receptors show very similar pharmacological profiles. Heterologous expression in HEK293 cells, radioligand binding, whole-cell electrophysiology comparing homomeric vs. heteromeric receptors Neuropharmacology High 11489465
2003 Picrotoxin selectively inhibits homomeric 5-HT3A receptors with 100-fold higher potency compared to heteromeric 5-HT3A/3B receptors, providing a pharmacological tool to distinguish receptor composition. Whole-cell patch-clamp in cells expressing mouse homomeric 5-HT3A vs. heteromeric 5-HT3A/3B receptors Brain research. Molecular brain research High 14625088
2007 Naturally occurring single nucleotide polymorphisms A33T, S253N, and M257I in the human 5-HT3A receptor reduce maximal 5-HT-induced responses to 3-64% of wild-type without altering 5-HT potency or antagonist affinities; A33T, M257I, and R344H display reduced surface expression (2-4-fold) despite similar total expression, indicating effects on receptor biogenesis/trafficking. Fluorescence-based calcium influx assays, [3H]GR65630 radioligand binding, surface expression assays in transfected cells expressing 5-HT3A variants Pharmacogenetics and genomics High 17496724
2014 Partial agonism of tryptamine at the 5-HT3A receptor results from reduced priming (decreased ability to overcome transitions to closed preopen states) rather than channel blockade; in contrast, 2-Me-5HT is not a genuine partial agonist since its low apparent efficacy is mainly due to channel blockade within the activating concentration range. Single-channel patch-clamp analysis of high-conductance 5-HT3A receptor, kinetic modeling, molecular docking The Journal of neuroscience High 25505338
2012 A coupled array of noncovalent interactions governs 5-HT3A receptor function in an agonist-specific manner: cation-π interaction with W183 (loop B), a hydrogen bond from E129 (loop A), and hydrogen bonds from D124 (loop A) to loop B backbone are tightly coupled and function as a unit. mCPBG (partial agonist) shows no cation-π at TrpB and extreme sensitivity to E129 positioning. Mutant cycle analyses using conventional and unnatural amino acid mutagenesis in Xenopus oocytes ACS chemical neuroscience High 23077719
2024 FOXD3-mediated transcriptional upregulation of ALKBH5 (m6A demethylase) in injured trigeminal ganglia neurons erases m6A sites on Htr3a mRNA, preventing YTHDF2 binding and mRNA degradation, thereby stabilizing and increasing 5-HT3A protein expression and channel currents, promoting neuropathic pain. Rat trigeminal nerve injury model, ALKBH5 knockdown/overexpression, ChIP-seq for H3K27ac and FOXD3 binding, m6A-seq, RIP for YTHDF2, patch-clamp for 5-HT3 currents, behavioral pain assays Proceedings of the National Academy of Sciences of the United States of America High 38285939
2021 The lncRNA linc01305 stabilizes HTR3A mRNA by interacting with RNA-binding proteins IGF2BP2 and IGF2BP3, promoting proliferation and metastasis of esophageal squamous cell carcinoma. linc01305 pulldown, mass spectrometry, RNA immunoprecipitation, mRNA stability assays, RNA-seq, FISH, transwell and colony formation assays The international journal of biochemistry & cell biology High 34022433
2012 Ethanol consumption induces tissue-specific DNA methylation changes at the Htr3a promoter in mouse brain and blood; reduced methylation in the dorsomedial striatum correlated with increased Htr3a mRNA expression (1.43-fold), suggesting promoter methylation inversely regulates Htr3a expression. Sequenom MassARRAY methylation quantification across 8-9 CpGs in 9 brain regions and blood, real-time PCR for Htr3a expression Alcoholism, clinical and experimental research Medium 22834954
2001 A variant C178T (Pro16Ser) in an upstream open reading frame (uORF) of the HTR3A 5' UTR increases reporter gene expression by 245% (C178T alone) or 138% (C178T+C195T) compared to wild-type, indicating this variant affects HTR3A expression at the translational level. Luciferase reporter constructs containing C178T allele transfected into cells, compared to wild-type Pharmacogenetics Medium 11505217
2012 Loss of 5-HT3A receptor in knockout mice causes exuberant apical dendritic complexity in cortical layer 2/3 pyramidal neurons, which reduces spike frequency adaptation and alters afterhyperpolarization development, demonstrating that 5-HT3A-mediated serotonergic input on Cajal-Retzius cells during early postnatal development shapes dendritic morphology and consequently neuronal excitability. 5-HT3A knockout mice, morphological reconstruction, whole-cell patch-clamp recording of layer 2/3 pyramidal neurons, computational modeling Journal of neurophysiology High 22696545
2017 In Htr3a knockout mice, fluoxetine effects are blunted while citalopram triggers 5-HT1A receptor desensitization in the dorsal raphe at lower doses than in wild-type, suggesting 5-HT3 receptor inactivation promotes SSRI efficacy via altered autoreceptor sensitivity. KO also prevents CSDS-induced cortical changes in CaMKIIa and SOD1. Htr3a KO mice, behavioral tests (EPM, FST, social interaction), in vitro dorsal raphe electrophysiology, gene expression analysis British journal of pharmacology Medium 28493335

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 160 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
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2004 Expression of 5-HT3A receptors in cells of the immune system. Scandinavian journal of rheumatology. Supplement 65 15515405
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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
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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
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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
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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
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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 18 38152983
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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
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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
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