Affinage

HTR2A

5-hydroxytryptamine receptor 2A · UniProt P28223

Length
471 aa
Mass
52.6 kDa
Annotated
2026-06-10
100 papers in source corpus 26 papers cited in narrative 26 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HTR2A encodes a Gq/11-coupled, cortex-enriched G-protein-coupled receptor that transduces serotonin signals into phosphoinositide hydrolysis and downstream calcium- and protein-kinase-dependent responses (PMID:1980030, PMID:12095161). Beyond canonical Gq-PLC coupling, the receptor displays pronounced functional selectivity: agonists drive differential efficacy toward PLA2-mediated arachidonic acid release versus PLC-mediated inositol phosphate accumulation (PMID:9928246), couple to G13/phospholipase D (PMID:15496511), and after chronic adolescent THC exposure acquire supersensitive coupling to inhibitory Gαi/o/z proteins through an Akt/mTOR-dependent mechanism (PMID:29748632). Receptor desensitization and trafficking are tightly regulated: agonist-induced desensitization proceeds without loss of surface receptor and is mediated in its intermediate phase by PKCα/ε (PMID:8531139), while ligand-selective endocytosis requires PKC phosphorylation and subsequent recycling depends on PP2A-mediated dephosphorylation (PMID:23034456). The receptor's C-terminal class I PDZ ligand confers selective binding to CIPP and other scaffolding proteins that govern its targeting (PMID:14988405), and the receptor physically heterocomplexes with dopamine D2 and metabotropic glutamate mGlu2 receptors, with consequences for ligand affinity and signaling that depend on the partner (PMID:21645528, PMID:22300836). In the cerebral cortex, 5-HT2AR is expressed most abundantly in layer V pyramidal neurons and in fast-spiking parvalbumin interneurons (PMID:20802802), where sustained activation drives GluA2-Ser880 phosphorylation, AMPA receptor internalization, and long-lasting depression of glutamatergic transmission (PMID:29917056); cortical Htr2a expression is itself acutely up-regulated by stress through an Egr3-dependent transcriptional program (PMID:25857407) and by glucocorticoid receptor signaling (PMID:19379741). Peripherally, the receptor activates MAPK/ERK in vascular smooth muscle (PMID:9928253), drives PI3K-PDK1-AKT-mTOR-dependent cardiomyocyte hypertrophy (PMID:32519137), mediates thermal hyperalgesia (PMID:9718253), blocks TNF-α-driven inflammation (PMID:24098382), and is required for CO2-induced arousal from sleep (PMID:25925320).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1990 High

    Establishing the receptor's identity and primary effector answered whether HTR2A was a functional serotonin GPCR and where it acts, anchoring all later mechanistic work.

    Evidence Somatic cell hybrid chromosomal mapping with functional inositol phospholipid hydrolysis annotation

    PMID:1980030

    Open questions at the time
    • Did not resolve G-protein identity or downstream branching
    • No cell-type resolution of cortical expression
  2. 1995 High

    Dissecting desensitization mechanism showed that signal attenuation can occur independently of receptor down-regulation, separating regulatory phases and implicating specific PKC isoforms.

    Evidence Stable cell line with radioligand binding, IP assays, isoform-selective antibodies, and F340L binding-incompetent mutant

    PMID:8531139

    Open questions at the time
    • Late-phase (24 h) desensitization mechanism left undefined
    • Did not address β-arrestin involvement
  3. 1998 Medium

    Demonstrating differential agonist efficacy for PLA2 versus PLC, ERK activation in smooth muscle, peripheral nociceptive expression, and dissociation of PLC from hallucinogenic behavior established that the receptor signals through multiple branched pathways with agonist-directed trafficking.

    Evidence Second-messenger assays in receptor-expressing cell lines, arterial contractile and Western blot assays, in vivo paw-withdrawal with in situ hybridization, and PC12 PI hydrolysis versus drug-discrimination comparison

    PMID:11900766 PMID:9718253 PMID:9928246 PMID:9928253

    Open questions at the time
    • Molecular basis of biased efficacy not resolved
    • Behavioral readout of hallucinogenesis remained mechanistically uncoupled from measured signaling
  4. 2002 Medium

    Linking receptor activation to de novo BDNF transcription identified a calcium- and kinase-dependent transcriptional output of 5-HT2AR signaling.

    Evidence RT-PCR/Northern blot of BDNF mRNA in C6 glioma with antagonist and kinase/calcium inhibitor dissection

    PMID:12095161

    Open questions at the time
    • Transcription factors mediating BDNF induction not identified
    • Performed in glioma cells, not neurons
  5. 2004 High

    Identifying a selective PDZ-ligand interaction with CIPP, heterologous desensitization of co-localized 5-HT1A receptors, and a hypofunctional His452Tyr variant defined the receptor's scaffolding and cross-talk machinery and a natural functional polymorphism.

    Evidence Peptide affinity chromatography with mass spectrometry and imaging; in vivo PVN microinjection with neuroendocrine readout and double-label immunocytochemistry; mutagenesis with PLC/PLD/GTPγS assays

    PMID:14988405 PMID:15064330 PMID:15496511

    Open questions at the time
    • Functional consequence of CIPP scaffolding on signaling not directly tested
    • Mechanism of 5-HT1A heterologous desensitization unresolved
  6. 2010 Medium

    Cataloging scaffolding/regulatory partners and constitutive activity refined how the receptor is targeted and how basal signaling is tuned, including RSK-mediated negative feedback.

    Evidence Co-IP and trafficking assays reviewed from primary work; cell-based and in vivo constitutive-activity pharmacology

    PMID:16269190 PMID:18640136

    Open questions at the time
    • Review-level evidence not from a single rigorous study
    • Physiological relevance of constitutive activity not fully established
  7. 2010 High

    Mapping cortical 5-HT2AR to layer V pyramidal neurons and parvalbumin interneurons answered which cells the receptor acts in and showed direct depolarizing excitation of interneurons.

    Evidence BAC transgenic EGFP reporter with KO antibody validation, immunohistochemistry, and whole-cell electrophysiology

    PMID:20802802

    Open questions at the time
    • Circuit-level integration of pyramidal versus interneuron effects unresolved
  8. 2011 Medium

    Demonstrating physical D2R and (later) mGlu2R heterocomplexes clarified that receptor-receptor interactions reciprocally modulate ligand affinity and signaling, but that complex formation does not always produce second-messenger crosstalk.

    Evidence Co-IP, radioligand binding, IP assays, and 5-HT2AR-KO locomotor pharmacology (D2R); quantitative SNAP/CLIP HTRF and Gq/Gi/cAMP assays (mGlu2)

    PMID:21645528 PMID:22300836

    Open questions at the time
    • Stoichiometry and in vivo prevalence of heterocomplexes unknown
    • Discrepant functional outcomes between partners unexplained
  9. 2012 High

    Resolving ligand-selective endocytosis and PP2A-dependent recycling established that trafficking is functionally selective, with distinct kinase/phosphatase requirements per ligand.

    Evidence Cell-based trafficking assays with PKC inhibition, phosphorylation measurement, and PP2A inhibition across multiple ligands

    PMID:23034456

    Open questions at the time
    • Identity of receptor phosphosites not mapped
    • DA/clozapine-induced internalization mechanism (PKC-independent) undefined
  10. 2013 High

    In vivo work established the receptor's role in dorsal raphe firing control, systemic anti-inflammatory action, and hepatic stellate cell activation, broadening its mechanistic reach beyond cortical signaling.

    Evidence In vivo electrophysiology/microdialysis with KO mice and noradrenergic lesion; systemic (R)-DOI with antagonist rescue and inflammatory marker profiling; LX-2 cell and rat cirrhosis antagonist studies

    PMID:23362947 PMID:23411676 PMID:24098382

    Open questions at the time
    • Downstream signaling for anti-inflammatory effect not delineated
    • Cell-type and pathway specificity in liver fibrosis incompletely defined
  11. 2015 Medium

    Defining stress- and serotonin-dependent regulation showed that Htr2a expression is acutely induced via Egr3 and that the receptor is permissively required for CO2-induced arousal.

    Evidence Sleep-deprivation qRT-PCR in Egr3-/- mice; subtype-selective pharmacology and Lmx1b serotonin-neuron-null arousal assays

    PMID:25857407 PMID:25925320

    Open questions at the time
    • Direct Egr3 binding to Htr2a regulatory region not shown
    • Neural circuit mediating arousal effect unresolved
  12. 2018 High

    Showing that chronic THC shifts the receptor toward Gαi/o coupling via Akt/mTOR established a mechanism for drug-induced pro-hallucinogenic signaling bias.

    Evidence Chronic THC in mice with [35S]GTPγS coupling assays across Gα subtypes, PPI behavior, and rapamycin co-treatment

    PMID:29748632

    Open questions at the time
    • Molecular link between Akt/mTOR and altered G-protein coupling unmapped
    • Durability and reversibility of the bias shift unknown
  13. 2019 High

    Establishing that sustained 5-HT2AR activation drives AMPA receptor internalization and LTD in cortical pyramidal neurons defined a synaptic plasticity mechanism with genetic causality.

    Evidence Patch-clamp in PFC slices with 5-HT2AR-KO, viral rescue, GluA2-Ser880 Western blot, and AMPA internalization assay

    PMID:29917056

    Open questions at the time
    • Signaling chain from receptor to GluA2 phosphorylation not fully traced
    • Behavioral correlate of cortical LTD not established here
  14. 2020 Medium

    Demonstrating PI3K-PDK1-AKT-mTOR-dependent cardiac hypertrophy linked the receptor to a peripheral growth-signaling cascade through gain- and loss-of-function.

    Evidence shRNA knockdown and adenoviral overexpression in neonatal rat cardiomyocytes with ISO hypertrophy, phospho-AKT/mTOR Western blot, and pathway inhibitors

    PMID:32519137

    Open questions at the time
    • Proximal coupling of receptor to PI3K not defined
    • In vivo cardiac relevance from intact-animal genetics not shown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How agonist-specific conformations are decoded into distinct effector branches (PLC vs PLA2 vs Gi/o vs PDZ-scaffolded outputs) and how this signaling diversity maps onto the receptor's many physiological roles remains the central open question.
  • No structural basis for biased signaling in the timeline
  • Receptor phosphosite code linking PKC/RSK to trafficking unmapped
  • Integration of cortical and peripheral functions under one mechanism unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-112316 Neuronal System 2 R-HSA-168256 Immune System 1
Partners
CIPPDLG4DRD2GRM2HTR1A

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1990 HTR2A (HTR2) encodes a G-protein-coupled receptor expressed primarily in the cerebral cortex that upon stimulation activates hydrolysis of inositol phospholipids, and the gene was chromosomally mapped to human chromosome 13 (near ESD and RB1) and mouse chromosome 14. Somatic cell hybrid analysis, linkage studies with RFLP Somatic cell and molecular genetics High 1980030
1995 Agonist-induced desensitization of 5-HT2A receptor-mediated phosphoinositide hydrolysis can occur without down-regulation of receptor number or surface expression; the intermediate phase (2–6 h) of desensitization is mediated by PKC alpha and/or epsilon isoforms, whereas the late phase (24 h) is independent of these PKC isoforms. A binding-incompetent mutant (F340L) showed that ligand binding is required for desensitization. Stable cell-line expressing cloned 5-HT2A receptor; radioligand binding, inositol phosphate assay, immunohistochemistry, Western blot with isoform-selective antibodies, phorbol ester-mediated PKC down-regulation, site-directed mutagenesis The Journal of pharmacology and experimental therapeutics High 8531139
1998 5-HT2A and 5-HT2C receptors couple to both phospholipase C (PLC-mediated IP accumulation) and phospholipase A2 (PLA2-mediated arachidonic acid release), and agonists show differential (biased) relative efficacies for these two pathways at the 5-HT2A receptor — all agonists tested had greater relative efficacy for PLA2-AA than for PLC-IP, supporting agonist-directed trafficking of receptor stimulus. Second-messenger assays (inositol phosphate accumulation and arachidonic acid release) in cell lines expressing cloned receptors Annals of the New York Academy of Sciences Medium 9928246
1998 5-HT2A receptor activation in arterial smooth muscle activates the MAPK/ERK pathway (MEK and ERK1/2 phosphorylation) in a receptor- and tyrosine kinase-dependent manner, partially independent of L-type calcium channel activation and PLC signaling. Isolated rat arteries (contractile assay with tyrosine kinase and MEK inhibitors); Western blot for phospho-MEK and phospho-ERK in cultured aortic smooth muscle cells Annals of the New York Academy of Sciences Medium 9928253
1998 5-HT2A receptor activation by 5-HT agonists (but not 5-HT3 agonists) induces peripheral thermal hyperalgesia in rats; 5-HT2 receptor mRNA was detected in dorsal root ganglia neurons, indicating peripheral expression mediating nociception. Intradermal injection of receptor-subtype-selective agonists/antagonists in rats with paw-withdrawal latency assay; in situ hybridization for 5-HT2 receptor mRNA in DRG Pain Medium 9718253
1998 5-HT2A receptor-stimulated phosphoinositide hydrolysis does not fully account for the discriminative (hallucinogenic) stimulus effects of psychedelics; non-hallucinogenic compounds (lisuride, quipazine, 6-F-DET) also activated PLC via 5-HT2A, and the rank order of PI hydrolysis efficacy did not correlate with hallucinogen drug-discrimination substitution. PC12 cells stably expressing rat 5-HT2A receptor; [3H]inositol phosphate accumulation assay; comparison with published drug-discrimination data Pharmacology, biochemistry, and behavior Medium 11900766
2002 5-HT2A receptor activation increases de novo BDNF mRNA synthesis in C6 glioma cells via a calcium-dependent and protein-kinase-dependent pathway; the effect is blocked by ketanserin (5-HT2A antagonist), actinomycin D (transcription inhibitor), EGTA (calcium chelator), staurosporine (PKC/PKA inhibitor), thapsigargin (Ca2+ ATPase inhibitor), and KN-62 (CaM kinase inhibitor), but not by cycloheximide. RT-PCR and Northern blot of BDNF mRNA in C6 glioma cells; pharmacological dissection with receptor antagonists, kinase inhibitors, and ion channel modulators Neuromolecular medicine Medium 12095161
2004 5-HT2A and 5-HT2C receptor C-termini each contain a class I PDZ ligand (SXV motif) and interact with distinct sets of PDZ proteins in vitro: 5-HT2A robustly binds CIPP but not Veli-3/CASK/Mint1 complex or SAP102, whereas 5-HT2C binds those complexes; residues at the -1 position and upstream of the PDZ ligand are major determinants of PDZ selectivity. These interactions also occur in living cells in intracellular compartments. Affinity chromatography using immobilized synthetic peptides + mass spectrometry; immunofluorescence; electron microscopy The Journal of biological chemistry High 14988405
2004 Activation of 5-HT2A receptors in the hypothalamic paraventricular nucleus (PVN) induces heterologous desensitization of co-localized 5-HT1A receptors in oxytocin and CRF neurons, reducing oxytocin and ACTH responses to a 5-HT1A agonist; 5-HT2A and 5-HT1A receptors co-localize within individual neuroendocrine cells in the PVN. In vivo pharmacology (microinjection of MDL100907 into PVN); neuroendocrine readout (oxytocin and ACTH plasma levels); double-label immunocytochemistry The Journal of pharmacology and experimental therapeutics Medium 15064330
2004 The naturally occurring His452Tyr SNP in the 5-HT2A receptor C-terminus reduces agonist-stimulated signaling through both Gq (phospholipase C) and G13 (phospholipase D) pathways, impairs agonist-induced high-affinity binding and GTPγS turnover, and alters receptor desensitization kinetics. Stable NIH3T3 cells expressing wild-type or 452Tyr variant; inositol phosphate and phospholipase D assays; [35S]GTPγS binding; agonist competition binding Molecular pharmacology High 15496511
2008 5-HT2A receptor trafficking, targeting, and signaling are regulated by scaffolding proteins (PSD-95, arrestin, caveolin) and by p90 ribosomal S6 kinase (RSK), which phosphorylates the receptor and attenuates its signaling. Co-immunoprecipitation, receptor trafficking assays, kinase interaction studies (as reviewed from primary experimental work) Neuropharmacology Medium 18640136
2010 5-HT2A and 5-HT2C receptors show constitutive activity in vitro; inverse agonists decrease basal signaling below baseline, and protean ligands can act as agonists for one response while acting as inverse agonists for another pathway coupled to the same receptor, demonstrating response-dependent constitutive activity. Evidence also suggests this constitutive activity is physiologically relevant in vivo. Cell-based second-messenger assays (inositol phosphate, arachidonic acid); in vivo behavioral pharmacology Trends in pharmacological sciences Medium 16269190
2011 5-HT2A receptor and dopamine D2 receptor form a physical heterocomplex (co-immunoprecipitation in HEK293 cells); D2R activation increases hallucinogenic agonist affinity for 5-HT2AR and decreases 5-HT2AR-induced inositol phosphate production; in vivo, 5-HT2AR expression is necessary for the full locomotor effects of D2R antagonist. Radioligand binding assays; inositol phosphate second-messenger assay; co-immunoprecipitation in HEK293 cells; in vivo locomotor activity in 5-HT2AR knockout mice Neuropharmacology Medium 21645528
2012 5-HT2A receptor endocytosis and recycling are functionally selective: serotonin (5-HT), dopamine (DA), DOI, and clozapine each trigger receptor endocytosis, but ketanserin does not. PKC-mediated receptor phosphorylation is required for 5-HT- and DOI-induced but not DA- or clozapine-induced internalization. Recycling back to the cell surface requires protein phosphatase 2A (PP2A)-mediated dephosphorylation for those ligands that required PKC for endocytosis. Cell-based receptor trafficking assays; PKC inhibition; phosphorylation assays; PP2A inhibition; quantitative receptor internalization/recycling measurements Molecular pharmacology High 23034456
2012 5-HT2A receptor forms heterocomplexes with mGlu2 receptor (confirmed by quantitative SNAP/CLIP-tag HTRF), but co-expression of both receptors in HEK-293 cells does not alter signaling mediated by either receptor individually (no change in Gq, Gi, or cAMP pathways), indicating that physical heterocomplex formation does not necessarily translate into functional second-messenger crosstalk. Quantitative SNAP/CLIP-tag HTRF assay for heterocomplex formation; Gq/Gi/cAMP second-messenger assays in HEK-293 cells; radioligand competition binding in prefrontal cortex membranes Neuropharmacology Medium 22300836
2013 Systemic activation of 5-HT2A receptors with (R)-DOI produces potent blockade of TNF-α-induced expression of pro-inflammatory adhesion molecules (ICAM-1, VCAM-1), cytokines (IL-6, IL-1β), and chemokines (MCP-1, CX3CL1) in the aorta and intestine in vivo, and reduces circulating IL-6; this anti-inflammatory effect is abolished by selective 5-HT2A receptor antagonists. Systemic drug administration in rats; gene expression analysis (qPCR) and protein immunostaining in tissues; receptor-selective antagonist rescue experiments PloS one High 24098382
2013 5-HT2A receptor antagonists (ketanserin, sarpogrelate) inhibit hepatic stellate cell (HSC) activation: they reduce viability, inhibit wound healing, induce apoptosis, and suppress α-SMA, procollagen type I, TGF-β, and Smad2/3 expression in LX-2 cells; in vivo, sarpogrelate reduces lobular inflammation and α-SMA, TGF-β, Smad2/3 expression in thioacetamide-induced cirrhosis. In vitro: cell viability, apoptosis, wound-healing, and gene expression assays in LX-2 cells; in vivo: rat cirrhosis model with histology and protein expression Liver international Medium 23362947
2015 5-HT2A receptor activation is necessary for CO2-induced arousal from sleep: selective 5-HT2A antagonists dose-dependently blocked CO2-induced arousal in wild-type mice; 5-HT2A (but not 5-HT2C) receptor agonists restored CO2-induced arousal in mice genetically lacking 5-HT neurons (Lmx1bf/f/p), demonstrating a permissive role downstream of serotonergic neuron activity. In vivo pharmacology with subtype-selective antagonists and agonists; CO2 and hypoxia arousal assays; genetic model (Lmx1bf/f/p mice lacking 5-HT neurons); dose-response analysis Journal of neurophysiology High 25925320
2015 Htr2a cortical expression responds rapidly (within 6 h) to acute environmental stress (sleep deprivation) with a twofold increase in Htr2a mRNA; this induction requires the immediate early gene Egr3, as it is absent in Egr3-/- mice. Sleep deprivation stress in wild-type and Egr3-/- mice; quantitative RT-PCR of cortical Htr2a mRNA ACS chemical neuroscience Medium 25857407
2018 Chronic THC exposure during adolescence induces pro-hallucinogenic signaling of the 5-HT2A receptor: supersensitive coupling toward inhibitory Gαi1, Gαi3, Gαo, and Gαz proteins without changes in canonical Gαq/11 pathway; this shift in signaling bias is blocked by the Akt/mTOR inhibitor rapamycin, which also prevents THC-induced prepulse inhibition disruption. Chronic THC administration in mice; G-protein coupling assays ([35S]GTPγS); behavioral PPI assay; rapamycin co-treatment; protein expression analysis Neuropsychopharmacology High 29748632
2019 Sustained 5-HT2A receptor activation (20 min exposure to serotonin or DOI) in layer V pyramidal neurons of the mouse prefrontal cortex produces long-lasting depression (LTD) of AMPA receptor-mediated excitatory postsynaptic currents; this LTD is absent in 5-HT2AR knockout mice, rescued by viral 5-HT2AR re-expression in pyramidal neurons, occludes electrically induced LTD, and involves phosphorylation of GluA2 at Ser880 and AMPA receptor internalization. Whole-cell patch-clamp electrophysiology in PFC slices; 5-HT2AR knockout mice; viral rescue; GluA2 phosphorylation (Western blot); AMPA receptor internalization assay Cerebral cortex High 29917056
2020 HTR2A promotes cardiac hypertrophy by activating the PI3K-PDK1-AKT-mTOR signaling cascade; HTR2A knockdown suppressed ISO-induced cardiomyocyte hypertrophy (reduced cell size, β-Mhc, Anp, Bnp expression), while overexpression promoted it; inhibition of PI3K, PDK1, or AKT-mTOR blocked HTR2A-driven hypertrophy. shRNA knockdown and adenoviral overexpression in neonatal rat cardiomyocytes; ISO-induced hypertrophy model; phospho-AKT/mTOR Western blot; pharmacological inhibitors (perifosine, rapamycin, PI3K inhibitor, PDK1 inhibitor) Cell stress & chaperones Medium 32519137
1999 In adult rat skeletal muscle, the 5-HT2A receptor localizes exclusively to plasma membranes (not transverse tubules), as determined by subcellular fractionation and immunoblot; this localization is the same in red and white muscle, indicating expression is independent of metabolic or contractile fiber type. The absence from TT makes 5-HT2AR an unlikely participant in excitation-contraction coupling. Subcellular fractionation of adult rat skeletal muscle; immunoblot of membrane fractions Biochemical and biophysical research communications Medium 10198219
2009 Glucocorticoid receptor (GR) activation increases 5-HT2A receptor levels: GR under-expressing mice show decreased hippocampal 5-HT2A protein and frontal cortex binding; GR over-expressing mice show increased 5-HT2A levels; corticosterone treatment of organotypic hippocampal cultures increases 5-HT2A receptor levels, and this is blocked by either the GR antagonist mifepristone or the mineralocorticoid receptor antagonist spironolactone. Western blot and radioligand binding ([3H]-MDL100907) in transgenic GR mice; organotypic hippocampal cultures with corticosterone and receptor antagonists Experimental neurology Medium 19379741
2010 Layer V pyramidal cells of anterior cortex constitute the largest 5-HT2A-receptor-expressing neuronal population in the cerebral cortex; parvalbumin-expressing fast-spiking GABAergic interneurons in middle layers also express 5-HT2A receptors and are depolarized and excited by serotonin through 5-HT2A receptor activation. BAC transgenic EGFP reporter mice; 5-HT2A knockout mice for antibody validation; immunohistochemistry; whole-cell electrophysiology Frontiers in neuroscience High 20802802
2013 5-HT2A receptor activation (DOI) decreases the firing rate of dorsal raphe 5-HT neurons in wild-type but not 5-HT2AR-/- mice; this inhibitory effect is mediated specifically through 5-HT2AR (not 5-HT2CR) and requires intact noradrenergic neurons (abolished by DSP4 noradrenergic neurotoxin); 5-HT2AR blockade (MDL100907) combined with escitalopram increases cortical norepinephrine outflow and produces antidepressant-like behavior. In vivo electrophysiology (dorsal raphe firing); microdialysis (cortical 5-HT and NE); 5-HT2AR knockout and 5-HT2CR knockout mice; DSP4 noradrenergic lesion; forced swim test Experimental brain research High 23411676

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 The therapeutic role of 5-HT1A and 5-HT2A receptors in depression. Journal of psychiatry & neuroscience : JPN 367 15309042
2023 Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A Genotypes and Serotonin Reuptake Inhibitor Antidepressants. Clinical pharmacology and therapeutics 322 37032427
2015 The role of serotonin 5-HT2A receptors in memory and cognition. Frontiers in pharmacology 272 26500553
2002 Synergistic action of 5-HT2A antagonists and selective serotonin reuptake inhibitors in neuropsychiatric disorders. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 210 12589395
1995 The role of 5-HT2A receptors in antipsychotic activity. Life sciences 191 7791509
1998 Meta-analysis of studies on genetic variation in 5-HT2A receptors and clozapine response. Schizophrenia research 187 9713904
2003 5-HT2A and 5-HT2C receptors and their atypical regulation properties. Life sciences 176 12650852
2013 Serotonin 5-HT2A receptor activation blocks TNF-α mediated inflammation in vivo. PloS one 166 24098382
2010 Htr2a Gene and 5-HT(2A) Receptor Expression in the Cerebral Cortex Studied Using Genetically Modified Mice. Frontiers in neuroscience 161 20802802
2004 Functions of 5-HT2A receptor and its antagonists in the cardiovascular system. Pharmacology & therapeutics 155 15500909
2002 Reduced 5-HT2A receptor binding after recovery from anorexia nervosa. Biological psychiatry 145 12399143
2003 Prefrontal 5-HT2a receptor binding index, hopelessness and personality characteristics in attempted suicide. Journal of affective disorders 131 12706516
2007 HTR2A gene variants and psychiatric disorders: a review of current literature and selection of SNPs for future studies. Current medicinal chemistry 123 17691947
2004 The serotonin 5-HT2A and 5-HT2C receptors interact with specific sets of PDZ proteins. The Journal of biological chemistry 120 14988405
2014 Synthesis and structure-activity relationships of N-benzyl phenethylamines as 5-HT2A/2C agonists. ACS chemical neuroscience 100 24397362
2015 Central serotonin-2A (5-HT2A) receptor dysfunction in depression and epilepsy: the missing link? Frontiers in pharmacology 97 25852551
2008 Current status of inverse agonism at serotonin2A (5-HT2A) and 5-HT2C receptors. Pharmacology & therapeutics 94 19109993
1998 Serotonin 5-HT2A receptors: molecular biology and mechanisms of regulation. Critical reviews in neurobiology 90 10348614
2005 Physiological relevance of constitutive activity of 5-HT2A and 5-HT2C receptors. Trends in pharmacological sciences 88 16269190
2000 Pontomedullary distribution of 5-HT2A receptor-like protein in the rat. The Journal of comparative neurology 88 10701830
2011 Functional crosstalk and heteromerization of serotonin 5-HT2A and dopamine D2 receptors. Neuropharmacology 87 21645528
1998 5-HT2A receptor subtype is involved in the thermal hyperalgesic mechanism of serotonin in the periphery. Pain 86 9718253
2012 Heterocomplex formation of 5-HT2A-mGlu2 and its relevance for cellular signaling cascades. Neuropharmacology 83 22300836
1999 5-HT2A receptor gene polymorphisms in anorexia nervosa and bulimia nervosa. Neuroscience letters 82 10624828
2003 Decreased 5-HT2a receptor binding in patients with anorexia nervosa. Journal of nuclear medicine : official publication, Society of Nuclear Medicine 81 12571204
2007 5-HT2A receptor density is decreased in the at-risk mental state. Psychopharmacology 77 17899021
1995 5-Hydroxytryptamine2A (5-HT2A) receptor desensitization can occur without down-regulation. The Journal of pharmacology and experimental therapeutics 77 8531139
2005 HTR2A: association and expression studies in neuropsychiatric genetics. Annals of medicine 76 16026119
2005 Higher postmortem prefrontal 5-HT2A receptor binding correlates with lifetime aggression in suicide. Biological psychiatry 76 16140277
2016 The 5-HT2A serotonin receptor in executive function: Implications for neuropsychiatric and neurodegenerative diseases. Neuroscience and biobehavioral reviews 75 26891819
1990 The serotonin receptor subtype 2 locus HTR2 is on human chromosome 13 near genes for esterase D and retinoblastoma-1 and on mouse chromosome 14. Somatic cell and molecular genetics 73 1980030
2004 Desensitization of 5-HT1A receptors by 5-HT2A receptors in neuroendocrine neurons in vivo. The Journal of pharmacology and experimental therapeutics 69 15064330
2003 Increased coronary events in depressed cardiovascular patients: 5-HT2A receptor as missing link? Psychosomatic medicine 69 14508013
1996 Regulation of central 5-HT2A receptors: a review of in vivo studies. Behavioural brain research 69 8788498
1996 Genomic imprinting of the human serotonin-receptor (HTR2) gene involved in development of retinoblastoma. American journal of human genetics 65 8900237
2002 Modulation by 5-hT2A receptors of aggressive behavior in isolated mice. Japanese journal of pharmacology 64 12083749
2015 5-HT2A receptor activation is necessary for CO2-induced arousal. Journal of neurophysiology 59 25925320
2016 Role for serotonin2A (5-HT2A) and 2C (5-HT2C) receptors in experimental absence seizures. Neuropharmacology 57 27085605
1998 Pleiotropic behavior of 5-HT2A and 5-HT2C receptor agonists. Annals of the New York Academy of Sciences 56 9928246
2014 Influence of 5-HTR2A genetic polymorphisms on the efficacy of antidepressants in the treatment of major depressive disorder: a meta-analysis. Journal of affective disorders 55 25108775
2004 His452Tyr polymorphism in the human 5-HT2A receptor destabilizes the signaling conformation. Molecular pharmacology 55 15496511
2002 5-HT2A receptor gene promoter polymorphism in relation to abdominal obesity and cortisol. Obesity research 55 12105278
2018 Chronic cannabis promotes pro-hallucinogenic signaling of 5-HT2A receptors through Akt/mTOR pathway. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 54 29748632
2006 Involvement of a polymorphism in the 5-HT2A receptor gene in impulsive behavior. Psychopharmacology 53 16767413
2005 Expression of the 5-HT2A serotoninergic receptor in human placenta and choriocarcinoma cells: mitogenic implications of serotonin. Placenta 53 15950062
2006 Cerebral 5-HT2A receptor binding is increased in patients with Tourette's syndrome. The international journal of neuropsychopharmacology 51 16945163
2010 Functional genomics of serotonin receptor 2A (HTR2A): interaction of polymorphism, methylation, expression and disease association. Neuromolecular medicine 50 20941551
2001 5-HT2A receptor gene promoter polymorphism -1438A/G and bipolar disorder. Psychiatric genetics 50 11702051
1998 Activation of the mitogen-activated protein kinase pathway via the 5-HT2A receptor. Annals of the New York Academy of Sciences 50 9928253
2008 Insights into the regulation of 5-HT2A serotonin receptors by scaffolding proteins and kinases. Neuropharmacology 49 18640136
2002 5-HT2A receptor-stimulated phosphoinositide hydrolysis in the stimulus effects of hallucinogens. Pharmacology, biochemistry, and behavior 49 11900766
2019 Sustained Activation of Postsynaptic 5-HT2A Receptors Gates Plasticity at Prefrontal Cortex Synapses. Cerebral cortex (New York, N.Y. : 1991) 48 29917056
2013 Functional anatomy of 5-HT2A receptors in the amygdala and hippocampal complex: relevance to memory functions. Experimental brain research 48 23591691
2005 Binding characteristics of the 5-HT2A receptor antagonists altanserin and MDL 100907. Synapse (New York, N.Y.) 48 16206185
1998 5-HT2A receptor antagonists block MK-801-induced stereotypy and hyperlocomotion. European journal of pharmacology 48 9808259
2013 Association of the HTR2A gene with alcohol and heroin abuse. Human genetics 47 24178752
2004 5-HT2A T102C receptor polymorphism and neuropsychiatric symptoms in Alzheimer's disease. International journal of geriatric psychiatry 47 15211529
2003 Serotoninergic polymorphisms (5-HTTLPR and 5-HT2A): association studies with psychosis in Alzheimer disease. Genetic testing 45 15000807
2013 5-HT2A receptor antagonists inhibit hepatic stellate cell activation and facilitate apoptosis. Liver international : official journal of the International Association for the Study of the Liver 44 23362947
2009 Involvement of pro-nociceptive 5-HT2A receptor in the pathogenesis of medication-overuse headache. Headache 42 20039957
2012 Functional selectivity in serotonin receptor 2A (5-HT2A) endocytosis, recycling, and phosphorylation. Molecular pharmacology 41 23034456
2010 Radiosynthesis and evaluation of 11C-CIMBI-5 as a 5-HT2A receptor agonist radioligand for PET. Journal of nuclear medicine : official publication, Society of Nuclear Medicine 40 20956470
2010 5-HT2A receptor levels increase in MPTP-lesioned macaques treated chronically with L-DOPA. Neurobiology of aging 39 20561716
2010 Role of 5-HT2A receptor antagonists in the treatment of insomnia. Nature and science of sleep 39 23616706
2014 The antidepressant 5-HT2A receptor antagonists pizotifen and cyproheptadine inhibit serotonin-enhanced platelet function. PloS one 38 24466319
2013 Role of the 5-HT₂A receptor in the locomotor hyperactivity produced by phenylalkylamine hallucinogens in mice. Neuropharmacology 38 23376711
2002 5-HT2A receptor activation leads to increased BDNF mRNA expression in C6 glioma cells. Neuromolecular medicine 37 12095161
1999 Activated astrocytes display increased 5-HT2a receptor expression in pathological states. Experimental neurology 37 10415157
1996 Intact 5-HT2A receptor exons and the adjoining intron regions in schizophrenia. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 37 8703302
2014 The developmental basis of epigenetic regulation of HTR2A and psychiatric outcomes. Journal of cellular biochemistry 36 25043477
2017 Stress exposure and psychopathology alter methylation of the serotonin receptor 2A (HTR2A) gene in preschoolers. Development and psychopathology 34 29162169
2016 Effect of 5-HT2A and 5-HT2C receptors on temporal discrimination by mice. Neuropharmacology 34 27020041
2011 Neuronal localization of 5-HT2A receptor immunoreactivity in the rat hippocampal region. Brain research bulletin 34 22119732
2014 Association of HTR2A T102C and A-1438G polymorphisms with susceptibility to major depressive disorder: a meta-analysis. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 33 25270656
2011 Pharmacological and behavioral characterization of the 5-HT2A receptor in C57BL/6N mice. Psychopharmacology 32 21340474
2010 Plaque deposition dependent decrease in 5-HT2A serotonin receptor in AbetaPPswe/PS1dE9 amyloid overexpressing mice. Journal of Alzheimer's disease : JAD 32 20413853
2007 Association between 5-HT2A, TPH1 and GNB3 genotypes and response to typical neuroleptics: a serotonergic approach. BMC psychiatry 32 17521439
2013 5-HT₂A receptor inactivation potentiates the acute antidepressant-like activity of escitalopram: involvement of the noradrenergic system. Experimental brain research 31 23411676
2006 ACP-103, a 5-HT2A receptor inverse agonist. Current opinion in investigational drugs (London, England : 2000) 30 16869120
2003 Behavioral evidence for mu-opioid and 5-HT2A receptor interactions. European journal of pharmacology 30 12909198
2016 Genomic structure and expression of the human serotonin 2A receptor gene (HTR2A) locus: identification of novel HTR2A and antisense (HTR2A-AS1) exons. BMC genetics 29 26738766
2016 5-HT2A and 5-HT2C receptors as hypothalamic targets of developmental programming in male rats. Disease models & mechanisms 28 26769798
2007 5-HT2A SNPs and the Temperament and Character Inventory. Progress in neuro-psychopharmacology & biological psychiatry 28 17590256
2006 Effects of 5-HT2A receptor stimulation on the discrimination of durations by rats. Behavioural pharmacology 28 16377963
2002 5-HT2A antagonists in psychiatric disorders. Current opinion in investigational drugs (London, England : 2000) 28 12054060
2010 Interactive effects of mGlu5 and 5-HT2A receptors on locomotor activity in mice. Psychopharmacology 27 21153406
2014 Long-lasting alterations in 5-HT2A receptor after a binge regimen of methamphetamine in mice. The international journal of neuropsychopharmacology 26 24763081
1993 Lithium enhances 5-HT2A receptor-mediated c-fos expression in rat cerebral cortex. Neuroreport 26 8298081
2020 HTR2A promotes the development of cardiac hypertrophy by activating PI3K-PDK1-AKT-mTOR signaling. Cell stress & chaperones 25 32519137
2009 Activation of glucocorticoid receptors increases 5-HT2A receptor levels. Experimental neurology 25 19379741
2009 Emotional management and 5-HT2A receptor gene variance in patients with schizophrenia. Biological psychology 25 19913072
1999 Biochemical localisation of the 5-HT2A (serotonin) receptor in rat skeletal muscle. Biochemical and biophysical research communications 25 10198219
2016 5-HT2A and mGlu2/3 receptor interactions: on their relevance to cognitive function and psychosis. Behavioural pharmacology 24 26292187
2015 Sarpogrelate, a 5-HT2A Receptor Antagonist, Protects the Retina From Light-Induced Retinopathy. Investigative ophthalmology & visual science 24 26200496
2021 A Complex Impact of Systemically Administered 5-HT2A Receptor Ligands on Conditioned Fear. The international journal of neuropsychopharmacology 23 34228806
2020 The serotonin receptor 2A (HTR2A) rs6313 variant is associated with higher ongoing pain and signs of central sensitization in neuropathic pain patients. European journal of pain (London, England) 23 33171011
2015 Htr2a Expression Responds Rapidly to Environmental Stimuli in an Egr3-Dependent Manner. ACS chemical neuroscience 23 25857407
2011 Variations in 5-HT2A influence spatial cognitive abilities and working memory. The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques 23 21320838
2007 The 5-HT2A receptor binding pattern in the human brain is strongly genetically determined. NeuroImage 23 18291676
2010 Association analysis of GRM2 and HTR2A with methamphetamine-induced psychosis and schizophrenia in the Japanese population. Progress in neuro-psychopharmacology & biological psychiatry 22 20211215

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