Affinage

HTR2C

5-hydroxytryptamine receptor 2C · UniProt P28335

Length
458 aa
Mass
51.8 kDa
Annotated
2026-06-10
100 papers in source corpus 33 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/8 claims corpus-supported (88%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HTR2C encodes the serotonin 5-HT2C receptor, a constitutively active class A GPCR that governs serotonergic control of appetite, neuronal network excitability, sleep, and cognitive flexibility, as established genetically by knockout mice that become obese and die from spontaneous seizures (PMID:7700379, PMID:12431861). The receptor couples through multiple signaling routes: it activates phospholipase C-driven inositol phosphate production (PMID:10501219), engages a G13/RhoA-dependent phospholipase D pathway (PMID:14722258), and drives ERK1/2 phosphorylation via PLD, PKC, and the Raf/MEK module (PMID:15935077), with agonists showing biased efficacy across these PLC, PLA2, and ERK outputs (agonist-directed trafficking) (PMID:10432492, PMID:9928246). Receptor activity is intrinsically constitutive, demonstrated by activating mutations at serine 312 that confer agonist-independent G-protein coupling and reveal inverse agonism by ligands such as mianserin (PMID:9282936). A defining regulatory feature is A-to-I RNA editing at up to five sites in the second intracellular loop, mediated by ADAR enzymes acting on an exon-intron RNA duplex; editing reduces basal activity, agonist affinity, and coupling efficiency (non-edited INI vs. fully edited VGV isoforms) and selects which downstream pathways the receptor engages, and the same stem-loop links editing to alternative splice-site choice (PMID:9928237, PMID:10501219, PMID:10432493, PMID:15087490, PMID:14722258). This editing is constrained in vivo by the imprinted snoRNA mbii-52 and is modulated by interferon-alpha via ADAR1 (PMID:19304781, PMID:15093687). The receptor's C-terminal PDZ ligand recruits scaffolding proteins including PSD-95, SAP102, MPP-3, and the Veli-3·CASK·Mint1 complex (PMID:14988405), and it forms constitutive homodimers and functional heteromers with the melatonin MT2 receptor that amplify Gq/PLC signaling and permit transactivation (PMID:15518545, PMID:25770211). In hypothalamic POMC neurons it inhibits the KCNQ-mediated M-current to raise excitability and produces hypophagia that requires downstream melanocortin MC4 receptors (PMID:22436698, PMID:18039773). Circuit-level studies place 5-HT2C in the substantia nigra pars reticulata, where activation inhibits SNc dopaminergic neurons and underlies SSRI-induced motor deficits (PMID:30120415), and in spinal motoneurons, where injury renders the receptor constitutively active to drive persistent calcium currents and muscle spasms reversible by inverse agonists (PMID:20980537).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1995 High

    Establishing the physiological role of 5-HT2C addressed whether this receptor controls organismal feeding and network excitability rather than acting as a redundant serotonin receptor.

    Evidence Targeted knockout mice scored for body weight, food intake, and seizure susceptibility

    PMID:7700379

    Open questions at the time
    • Does not identify the cell types or circuits mediating appetite vs. seizure phenotypes
    • Mechanism linking receptor loss to network hyperexcitability unresolved at the molecular level
  2. 1995 Medium

    Early functional and structural characterization defined the receptor's signaling outputs beyond simple phosphoinositide turnover and its gene architecture.

    Evidence Choroid plexus tissue assays for cGMP/PI turnover, 3T3 cell APPs secretion with PKC/PLA2 inhibitors, and genomic cloning of the six-exon gene with an alternatively spliced isoform

    PMID:7798914 PMID:8626761 PMID:8812491

    Open questions at the time
    • The physiological relevance of cGMP and APPs outputs in neurons was not established
    • Functional consequence of the truncated splice isoform not determined
  3. 1997 High

    Demonstrating that point mutations at serine 312 produce agonist-independent coupling answered whether 5-HT2C possesses intrinsic constitutive activity and whether ligands can act as inverse agonists.

    Evidence Site-directed mutagenesis (S312F/S312K) in COS-7 cells with radioligand binding and PI hydrolysis assays

    PMID:9282936

    Open questions at the time
    • Whether wild-type receptor shows comparable constitutive activity in native tissue was not addressed here
    • Structural basis of the conformational switch not resolved
  4. 1998 High

    Discovery of A-to-I RNA editing in the second intracellular loop answered how a single gene generates functionally distinct receptor isoforms.

    Evidence In vitro ADAR editing assays with RNA duplex structural analysis and PLC coupling assays of edited isoforms

    PMID:9928237

    Open questions at the time
    • Tissue- and disease-specific editing patterns not yet quantified
    • Relative contribution of individual ADAR family members not separated
  5. 1998 Medium

    Documenting differential agonist efficacy across PLC versus PLA2 readouts established that a single receptor activates distinct signaling subsets (agonist-directed trafficking).

    Evidence Cell-based IP accumulation and arachidonic acid release assays with multiple agonists

    PMID:9928246

    Open questions at the time
    • Molecular basis of biased coupling (distinct receptor conformations vs. G-protein availability) not resolved
  6. 1999 High

    Quantitative isoform comparison established that editing tunes receptor pharmacology, reducing basal activity, agonist affinity, and coupling in proportion to agonist efficacy.

    Evidence COS-7 expression of INI vs. VGV and multi-site human isoforms with IP and radioligand binding assays, including LSD versus 5-HT trafficking

    PMID:10432492 PMID:10432493 PMID:10501219

    Open questions at the time
    • In vivo editing ratios across brain regions and their behavioral impact not yet linked
    • Energetic model of ternary-complex alteration inferred rather than structurally demonstrated
  7. 1999 Medium

    Chronic inverse agonist studies probed how constitutive activity adapts, showing pathway-selective sensitization of IP but not arachidonic acid signaling.

    Evidence CHO cells stably expressing human 5-HT2C with IP and AA release assays under chronic ligand treatment

    PMID:10220565

    Open questions at the time
    • Direct evidence for Galpha subunit expression changes was inferential
    • Relevance to chronic drug treatment in vivo not tested
  8. 2002 High

    Sleep phenotyping of knockout mice extended the receptor's physiological role to sleep expression and homeostasis.

    Evidence Polysomnographic recording in 5-HT2C null mice with sleep deprivation challenge

    PMID:12431861

    Open questions at the time
    • Circuit and signaling mechanisms underlying altered wakefulness not identified
  9. 2003 High

    Identification of a selective positive allosteric modulator answered whether 5-HT2C affinity and constitutive activity could be pharmacologically enhanced from an allosteric site.

    Evidence Radioligand binding, GTPgammaS, IP3, and IP assays across a receptor selectivity panel with SAR analysis of PNU-69176E

    PMID:12815163

    Open questions at the time
    • Allosteric binding site location not mapped
    • In vivo efficacy of the PAM not established
  10. 2004 High

    Defining the C-terminal PDZ interactome and homodimerization established how the receptor is scaffolded and organized at the membrane.

    Evidence Affinity chromatography/MS, co-IP, and imaging for PDZ partners; IP/WB, BRET, and FRET for constitutive homodimers

    PMID:14988405 PMID:15518545

    Open questions at the time
    • Functional consequences of each scaffold interaction for signaling/trafficking not dissected
    • Whether dimerization affects coupling efficiency not tested
  11. 2004 High

    Mechanistic studies connected editing to both pathway selection and splicing, showing editing controls G13/RhoA/PLD coupling and intron 5 splice-site choice.

    Evidence Isoform-specific PLD and RhoA assays with G-protein inhibitors; in vitro editing plus base-substitution splicing analysis with human brain validation; IFN-alpha modulation of ADAR1/editing in glioblastoma cells

    PMID:14722258 PMID:15087490 PMID:15093687

    Open questions at the time
    • In vivo coupling between editing-driven splicing and receptor function not quantified
    • Physiological triggers of IFN-alpha-mediated editing changes in brain unclear
  12. 2005 High

    Pathway dissection of ERK1/2 activation defined a PLD/PKC/Raf-MEK route independent of tyrosine kinases, PLC, and endocytosis, reinforcing biased signaling.

    Evidence ERK1/2 phosphorylation assays in CHO cells with a panel of pathway inhibitors and divergent agonists

    PMID:15935077

    Open questions at the time
    • Downstream transcriptional/cellular consequences of ERK activation not addressed
    • Endogenous neuronal validation absent
  13. 2007 High

    Genetic epistasis established the downstream circuit for hypophagia, placing MC4R-expressing melanocortin signaling as a requisite effector of 5-HT2C anorectic action.

    Evidence POMC coexpression studies, chronic agonist infusion in obese mice, and MC4R knockout epistasis; plus promoter haplotype reporter assays linking polymorphisms to weight-gain susceptibility

    PMID:17376412 PMID:18039773

    Open questions at the time
    • Promoter polymorphism findings (Medium) await in vivo validation
    • Exact synaptic relationship between 5-HT2C+ neurons and POMC/MC4R circuit not fully mapped
  14. 2009 High

    Identifying snoRNA mbii-52 as a negative regulator of editing established an in vivo control point linking the Prader-Willi locus to 5-HT2C function.

    Evidence PWS-IC+/- mouse model with quantitative editing analysis and pharmacologically confirmed behavioral readouts

    PMID:19304781

    Open questions at the time
    • Molecular mechanism by which mbii-52 suppresses editing not defined
    • Contribution to the full Prader-Willi phenotype not isolated
  15. 2010 High

    Region-specific pharmacological manipulation localized cognitive-flexibility and spinal motor roles, distinguishing where the receptor exerts behavioral and constitutive-activity effects.

    Evidence Intra-OFC antagonist microinfusion in a reversal-learning task; chronic spinal rat preparation distinguishing agonist, neutral antagonist, and inverse agonist effects on Ca PICs and reflexes

    PMID:20089901 PMID:20980537

    Open questions at the time
    • Cellular signaling underlying OFC behavioral effect not defined
    • How spinal injury triggers acquired constitutive activity is unknown
  16. 2012 High

    Direct electrophysiology in identified POMC neurons established M-current (KCNQ) inhibition as the ionic mechanism by which 5-HT2C raises excitability to suppress feeding.

    Evidence Visualized patch-clamp in eGFP-POMC neurons with selective agonists/antagonists and KCNQ blockade

    PMID:22436698

    Open questions at the time
    • Signaling intermediates linking receptor to KCNQ channel closure not delineated
  17. 2015 High

    Demonstration of MT2/5-HT2C heteromers in human brain established a cross-receptor signaling module relevant to antidepressant action.

    Evidence Co-IP, BRET, and pharmacology in transfected cells and human cortex/hippocampus, including agomelatine bias

    PMID:25770211

    Open questions at the time
    • Physiological and behavioral significance of the heteromer in vivo not established
    • Stoichiometry and structural arrangement unknown
  18. 2018 High

    Circuit dissection placed SNr 5-HT2C upstream of SNc dopaminergic inhibition, explaining SSRI-induced motor deficits.

    Evidence SSRI treatment with site-specific SNr antagonism and optogenetic manipulation of SNc neurons in mice

    PMID:30120415

    Open questions at the time
    • Cell-autonomous signaling of SNr 5-HT2C not resolved
    • Editing/isoform contribution to this circuit not examined
  19. 2019 Medium

    Lateral habenula studies extended the receptor-M-channel relationship to a withdrawal-anxiety circuit.

    Evidence Intra-LHb antagonist/agonist microinfusion with behavioral tests, c-Fos, and KCNQ2/3 Western blot in alcohol-withdrawn rats

    PMID:31778691

    Open questions at the time
    • Single-lab pharmacological study without genetic confirmation
    • Direct electrophysiological link to M-current in LHb not measured
  20. 2022 Medium

    Human iPSC modeling connected reduced 5-HT2C expression to GABAergic interneuron dysfunction in suicidal depression, with rescue establishing causality.

    Evidence iPSC-derived interneurons and organoids from sMDD patients with calcium imaging, electrophysiology, and pharmacological/genetic 5-HT2C restoration

    PMID:36373384

    Open questions at the time
    • Single-lab human model not replicated
    • Mechanism linking receptor loss to altered firing/calcium signaling not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RNA-editing-defined isoforms, biased signaling, dimerization/heteromerization, and scaffolding are integrated within specific neuronal circuits to produce distinct behavioral outputs remains unresolved.
  • No structural model of edited vs. unedited receptor coupling states
  • Causal in vivo role of MT2 heteromers and PDZ scaffolds not established
  • Mechanism of acquired constitutive activity after spinal injury unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4
Localization
GO:0005886 plasma membrane 4 GO:0005634 nucleus 1
Pathway
R-HSA-8953854 Metabolism of RNA 4 R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3
Partners
ADARADAR1APBA1CASKDLG3DLG4MTNR1B
Complex memberships
5-HT2C receptor homodimerMT2/5-HT2C receptor heteromerVeli-3·CASK·Mint1 complex

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 5-HT2C receptor-deficient (knockout) mice are overweight due to abnormal control of feeding behaviour, establishing a role for this receptor in serotonergic control of appetite; mutant animals also exhibit spontaneous death from seizures, implicating 5-HT2C receptors in tonic inhibition of neuronal network excitability. Targeted gene knockout mice with phenotypic readouts (body weight, food intake, seizure susceptibility) Nature High 7700379
1995 A Cys23Ser substitution in the first hydrophobic region of the human 5-HT2C receptor (HTR2C on Xq24) was identified; when expressed in Xenopus oocytes, concentration-response curves to 5-HT were not significantly different between the two forms, indicating no functional difference under baseline conditions. SSCP analysis, linkage analysis, heterologous expression in Xenopus oocytes with electrophysiological recording Genomics Medium 7557992
1995 Activation of 5-HT2C receptors stimulates APP ectodomain (APPs) secretion via a mechanism requiring both PKC and phospholipase A2 (PLA2), as demonstrated in 3T3 cells stably overexpressing 5-HT2cR; this is distinct from 5-HT2A receptor coupling, which requires PLA2 but not PKC. Stable cell line overexpression, pharmacological inhibitors of PKC and PLA2, APPs secretion assay The Journal of biological chemistry Medium 8626761
1995 Activation of 5-HT2C receptor in choroid plexus triggers cyclic GMP (cGMP) formation in a calcium-, phospholipase A2-, and lipoxygenase-dependent manner, in addition to phosphoinositide turnover. Porcine choroid plexus tissue slices, pharmacological antagonists, cGMP assay, pertussis toxin pretreatment, PLA2 and lipoxygenase inhibitors Journal of neurochemistry Medium 7798914
1996 The human 5-HT2C receptor gene (HTR2C) contains six exons and five introns spanning at least 230 kb; an alternatively spliced isoform with a 95-nt deletion in the region coding for the second intracellular loop produces a truncated 248-aa protein. Transcription initiates at multiple sites with no classical TATA box. Genomic cloning, cDNA isolation, sequencing, RT-PCR, luciferase reporter assay Genomics Medium 8812491
1996 Fluoxetine and other SSRIs (norfluoxetine, citalopram) act as antagonists at the 5-HT2C receptor, inhibiting 5-HT-stimulated phosphoinositide hydrolysis without inverse agonist activity, as demonstrated in choroid plexus and clonal cell lines expressing the cloned rat 5-HT2C receptor. Radioligand binding ([3H]mesulergine), phosphoinositide (PI) hydrolysis assay, cloned receptor cell lines and rat choroid plexus Psychopharmacology Medium 8876023
1998 RNA editing of the 5-HT2C receptor at four major adenosine-to-inosine positions (A, B, C, D) in the second intracellular loop alters receptor isoforms' ability to interact with the phospholipase C signaling cascade; editing is mediated by at least two members of the ADAR family and requires an extensive RNA duplex structure formed by exonic and intronic sequences of 5-HT2C pre-mRNA. In vitro transcription, ADAR family enzyme assays, transfected cell line functional assays (phospholipase C coupling), structural analysis of RNA duplex Annals of the New York Academy of Sciences High 9928237
1997 Site-directed mutagenesis of serine 312 to phenylalanine (S312F) or lysine (S312K) in the 5-HT2C receptor creates constitutively active receptors that spontaneously couple to G proteins and stimulate phosphatidylinositol hydrolysis in the absence of agonist; mianserin and mesulergine act as inverse agonists on the S312K mutant receptor. Site-directed mutagenesis, COS-7 cell expression, [3H]mesulergine and [3H]5-HT radioligand binding, PI hydrolysis assay, GppNHp treatment Journal of neurochemistry High 9282936
1999 RNA editing of the 5-HT2C receptor decreases receptor basal (constitutive) activity, agonist affinity, and agonist potency for inositol phosphate production. The non-edited isoform (INI) shows fourfold greater basal IP production than the fully edited isoform (VGV); 5-HT competes for two binding sites on INI but only one site on VGV. COS-7 cell transient expression, inositol phosphate assay, radioligand binding ([3H]mesulergine, [3H]5-HT), dose-response analysis Journal of neurochemistry High 10501219
1999 RNA editing of the human 5-HT2C receptor at five sites (including a novel 5th site) reduces agonist binding affinity and functional potency in proportion to agonist intrinsic activity; full agonists are most affected and antagonists are unaffected, suggesting editing alters coupling energetics within the ternary complex. Analysis of human brain/hypothalamic RNA, cloning of isoforms, radioligand binding and functional assays in recombinant receptor systems Neuropsychopharmacology High 10432493
1999 Prolonged treatment (24 h) with inverse agonists at human 5-HT2C receptors selectively enhances 5-HT2C-mediated inositol phosphate (IP) accumulation but not arachidonic acid (AA) release; this enhanced responsiveness is not due to receptor up-regulation but may involve changes in expression of Gαq/11 and possibly Gα12/Gα13. CHO cells stably expressing human 5-HT2C receptor, IP accumulation assay, AA release assay, pharmacological dissection with neutral antagonists and agonists Molecular pharmacology Medium 10220565
1999 LSD signals differently from serotonin (5-HT) at the 5-HT2C receptor; specifically, RNA editing of the 5-HT2C receptor dramatically alters the ability of LSD to stimulate phosphatidylinositol signaling, demonstrating agonist-directed trafficking at this receptor. Cell-based phosphatidylinositol signaling assay with edited and non-edited receptor isoforms, comparison of LSD vs. 5-HT efficacy Neuropsychopharmacology Medium 10432492
1998 5-HT2C receptors in the hippocampal formation are required for normal long-term potentiation specifically at medial perforant path-dentate gyrus synapses; 5-HT2C receptor null mutant mice show selective LTP impairment at this synapse accompanied by abnormal Morris water maze performance and reduced novelty aversion. 5-HT2C receptor knockout mice, electrophysiological LTP recording at four hippocampal pathways, Morris water maze behavioral testing Proceedings of the National Academy of Sciences of the United States of America High 9844009
2000 5-HT2C receptor protein is expressed on neuronal cell bodies throughout the CNS, including hippocampus, amygdala, thalamus, caudate-putamen, cortex, and dorsal raphé nuclei, consistent with postsynaptic localization to serotonergic neurons and possible autoreceptor function in raphé. Immunohistochemistry with polyclonal antibodies against rat 5-HT2C receptor protein, Western blot, immunofluorescence in transfected HEK293 cells, peptide competition controls Neuropharmacology Medium 10665825
2004 The 5-HT2C receptor C-terminus (PDZ ligand SXV) interacts with a specific set of PDZ proteins distinct from those binding the 5-HT2A receptor: 5-HT2C binds the Veli-3·CASK·Mint1 ternary complex, SAP102, PSD-95, and MPP-3; residues at the -1 position and upstream of the PDZ ligand determine partner specificity. These interactions occur in intracellular compartments in living cells. Affinity chromatography with immobilized synthetic PDZ ligand peptides, mass spectrometry, co-immunoprecipitation, immunofluorescence, electron microscopy The Journal of biological chemistry High 14988405
2004 RNA editing of the human 5-HT2C receptor modulates splice site selection; editing at multiple sites in a stable stem-loop encompassing the normal and alternative 5' splice sites of intron 5 profoundly alters relative splicing at normal versus alternative upstream splice sites, linking A-to-I editing to control of pre-mRNA splicing. In vitro editing, cell culture base-substitution experiments, human brain splice variant analysis Nucleic acids research High 15087490
2004 RNA editing at the non-edited (INI) 5-HT2C receptor isoform activates phospholipase D via the G13 heterotrimer G-protein, requiring transactivation of the small G-protein RhoA; the fully edited VGV isoform does not activate RhoA or phospholipase D, demonstrating that editing regulates signaling pathway selection including pathways linked to actin cytoskeletal organization. Transfected cell lines expressing INI vs. VGV isoforms, phospholipase D activity assay, RhoA activation assay, pharmacological G-protein inhibitors Molecular pharmacology High 14722258
2004 5-HT2C receptors exist as constitutive homodimers on the plasma membrane of living cells, demonstrated by immunoprecipitation/Western blot showing monomer and dimer bands, BRET (Renilla luciferase/YFP), and confocal FRET (CFP/YFP donor-acceptor pairs) on the plasma membrane; BRET levels were not altered by serotonin pretreatment, indicating constitutive (agonist-independent) dimerization. Immunoprecipitation, Western blot, BRET in HEK293 cells, confocal FRET by acceptor photobleaching Biochemistry High 15518545
2004 Interferon-alpha (IFN-α) rapidly alters ADAR1 expression and the pattern of 5-HT2C receptor mRNA editing in human glioblastoma cells, leading to dominant expression of the 5-HT2C-VSI isoform predicted to have reduced G-protein coupling functions. Human glioblastoma cell line treatment with IFN-α, RT-PCR analysis of editing patterns, ADAR1 expression analysis Brain research. Molecular brain research Medium 15093687
2005 5-HT2C receptor couples to ERK1/2 via a pathway requiring phospholipase D, protein kinase C, and the Raf/MEK/ERK module, but independent of receptor and non-receptor tyrosine kinases, PLC, PI3K, and endocytosis; agonist-directed trafficking was observed whereby DOI and quipazine showed reversal of efficacy between PI/Ca2+ pathways and ERK1/2 phosphorylation. CHO cells stably expressing non-edited 5-HT2C receptor, ERK1/2 phosphorylation assay, pharmacological inhibitors of multiple signaling intermediates Journal of neurochemistry High 15935077
2003 PNU-69176E acts as a positive allosteric modulator (PAM) of the human 5-HT2C receptor; at low micromolar concentrations it markedly enhances [3H]5-HT binding (>300%) by increasing agonist affinity without affecting antagonist binding ([3H]mesulergine), and renders receptors constitutively active (GTPγS binding, IP3 release, IP accumulation). This selectivity is for 5-HT2C over 5-HT2A, 5-HT2B, 5-HT6, 5-HT7, D2L, and D3 receptors. Radioligand binding, GTPγS binding, IP3 measurement, IP accumulation assay across multiple cell lines and receptor types; structure-activity relationship of alkyl chain length Molecular pharmacology High 12815163
2007 5-HT2C receptor agonism produces hypophagia downstream via activation of melanocortin 4 receptors (MC4R); 5-HT2CRs are coexpressed with POMC neurons in the arcuate nucleus, and mice lacking MC4R are not responsive to 5-HT2CR agonist-induced hypophagia, establishing that melanocortins acting on MC4R are a requisite downstream pathway. Coexpression studies (5-HT2CR/POMC), chronic BVT.X infusion in obese mice measuring Pomc mRNA and body weight, genetic epistasis using MC4R knockout mice Endocrinology High 18039773
1998 5-HT2C and 5-HT2A receptors exhibit agonist-directed trafficking of receptor stimulus: relative efficacies of agonists differ depending on whether phospholipase C-mediated IP accumulation or PLA2-mediated arachidonic acid release is measured, demonstrating that different agonists selectively activate subsets of multiple signaling pathways coupled to a single receptor. Cell-based assays measuring IP accumulation and arachidonic acid release with multiple agonists; relative efficacy referenced to 5-HT Annals of the New York Academy of Sciences Medium 9928246
2009 Loss of the imprinted snoRNA mbii-52 (h/mbii-52) in a mouse model of Prader-Willi syndrome leads to increased A-to-I editing of the 5-HT2C receptor (5htr2c) pre-RNA, establishing that mbii-52 negatively regulates 5htr2c editing in vivo; increased editing is associated with alterations in 5-HT2CR-related behaviours (impulsive responding, locomotor activity, food reactivity) confirmed by pharmacological challenge. PWS-IC+/- mouse model, quantitative editing analysis, behavioral testing with pharmacological (5-HT2CR drug challenge) confirmation of mechanism Human molecular genetics High 19304781
2010 5-HT2C receptor antagonism within the orbitofrontal cortex (OFC), but not the medial prefrontal cortex or nucleus accumbens, improves spatial reversal learning by reducing perseverative errors, establishing a neuroanatomically specific role for OFC 5-HT2C receptors in cognitive flexibility. Site-specific intracerebral microinfusion of selective 5-HT2C antagonist SB 242084 into OFC, mPFC, or NAc; spatial reversal learning behavioral paradigm The Journal of neuroscience Medium 20089901
2010 After spinal cord injury, 5-HT2B and 5-HT2C receptors on motoneurons become constitutively active and facilitate persistent calcium currents (Ca PICs) and long-lasting reflexes (muscle spasms); inverse agonists blocking constitutive 5-HT2C/2B activity reduce spasms, while neutral antagonists (which do not block constitutive activity) have no effect alone. Chronic spinal rat in vitro preparation, ventral root recording of long-lasting reflexes, intracellular recording of Ca PICs, selective agonists/antagonists/inverse agonists, immunolabeling of 5-HT2B/2C on motoneurons Journal of neurophysiology High 20980537
2012 5-HT2C receptor activation in hypothalamic POMC neurons inhibits the M-current (KCNQ channel-mediated) by 34–42%, increasing neuronal excitability; the selective 5-HT2C antagonist RS-102221 abrogates this effect, establishing 5-HT2C-mediated inhibition of M-current as a mechanism for serotonin-induced POMC activation and reduced food intake. Visualized-patch clamp recording in eGFP-POMC transgenic mouse hypothalamic neurons, selective pharmacological agonists/antagonists (DOI, mCPP, RS-102221), KCNQ blocker XE-991 American journal of physiology. Endocrinology and metabolism High 22436698
2015 Melatonin MT2 and 5-HT2C receptors form functional heteromers both in transfected cells and in human cortex and hippocampus; MT2/5-HT2C heteromers amplify 5-HT-mediated Gq/PLC response and enable melatonin-induced unidirectional transactivation of the 5-HT2C protomer; the antidepressant agomelatine shows biased signaling at these heteromers. Co-immunoprecipitation, bioluminescence resonance energy transfer (BRET), pharmacological assays in transfected cells and human brain tissue The Journal of biological chemistry High 25770211
2018 SSRIs impair motor function through 5-HT2C receptors in the substantia nigra pars reticulata (SNr), which inhibit dopaminergic neurons in the substantia nigra pars compacta (SNc); SSRI-induced SNr hyperactivity and SNc hypoactivity are reversed by systemic or SNr-localized 5-HT2C receptor antagonism; optogenetic inhibition of SNc neurons mimics SSRI motor deficits and 5-HT2C antagonism or optogenetic SNc activation reverses them. Mouse model with systemic SSRIs, localized SNr 5-HT2C receptor antagonism, optogenetic activation/inhibition of SNc dopaminergic neurons, motor function behavioral assays Molecular psychiatry High 30120415
2002 5-HT2C receptor null mutant mice show more wakefulness, abnormalities in REM sleep expression, and enhanced response to sleep deprivation compared to wild-type mice, establishing a role for 5-HT2C receptors in sleep expression and sleep homeostasis. 5-HT2C receptor knockout mice, polysomnographic sleep recording, sleep deprivation protocol Neuropsychopharmacology High 12431861
2007 5-HT2C receptor promoter polymorphisms (-759C/T and -697G/C) alter promoter activity in SH-SY5Y neuroblastoma cells; the -759T and -697C alleles reduce promoter activity, and the haplotype associated with resistance to antipsychotic-induced weight gain shows reduced activity compared to the most common haplotype. Luciferase reporter constructs with four promoter haplotypes transfected into SH-SY5Y cells, in presence or absence of constitutively active 5-HT2C receptor Brain research Medium 17376412
2019 In the lateral habenula (LHb), 5-HT2C receptor levels and 5-HIAA/5-HT ratio are increased in alcohol-withdrawn rats; intra-LHb 5-HT2C receptor antagonism (SB242084) alleviates anxiety-like behaviors and reduces elevated c-Fos expression, and increases KCNQ2/3 membrane protein expression in LHb, establishing that enhanced LHb 5-HT2C receptor signaling interacts with M-channels to trigger withdrawal anxiety. Intra-LHb microinfusion of SB242084 or WAY161503, elevated plus-maze, open-field, marble-burying tests, c-Fos immunohistochemistry, Western blot of KCNQ2/3 and 5-HT2C protein Neuropharmacology Medium 31778691
2022 In iPSC-derived GABAergic interneurons from patients with major depressive disorder with suicide behavior (sMDD), 5-HT2C receptor expression is decreased and neuronal activity is abnormal (increased firing, weakened calcium signaling); pharmacological agonism or genetic restoration of 5-HT2C receptor rescues neuronal activity deficits, establishing 5-HT2C as a mechanistic determinant of interneuron dysfunction in sMDD. iPSC-derived GABAergic interneurons and ventral forebrain organoids from sMDD patients, transcriptomic sequencing, calcium imaging, electrophysiology, pharmacological and genetic 5-HT2C receptor manipulation EMBO molecular medicine Medium 36373384

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 Eating disorder and epilepsy in mice lacking 5-HT2c serotonin receptors. Nature 1038 7700379
1997 SB 242084, a selective and brain penetrant 5-HT2C receptor antagonist. Neuropharmacology 458 9225286
2000 Immunohistochemical localisation of the 5-HT2C receptor protein in the rat CNS. Neuropharmacology 300 10665825
1998 5-HT2C receptor agonists: pharmacological characteristics and therapeutic potential. The Journal of pharmacology and experimental therapeutics 258 9694950
2005 Serotonin 5-HT2C receptors as a target for the treatment of depressive and anxious states: focus on novel therapeutic strategies. Therapie 216 16433010
2007 Serotonin 5-HT2C receptor agonist promotes hypophagia via downstream activation of melanocortin 4 receptors. Endocrinology 199 18039773
1997 RS-102221: a novel high affinity and selective, 5-HT2C receptor antagonist. Neuropharmacology 195 9225287
1995 Identification, expression, and pharmacology of a Cys23-Ser23 substitution in the human 5-HT2c receptor gene (HTR2C). Genomics 194 7557992
1996 Serotonin 5-HT2a and 5-HT2c receptors stimulate amyloid precursor protein ectodomain secretion. The Journal of biological chemistry 186 8626761
2003 5-HT2A and 5-HT2C receptors and their atypical regulation properties. Life sciences 176 12650852
1996 Interactions of selective serotonin reuptake inhibitors with the serotonin 5-HT2c receptor. Psychopharmacology 174 8876023
1998 5-HT2A and 5-HT2C receptor polymorphisms and psychopathology in late onset Alzheimer's disease. Human molecular genetics 164 9700207
1994 In vivo properties of SB 200646A, a 5-HT2C/2B receptor antagonist. British journal of pharmacology 157 7912626
1999 Serotonin 5-HT2C receptor RNA editing alters receptor basal activity: implications for serotonergic signal transduction. Journal of neurochemistry 147 10501219
2009 Loss of the imprinted snoRNA mbii-52 leads to increased 5htr2c pre-RNA editing and altered 5HT2CR-mediated behaviour. Human molecular genetics 133 19304781
2003 Serotonin and drug reward: focus on 5-HT2C receptors. European journal of pharmacology 133 14623358
1999 Messenger RNA editing of the human serotonin 5-HT2C receptor. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 124 10432493
2004 The serotonin 5-HT2A and 5-HT2C receptors interact with specific sets of PDZ proteins. The Journal of biological chemistry 120 14988405
1996 Increased 5-HT2C receptor responsiveness occurs on rearing rats in social isolation. Psychopharmacology 119 8867874
2006 The 5-HT2C receptor and antipsychoticinduced weight gain - mechanisms and genetics. Journal of psychopharmacology (Oxford, England) 116 16785265
2010 Motoneuron excitability and muscle spasms are regulated by 5-HT2B and 5-HT2C receptor activity. Journal of neurophysiology 115 20980537
1999 Attenuation of haloperidol-induced catalepsy by a 5-HT2C receptor antagonist. British journal of pharmacology 115 10188965
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