Affinage

HTR6

5-hydroxytryptamine receptor 6 · UniProt P50406

Length
440 aa
Mass
47.0 kDa
Annotated
2026-04-28
100 papers in source corpus 25 papers cited in narrative 25 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HTR6 (5-HT6 receptor) is a Gs-coupled serotonin receptor expressed predominantly in the CNS—on dendrites, primary cilia, and somata of striatal, cortical, and hippocampal neurons—where it regulates cholinergic, GABAergic, and glutamatergic neurotransmission, neuronal morphogenesis, and cognition. The receptor couples exclusively to Gαs to stimulate adenylyl cyclase/cAMP production and exhibits strong constitutive activity dependent on the BBXXB motif in the third intracellular loop and on a physical association with neurofibromin via its PH domain (PMID:8389146, PMID:11406289, PMID:27791021). Constitutive interaction with Cdk5 drives agonist-independent neurite outgrowth through Cdk5-mediated phosphorylation of Ser350 and downstream Cdc42 activation, while Fyn kinase binds the C-terminal tail via its SH3 domain to activate ERK1/2 signaling, and SNX14 dually attenuates signaling by sequestering Gαs and promoting receptor degradation (PMID:24880860, PMID:17189269, PMID:25795301). Ciliary targeting requires redundant sequences in IC3 and the C-terminal tail acting through TULP3 and RABL2 adaptors, and loss of HTR6 in mice disrupts Sonic Hedgehog signaling, dendritic morphology, and cognitive function (PMID:33372037, PMID:33960602).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1993 High

    Cloning and heterologous expression established HTR6 as a Gs-coupled GPCR that stimulates cAMP production, resolving its signal transduction mechanism and distinguishing it from inhibitory serotonin receptor subtypes.

    Evidence Transient transfection in COS-7 and HEK293 cells with cAMP measurement and radioligand binding; replicated with human ortholog and pharmacological profiling

    PMID:8389146 PMID:8522988 PMID:9225298

    Open questions at the time
    • Exclusive Gαs coupling was not formally demonstrated until 2008
    • No structural basis for G-protein selectivity
  2. 1995 High

    Antisense knockdown in vivo revealed that HTR6 tonically suppresses cholinergic neurotransmission in the brain, establishing its first physiological role and differentiating it from dopaminergic modulation.

    Evidence Intracerebroventricular antisense oligonucleotides in rats with behavioral pharmacology (atropine rescue) and radioligand binding

    PMID:7616396 PMID:8788511 PMID:9884085

    Open questions at the time
    • Mechanism by which HTR6 on non-cholinergic neurons suppresses ACh release was not identified
    • Direct measurement of acetylcholine levels was not performed
  3. 1997 High

    Immunohistochemistry and electron microscopy localized HTR6 protein to dendritic processes in striatum and hippocampus, defining its subcellular distribution for the first time.

    Evidence Affinity-purified C-terminal antibodies with IHC and EM in rat brain

    PMID:9037500

    Open questions at the time
    • Ciliary localization was not recognized until later studies
    • Distribution across cortical layers and interneuron subtypes was not assessed
  4. 2001 High

    Mutagenesis of the BBXXB motif in the third intracellular loop demonstrated that constitutive (agonist-independent) Gs activity is an intrinsic property of HTR6, not an artifact of overexpression.

    Evidence Site-directed mutagenesis with cAMP-responsive reporter in JEG-3 and COS-7 cells

    PMID:11406289

    Open questions at the time
    • Whether constitutive activity occurs at endogenous expression levels in neurons was not shown
    • Structural basis of constitutive activity beyond the BBXXB motif was unknown
  5. 2006 High

    Identification of Fyn kinase as a direct binding partner of the HTR6 C-terminal tail revealed a non-canonical signaling branch linking HTR6 to ERK1/2 activation beyond the canonical cAMP pathway.

    Evidence Yeast two-hybrid, GST pulldown, reciprocal co-immunoprecipitation in cell lines and rat brain, ERK1/2 phosphorylation assay

    PMID:17189269

    Open questions at the time
    • Physiological consequences of Fyn-dependent ERK signaling in neurons were not determined
    • Whether Fyn engagement is constitutive or agonist-dependent was not resolved
  6. 2007 High

    In vivo microdialysis and electrophysiology showed that HTR6 agonism selectively increases extracellular GABA and modulates glutamatergic excitatory transmission in striatal and cortical neurons, broadening the receptor's role beyond cholinergic modulation.

    Evidence In vivo microdialysis in multiple brain regions, patch-clamp electrophysiology in striatal MSNs and cortical pyramidal neurons, selective pharmacological tools

    PMID:17428998 PMID:17625499 PMID:21619890

    Open questions at the time
    • Direct versus indirect mechanisms of GABAergic modulation were not fully resolved
    • Cell-type specificity of electrophysiological effects was not mapped onto HTR6-expressing subtypes
  7. 2007 Medium

    Region-specific viral overexpression demonstrated that striatal HTR6 impairs instrumental learning while nucleus accumbens HTR6 selectively blocks cocaine reward, establishing circuit-level functional specificity.

    Evidence Viral gene transfer for regional overexpression, instrumental learning, conditioned place preference, pharmacological rescue with 5-HT6 antagonist

    PMID:17192775 PMID:17631868

    Open questions at the time
    • Downstream signaling pathways mediating region-specific behavioral effects were not identified
    • Results are from gain-of-function; knockout confirmation in each region was lacking
  8. 2008 High

    GTPγS/antibody-immunocapture formally proved exclusive Gαs coupling of HTR6, ruling out Gi/o and Gq engagement and clarifying that all downstream effects flow through the cAMP axis.

    Evidence Scintillation proximity assay with Gα-specific antibodies in HEK293 stable expression system with broad ligand panel

    PMID:18511034

    Open questions at the time
    • Non-G-protein signaling (e.g., β-arrestin) was not assessed
    • Whether exclusive Gαs coupling holds in native neuronal membranes was not tested
  9. 2014 High

    Proteomic identification of Cdk5 as a constitutive interactor of HTR6 revealed an agonist-independent mechanism for neurite outgrowth driven by Cdk5-mediated phosphorylation of Ser350 and Cdc42 activation, reframing HTR6 as a developmental signaling hub.

    Evidence Proteomic co-purification, co-immunoprecipitation, S350A mutagenesis, siRNA knockdown, neurite outgrowth assay in NG108-15 and primary neurons

    PMID:24880860

    Open questions at the time
    • In vivo developmental consequences of S350A mutation were not tested
    • Whether Cdk5 interaction is regulated by ciliary versus non-ciliary pools of HTR6 was unknown
  10. 2015 High

    SNX14 was identified as a dual negative regulator that sequesters Gαs via its RGS domain and promotes HTR6 endocytic degradation upon PKA-mediated phosphorylation, establishing a feedback loop for signal termination.

    Evidence Co-immunoprecipitation, siRNA knockdown, internalization assay, cAMP measurement, PKA phosphorylation and GTPase activity assays

    PMID:25795301

    Open questions at the time
    • In vivo relevance of SNX14-mediated HTR6 regulation was not demonstrated
    • Whether SNX14 loss-of-function mutations (linked to cerebellar ataxia) affect HTR6 signaling was not tested
  11. 2015 High

    Systematic double in situ hybridization mapped HTR6 mRNA to D1/D2-expressing MSNs, glutamatergic cortical/hippocampal neurons, and a subset of 5-HT3aR+ interneurons, while excluding serotonergic, dopaminergic, and cholinergic neurons—defining the cellular substrate for circuit-level effects.

    Evidence Double in situ hybridization with multiple neuronal and interneuronal markers across brain regions

    PMID:26424380

    Open questions at the time
    • Protein-level confirmation of cell-type expression was not provided
    • Expression in non-neuronal cells (e.g., glia) was not systematically examined
  12. 2016 High

    Neurofibromin was shown to physically associate with HTR6 via its PH domain and to be required for constitutive Gs signaling, linking NF1 loss to impaired tonic cAMP/CREB signaling in prefrontal cortex.

    Evidence Co-immunoprecipitation, siRNA knockdown, PH domain rescue, CREB phosphorylation in Nf1+/- mice, inverse agonist treatment in vivo

    PMID:27791021

    Open questions at the time
    • Whether neurofibromin modulates agonist-stimulated versus only constitutive signaling was not dissected
    • Structural basis of the HTR6–NF1 PH domain interaction was not determined
  13. 2017 Medium

    Discovery that HTR6 is concentrated on neuronal primary cilia and regulates cilia length, ARL13B distribution, and axon initial segment morphology repositioned the receptor as a ciliary signaling organizer in hippocampal neurons.

    Evidence Immunostaining for ciliary markers, overexpression/knockdown in primary hippocampal neurons, behavioral rescue in APP/PS1 mice

    PMID:28931427

    Open questions at the time
    • Whether signaling outputs differ between ciliary and non-ciliary pools of HTR6 was unknown
    • Mechanism linking ciliary HTR6 to AIS morphology was not identified
  14. 2020 High

    Systematic mutagenesis identified redundant ciliary targeting sequences in IC3 (CTS1, RKQ motif) and the C-terminal tail (CTS2, LPG motif) that function through TULP3 and RABL2 adaptors, defining the molecular determinants of HTR6 ciliary localization.

    Evidence IC3/CT mutagenesis, chimeric receptor constructs, live-cell ciliary imaging, interaction studies with TULP3 and RABL2

    PMID:33372037

    Open questions at the time
    • Whether CTS disruption affects in vivo neuronal function was not tested
    • Relative contributions of TULP3 vs. RABL2 pathways in different neuronal subtypes were not resolved
  15. 2021 Medium

    HTR6 knockout mice displayed cognitive deficits, anxiety, disrupted Sonic Hedgehog signaling in primary cilia, altered dendritic morphology, and increased neuronal excitability, integrating ciliary, morphological, and functional phenotypes into a unified loss-of-function picture.

    Evidence Constitutive knockout mouse, behavioral testing, immunofluorescence, electrophysiology, Shh pathway analysis

    PMID:33960602

    Open questions at the time
    • Whether cognitive phenotypes are developmental or reflect ongoing signaling loss was not dissected
    • Cell-type-specific contributions to the knockout phenotype were not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how ciliary versus non-ciliary pools of HTR6 differentially contribute to cAMP/Cdk5/mTORC1 signaling, whether β-arrestin-dependent signaling occurs, and what structural features underlie the receptor's strong constitutive activity.
  • No high-resolution structure of HTR6 in active or inactive state
  • β-arrestin coupling has not been assessed
  • Relative signaling outputs from ciliary vs. plasma membrane pools are unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 5
Localization
GO:0005929 cilium 3 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-112316 Neuronal System 4 R-HSA-1266738 Developmental Biology 2
Partners
CDK5FYNNF1RABL2SNX14TULP3

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 The rat 5-HT6 receptor, when transiently expressed in COS-7 cells, is positively coupled to cyclic AMP (adenylyl cyclase) production, establishing it as a Gs-coupled GPCR. Transient transfection in COS-7 cells with cAMP measurement Biochemical and biophysical research communications High 8389146
1996 The human 5-HT6 receptor (440 aa) is positively coupled to adenylyl cyclase, has high affinity for typical and atypical antipsychotics including clozapine, and its gene maps to chromosome 1p35-p36. Heterologous expression, cAMP assay, radioligand binding, chromosomal mapping Journal of neurochemistry High 8522988
1997 5-HT6 receptor-like immunoreactivity is localized to dendritic processes in the striatum and dentate gyrus of the hippocampus, indicating the receptor protein is expressed on somas and/or dendrites near its synthesis site. Immunohistochemistry and electron microscopy with affinity-purified antibodies against the C-terminal domain Brain research High 9037500
1997 Rat 5-HT6 receptor stably expressed in HEK293 cells stimulates cAMP accumulation; rank order of agonist potency established with LSD as most potent partial agonist relative to 5-HT; antagonists methiothepin and clozapine block this response. Stable expression in HEK293 cells, radioligand binding ([3H]-LSD, [3H]-5-HT), cAMP accumulation assay Neuropharmacology High 9225298
1995 Intracerebroventricular antisense oligonucleotide knockdown of 5-HT6 receptor in rats produces a behavioral syndrome (yawning, stretching, chewing) that is antagonized by atropine but not haloperidol, indicating 5-HT6 receptors tonically control cholinergic (not dopaminergic) neurotransmission in the rat brain. Antisense oligonucleotide knockdown in vivo, radioligand binding, behavioral pharmacology with muscarinic and dopaminergic antagonists The Journal of pharmacology and experimental therapeutics High 7616396
1996 Antisense oligonucleotide knockdown of 5-HT6 receptor in rats reduces [3H]LSD binding in frontal lobes and produces a specific behavioral syndrome of yawning, stretching, and chewing, confirming the receptor has physiological function under tonic 5-HT control. Phosphorothioate antisense oligonucleotides, radioligand binding, behavioral observation Behavioural brain research High 8788511
1998 5-HT6 receptor antagonism (Ro 04-6790) inhibits rotational behavior in 6-OHDA lesioned rats induced by muscarinic antagonists scopolamine and atropine, but not by L-Dopa or amphetamine, supporting that 5-HT6 receptors control cholinergic (not dopaminergic) neurotransmission in the nigrostriatal system. In vivo pharmacology with selective 5-HT6 antagonist in 6-OHDA lesion model; behavioral readout of cholinergic vs dopaminergic manipulation British journal of pharmacology Medium 9884085
2001 The mouse 5-HT6 receptor exhibits strong constitutive (agonist-independent) activity when expressed in JEG-3 or COS-7 cells; point mutations in the BBXXB motif of the third cytoplasmic loop (K264I, K267A, A268R) reduce this constitutive activity. Site-directed mutagenesis of third cytoplasmic loop, cAMP-responsive reporter gene assay in transiently transfected cells Brain research. Molecular brain research High 11406289
2006 The C-terminal region of the human 5-HT6 receptor physically interacts with the Fyn tyrosine kinase via Fyn's SH3 domain; this interaction was confirmed by yeast two-hybrid, GST pulldown, co-immunoprecipitation in two cell lines and rat brain, and co-localization in cells and brain. 5-HT6R activation stimulates ERK1/2 via an Fyn-dependent pathway. Yeast two-hybrid, GST pulldown, co-immunoprecipitation, immunocytochemistry/immunohistochemistry, ERK1/2 phosphorylation assay The Journal of biological chemistry High 17189269
2007 5-HT6 receptor agonism (WAY-181187, WAY-208466) selectively increases extracellular GABA in rat frontal cortex, hippocampus, striatum, and amygdala without altering glutamate or norepinephrine; cortical effects on catecholamines are mediated via local GABA-A receptors. Chronic administration does not produce neurochemical tolerance. In vivo microdialysis in multiple brain regions, pharmacological blockade with GABA-A antagonist bicuculline, ex vivo hippocampal slice glutamate release assay Neuropsychopharmacology High 17625499
2007 5-HT6 receptor stimulation (EMDT agonist) increases phosphorylation of Thr34-DARPP-32 and Ser845-GluR1 in brain slices and intact brain, independently of D1 receptor stimulation, and increases c-fos mRNA; these effects are blocked by 5-HT6 antagonist SB271046, linking 5-HT6R signaling to DARPP-32 and AMPA receptor phosphorylation pathways. Pharmacological manipulation with selective agonist/antagonist, Western blotting for phosphoproteins in brain slices and in vivo, in situ hybridization for c-fos The Journal of neuroscience High 17428998
2011 5-HT6 receptor activation by agonist ST1936 reduces the frequency and amplitude of spontaneous excitatory postsynaptic currents in striatal medium spiny neurons via a postsynaptic mechanism, and reduces the frequency (presynaptically or indirectly) in cortical layer V pyramidal neurons; effects are blocked by SB258585. Whole-cell patch-clamp electrophysiology in striatal and cortical neurons, paired-pulse analysis, miniature EPSC recordings, pharmacological validation Neuropharmacology High 21619890
2014 5-HT6 receptors constitutively interact with Cdk5; expression of 5-HT6R in NG108-15 cells drives agonist-independent neurite growth and voltage-gated Ca2+ channel expression requiring Cdk5-mediated phosphorylation of receptor Ser350 and Cdc42 activity. Mutation of Ser350 to alanine or silencing 5-HT6R reduces neurite growth in primary neurons. Proteomic co-purification, co-immunoprecipitation, site-directed mutagenesis (S350A), siRNA knockdown, neurite outgrowth assay, inverse agonist pharmacology Nature chemical biology High 24880860
2015 SNX14 directly interacts with the 5-HT6 receptor, dramatically increasing its internalization and degradation; SNX14's RGS domain binds and sequesters Gαs to inhibit cAMP production; PKA-mediated phosphorylation of SNX14 shifts it from Gαs binding to 5-HT6R binding, promoting receptor endocytic degradation. SNX14 thus dually regulates 5-HT6R signaling and trafficking. Co-immunoprecipitation, siRNA knockdown, internalization assay, cAMP measurement, PKA phosphorylation assay, GTPase activity assay Journal of cell science High 25795301
2016 Neurofibromin (NF1 gene product) physically associates with the 5-HT6 receptor via its Pleckstrin Homology (PH) domain; this interaction is required for constitutive Gs/adenylyl cyclase signaling by the receptor. Silencing neurofibromin or disrupting the 5-HT6R-neurofibromin interaction reduces constitutive cAMP signaling and CREB phosphorylation in prefrontal cortex. Co-immunoprecipitation, siRNA knockdown, PH domain expression rescue, CREB phosphorylation in Nf1+/- mice, in vivo inverse agonist treatment Proceedings of the National Academy of Sciences of the United States of America High 27791021
2008 Selective activation of a Gs-coupled DREADD or the 5-HT6 receptor on transplanted dopaminergic neurons is sufficient to induce graft-induced dyskinesias in a Parkinson's disease rat model, establishing a mechanistic link between 5-HT6 receptor-mediated cAMP signaling on DA neurons and dyskinesia, likely via counteraction of D2 autoreceptor feedback. Chemogenetic (DREADD) approach in transplanted DA neurons in 6-OHDA rat PD model, behavioral dyskinesia scoring Neuron Medium 27161524
2015 5-HT6R mRNA is expressed in medium spiny neurons co-expressing dopamine D1 and D2 receptor mRNA in striatum, in glutamatergic (vGluT1+) neurons in cortex and hippocampus, and in ~15% of GAD67+ interneurons (predominantly the 5-HT3aR-expressing subpopulation), but not in serotonergic, dopaminergic, or cholinergic neurons. Double in situ hybridization with multiple neuronal and interneuronal markers across brain regions Neuroscience High 26424380
2017 5-HT6 receptor, localized almost exclusively to primary cilia, regulates cilia length and morphology in hippocampal neurons; its overexpression or knockdown alters ARL13B and AnkG localization and axon initial segment morphology, and reduces axonal length. In APP/PS1 AD mice, primary cilia are elongated and 5-HT6 antagonism reverses cognitive deficits. Immunostaining of primary cilia, 5-HT6 overexpression/knockdown in primary hippocampal neurons, Morris water maze, Y-maze, fear conditioning in APP/PS1 mice Alzheimer's research & therapy Medium 28931427
2019 HTR6-mediated mTORC1 signaling in hippocampal neurons mediates dietary restriction-induced memory enhancement; HTR6 inactivation prevents DR-induced reductions in dendritic complexity, increases in spine density, and enhancement of long-term potentiation (LTP). HTR6 knockout/knockdown, LTP electrophysiology, dendritic morphology imaging, mTORC1 pathway analysis in hippocampal neurons PLoS biology Medium 30883547
2020 HTR6 ciliary targeting requires redundant ciliary targeting sequences (CTS) in both the third intracellular loop (IC3; CTS1) and C-terminal tail (CT; CTS2); RKQ and LPG motifs are critical for CTS1 and CTS2 function respectively; ciliary localization is mediated through binding to ciliary trafficking adaptors TULP3 and RABL2. Mutagenesis of IC3 and CT regions, chimeric receptor constructs, live-cell imaging of ciliary localization, interaction studies with TULP3 and RABL2 Life science alliance High 33372037
2021 5-HT6R null mutant mice exhibit cognitive deficiencies, abnormal anxiety, altered Sonic Hedgehog signaling in primary cilia, changes in dendritic complexity and axon initial segment morphology, and increased neuronal excitability. 5-HT6R knockout mouse model, behavioral testing, immunofluorescence for neuronal morphology, electrophysiology for neuronal excitability, Shh pathway analysis Aging cell Medium 33960602
2008 Mice carrying a non-functional 5-HT6 receptor consume less food and gain significantly less weight on a high-fat diet compared to wild-type controls, with reduced fat accumulation, establishing a functional role for 5-HT6R in regulating feeding and body weight. 5-HT6R loss-of-function mutant mice, high-fat diet feeding paradigm, body weight and composition analysis Brain research Medium 18755168
2007 Increased 5-HT6 receptor expression in the dorsomedial striatum (via viral gene transfer) impairs acquisition of instrumental learning (striatum-dependent) but not Morris water maze performance (hippocampus-dependent); this deficit is reversed by 5-HT6 antagonist SB-258585, demonstrating a region-specific role of striatal 5-HT6R in new learning. Viral-mediated gene transfer for region-specific 5-HT6R overexpression, behavioral testing (instrumental learning vs. Morris water maze), pharmacological rescue Neuropsychopharmacology Medium 17192775
2007 Increased 5-HT6 receptor expression in the nucleus accumbens blocks cocaine conditioned place preference (reward) but has no effect on acute locomotor response or psychomotor sensitization; conversely, 5-HT6 antagonism facilitates CPP acquisition, establishing a role for NAc 5-HT6R in selectively modulating drug reward. Viral-mediated gene transfer for NAc-specific 5-HT6R overexpression, conditioned place preference, locomotor sensitization, selective 5-HT6 antagonist pharmacology Biological psychiatry Medium 17631868
2008 5-HT6 receptor couples exclusively to Gαs (not Gi/o or Gq) as demonstrated by GTPγS/antibody-immunocapture SPA assay; serotonin, LSD, and several tryptamines act as full agonists while WAY-181187 and WAY-208466 act as partial agonists at Gαs coupling. Scintillation Proximity Assay (SPA)/antibody-immunocapture of [35S]GTPγS binding to specific Gα subunits in HEK293 stable expression system European journal of pharmacology High 18511034

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1993 A novel rat serotonin (5-HT6) receptor: molecular cloning, localization and stimulation of cAMP accumulation. Biochemical and biophysical research communications 333 8389146
1996 Cloning, characterization, and chromosomal localization of a human 5-HT6 serotonin receptor. Journal of neurochemistry 305 8522988
1997 Immuno-localization of serotonin 5-HT6 receptor-like material in the rat central nervous system. Brain research 256 9037500
2008 A role for the 5-HT(1A), 5-HT4 and 5-HT6 receptors in learning and memory. Trends in pharmacological sciences 234 19086256
2004 5-ht6 receptors. Current drug targets. CNS and neurological disorders 220 14965245
2008 5-HT6 receptor antagonists as novel cognitive enhancing agents for Alzheimer's disease. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 202 18625457
2005 5-HT6 receptors: a novel target for cognitive enhancement. Pharmacology & therapeutics 193 16005519
2001 A role for 5-ht6 receptors in retention of spatial learning in the Morris water maze. Neuropharmacology 164 11489457
2007 Neuropharmacological profile of novel and selective 5-HT6 receptor agonists: WAY-181187 and WAY-208466. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 159 17625499
1995 Determination of the role of the 5-ht6 receptor in the rat brain: a study using antisense oligonucleotides. The Journal of pharmacology and experimental therapeutics 148 7616396
2007 Selective 5-HT6 receptor ligands: progress in the development of a novel pharmacological approach to the treatment of obesity and related metabolic disorders. Pharmacology & therapeutics 144 18068807
2001 5-HT6 receptor antagonists enhance retention of a water maze task in the rat. Psychopharmacology 127 11702084
2014 Serotonin 5-HT6 receptor antagonists for the treatment of cognitive deficiency in Alzheimer's disease. Journal of medicinal chemistry 123 24850589
2006 The novel cellular mechanism of human 5-HT6 receptor through an interaction with Fyn. The Journal of biological chemistry 123 17189269
2007 Biochemical and behavioral evidence for antidepressant-like effects of 5-HT6 receptor stimulation. The Journal of neuroscience : the official journal of the Society for Neuroscience 120 17428998
2005 5-HT6 receptor antagonists improve performance in an attentional set shifting task in rats. Psychopharmacology 101 15846482
2014 Cdk5 induces constitutive activation of 5-HT6 receptors to promote neurite growth. Nature chemical biology 99 24880860
2010 Double-blind, controlled phase II study of a 5-HT6 receptor antagonist, SB-742457, in Alzheimer's disease. Current Alzheimer research 98 20043816
2006 Serotonin 5-HT2A and 5-HT6 receptors in the prefrontal cortex of Alzheimer and normal aging patients. BMC neuroscience 98 16640790
2003 Reversal of a cholinergic-induced deficit in a rodent model of recognition memory by the selective 5-HT6 receptor antagonist, Ro 04-6790. Psychopharmacology 98 13680084
2010 Potential role of the 5-HT6 receptor in depression and anxiety: an overview of preclinical data. Pharmacological reports : PR 96 20884998
2010 Lu AE58054, a 5-HT6 antagonist, reverses cognitive impairment induced by subchronic phencyclidine in a novel object recognition test in rats. The international journal of neuropsychopharmacology 94 20569520
1999 Investigation of stretching behaviour induced by the selective 5-HT6 receptor antagonist, Ro 04-6790, in rats. British journal of pharmacology 87 10323584
2007 Pro-cognitive effects of 5-HT6 receptor antagonists in the social recognition procedure in rats: implication of the frontal cortex. Psychopharmacology 86 17922111
2003 An assessment of the effects of serotonin 6 (5-HT6) receptor antagonists in rodent models of learning. The Journal of pharmacology and experimental therapeutics 82 12975483
2001 Cloning of the mouse 5-HT6 serotonin receptor and mutagenesis studies of the third cytoplasmic loop. Brain research. Molecular brain research 82 11406289
2013 5-HT6 receptors and Alzheimer's disease. Alzheimer's research & therapy 80 23607787
2017 Serotonin 5-HT6 receptors affect cognition in a mouse model of Alzheimer's disease by regulating cilia function. Alzheimer's research & therapy 78 28931427
1997 Functional and radioligand binding characterization of rat 5-HT6 receptors stably expressed in HEK293 cells. Neuropharmacology 74 9225298
2018 The role of 5 HT6-receptor antagonists in Alzheimer's disease: an update. Expert opinion on investigational drugs 72 29848076
2016 Physical interaction between neurofibromin and serotonin 5-HT6 receptor promotes receptor constitutive activity. Proceedings of the National Academy of Sciences of the United States of America 72 27791021
2005 A three-dimensional pharmacophore model for 5-hydroxytryptamine6 (5-HT6) receptor antagonists. Journal of medicinal chemistry 70 15974573
2000 5-ht6 receptors as emerging targets for drug discovery. Annual review of pharmacology and toxicology 70 10836139
2008 Effects of 5-HT6 receptor antagonism and cholinesterase inhibition in models of cognitive impairment in the rat. British journal of pharmacology 68 18622410
2011 Influence of social isolation in the rat on serotonergic function and memory--relevance to models of schizophrenia and the role of 5-HT₆ receptors. Neuropharmacology 67 21414329
2002 5-HT6 receptor binding sites in schizophrenia and following antipsychotic drug administration: autoradiographic studies with [125I]SB-258585. Synapse (New York, N.Y.) 67 12112397
1998 Involvement of 5-HT6 receptors in nigro-striatal function in rodents. British journal of pharmacology 67 9884085
2001 Lack of association between the T-->C 267 serotonin 5-HT6 receptor gene (HTR6) polymorphism and prediction of response to clozapine in schizophrenia. Schizophrenia research 65 11163544
2010 Antidepressant and anxiolytic effects of selective 5-HT6 receptor agonists in rats. Psychopharmacology 64 20217056
2006 Increased expression of 5-HT6 receptors in the rat dorsomedial striatum impairs instrumental learning. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 64 17192775
2015 Therapeutic Potential of 5-HT6 Receptor Agonists. Journal of medicinal chemistry 63 26099069
2010 5-HT6 receptor antagonists as potential therapeutics for cognitive impairment. Current topics in medicinal chemistry 63 20166958
2016 Novel 1H-Pyrrolo[3,2-c]quinoline Based 5-HT6 Receptor Antagonists with Potential Application for the Treatment of Cognitive Disorders Associated with Alzheimer's Disease. ACS chemical neuroscience 60 27100049
2015 5-HT6 Receptor Antagonists: Potential Efficacy for the Treatment of Cognitive Impairment in Schizophrenia. Current pharmaceutical design 59 26044973
2009 Dimebolin is a 5-HT6 antagonist with acute cognition enhancing activities. Biochemical pharmacology 57 19549510
2009 The serotonin 5-HT6 receptor: a viable drug target for treating cognitive deficits in Alzheimer's disease. Expert review of neurotherapeutics 54 19589055
2015 Distribution of serotonin receptor 5-HT6 mRNA in rat neuronal subpopulations: A double in situ hybridization study. Neuroscience 53 26424380
2016 DREADD Modulation of Transplanted DA Neurons Reveals a Novel Parkinsonian Dyskinesia Mechanism Mediated by the Serotonin 5-HT6 Receptor. Neuron 52 27161524
2008 5-HT6 receptor antagonists: prospects for the treatment of cognitive disorders including dementia. Current opinion in drug discovery & development 52 18729016
2001 Role of 5-HT6 receptors in memory formation. Drug news & perspectives 50 12813582
2008 Serotonin 5-HT6 receptor antagonists for the treatment of Alzheimer's disease. Current topics in medicinal chemistry 49 18691131
2009 Procognitive 5-HT6 antagonists in the rat forced swimming test: potential therapeutic utility in mood disorders associated with Alzheimer's disease. Life sciences 48 19302808
2011 5-HT6 receptor memory and amnesia: behavioral pharmacology--learning and memory processes. International review of neurobiology 47 21329783
2011 The 5-HT6 receptor agonist EMD 386088 produces antidepressant and anxiolytic effects in rats after intrahippocampal administration. Psychopharmacology 47 21499701
1994 5-Hydroxytryptamine receptors with a 5-HT6 receptor-like profile stimulating adenylyl cyclase activity in pig caudate membranes. Naunyn-Schmiedeberg's archives of pharmacology 47 7845473
2015 5-HT6 Receptor: A New Player Controlling the Development of Neural Circuits. ACS chemical neuroscience 46 25590789
2014 Memory formation and memory alterations: 5-HT6 and 5-HT7 receptors, novel alternative. Reviews in the neurosciences 46 24698823
2012 Activation of 5-HT6 receptors modulates sleep-wake activity and hippocampal theta oscillation. ACS chemical neuroscience 46 23336058
2005 2-Alkyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles as novel 5-HT6 receptor agonists. Bioorganic & medicinal chemistry letters 46 16055331
2004 Risperidone response and 5-HT6 receptor gene variance: genetic association analysis with adjustment for nongenetic confounders. Schizophrenia research 46 14741325
1996 Effects of altered 5-ht6 expression in the rat: functional studies using antisense oligonucleotides. Behavioural brain research 45 8788511
1999 Association analysis of the 5-HT6 receptor polymorphism C267T in Alzheimer's disease. Neuroscience letters 44 10624811
2007 Memory consolidation and amnesia modify 5-HT6 receptors expression in rat brain: an autoradiographic study. Behavioural brain research 42 17267053
2007 Increased expression of 5-HT6 receptors in the nucleus accumbens blocks the rewarding but not psychomotor activating properties of cocaine. Biological psychiatry 40 17631868
1999 Effects of clozapine and haloperidol on 5-HT6 receptor mRNA levels in rat brain. Schizophrenia research 40 10427606
2015 Investigational drugs targeting 5-HT6 receptors for the treatment of Alzheimer's disease. Expert opinion on investigational drugs 39 26548316
2011 The effects of PRX-07034, a novel 5-HT6 antagonist, on cognitive flexibility and working memory in rats. Psychopharmacology 38 21989804
2009 Indene-based scaffolds. 2. An indole-indene switch: discovery of novel indenylsulfonamides as 5-HT6 serotonin receptor agonists. Journal of medicinal chemistry 38 19159187
2009 Role of peripheral and spinal 5-HT6 receptors according to the rat formalin test. Neuroscience 38 19422883
2016 N1-Azinylsulfonyl-1H-indoles: 5-HT6 Receptor Antagonists with Procognitive and Antidepressant-Like Properties. ACS medicinal chemistry letters 37 27326337
2012 5-HT6 receptor blockade differentially affects scopolamine-induced deficits of working memory, recognition memory and aversive learning in mice. Psychopharmacology 37 22367167
2011 Activation of 5-HT6 receptors inhibits corticostriatal glutamatergic transmission. Neuropharmacology 36 21619890
2015 5-HT6 receptor agonism facilitates emotional learning. Frontiers in pharmacology 35 26441657
2008 Actions of novel agonists, antagonists and antipsychotic agents at recombinant rat 5-HT6 receptors: a comparative study of coupling to G alpha s. European journal of pharmacology 35 18511034
2008 Reduced sensitivity to diet-induced obesity in mice carrying a mutant 5-HT6 receptor. Brain research 35 18755168
2005 Bicyclic heteroarylpiperazines as selective brain penetrant 5-HT6 receptor antagonists. Bioorganic & medicinal chemistry letters 35 16143522
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