{"gene":"HTR6","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":1993,"finding":"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.","method":"Transient transfection in COS-7 cells with cAMP measurement","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 — functional reconstitution in heterologous expression system; foundational paper replicated by multiple subsequent studies","pmids":["8389146"],"is_preprint":false},{"year":1996,"finding":"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.","method":"Heterologous expression, cAMP assay, radioligand binding, chromosomal mapping","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 1 — functional reconstitution with pharmacological characterization; replicated across labs","pmids":["8522988"],"is_preprint":false},{"year":1997,"finding":"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.","method":"Immunohistochemistry and electron microscopy with affinity-purified antibodies against the C-terminal domain","journal":"Brain research","confidence":"High","confidence_rationale":"Tier 2 — direct localization by IHC/EM with functional context; antibody specificity validated","pmids":["9037500"],"is_preprint":false},{"year":1997,"finding":"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.","method":"Stable expression in HEK293 cells, radioligand binding ([3H]-LSD, [3H]-5-HT), cAMP accumulation assay","journal":"Neuropharmacology","confidence":"High","confidence_rationale":"Tier 1 — reconstituted functional assay with multiple agonists/antagonists in stable cell line","pmids":["9225298"],"is_preprint":false},{"year":1995,"finding":"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.","method":"Antisense oligonucleotide knockdown in vivo, radioligand binding, behavioral pharmacology with muscarinic and dopaminergic antagonists","journal":"The Journal of pharmacology and experimental therapeutics","confidence":"High","confidence_rationale":"Tier 2 — genetic (antisense) loss-of-function with pharmacological rescue; replicated by independent labs","pmids":["7616396"],"is_preprint":false},{"year":1996,"finding":"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.","method":"Phosphorothioate antisense oligonucleotides, radioligand binding, behavioral observation","journal":"Behavioural brain research","confidence":"High","confidence_rationale":"Tier 2 — independent replication of antisense knockdown approach with specific receptor binding controls","pmids":["8788511"],"is_preprint":false},{"year":1998,"finding":"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.","method":"In vivo pharmacology with selective 5-HT6 antagonist in 6-OHDA lesion model; behavioral readout of cholinergic vs dopaminergic manipulation","journal":"British journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — clean pharmacological epistasis in vivo; single lab but internally consistent","pmids":["9884085"],"is_preprint":false},{"year":2001,"finding":"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.","method":"Site-directed mutagenesis of third cytoplasmic loop, cAMP-responsive reporter gene assay in transiently transfected cells","journal":"Brain research. Molecular brain research","confidence":"High","confidence_rationale":"Tier 1 — structure-function mutagenesis with functional cAMP readout","pmids":["11406289"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Yeast two-hybrid, GST pulldown, co-immunoprecipitation, immunocytochemistry/immunohistochemistry, ERK1/2 phosphorylation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal biochemical methods (Y2H + GST pulldown + reciprocal Co-IP) plus functional downstream signaling assay","pmids":["17189269"],"is_preprint":false},{"year":2007,"finding":"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.","method":"In vivo microdialysis in multiple brain regions, pharmacological blockade with GABA-A antagonist bicuculline, ex vivo hippocampal slice glutamate release assay","journal":"Neuropsychopharmacology","confidence":"High","confidence_rationale":"Tier 2 — in vivo microdialysis with pharmacological dissection in multiple brain regions, replicated across brain areas","pmids":["17625499"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Pharmacological manipulation with selective agonist/antagonist, Western blotting for phosphoproteins in brain slices and in vivo, in situ hybridization for c-fos","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — multiple phosphoprotein targets validated in both ex vivo and in vivo preparations with selective pharmacological tools","pmids":["17428998"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Whole-cell patch-clamp electrophysiology in striatal and cortical neurons, paired-pulse analysis, miniature EPSC recordings, pharmacological validation","journal":"Neuropharmacology","confidence":"High","confidence_rationale":"Tier 1 — direct electrophysiological recordings with receptor-specific pharmacological controls and multiple analytical approaches","pmids":["21619890"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Proteomic co-purification, co-immunoprecipitation, site-directed mutagenesis (S350A), siRNA knockdown, neurite outgrowth assay, inverse agonist pharmacology","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1 — reconstitution with mutagenesis, proteomic identification of partner, validated in primary neurons with multiple orthogonal approaches","pmids":["24880860"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Co-immunoprecipitation, siRNA knockdown, internalization assay, cAMP measurement, PKA phosphorylation assay, GTPase activity assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (Co-IP, KD, functional cAMP, trafficking assay) in single study; mechanistically detailed","pmids":["25795301"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Co-immunoprecipitation, siRNA knockdown, PH domain expression rescue, CREB phosphorylation in Nf1+/- mice, in vivo inverse agonist treatment","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — multiple biochemical and genetic approaches including mouse model; mechanistically linked constitutive activity to specific protein-protein interaction domain","pmids":["27791021"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Chemogenetic (DREADD) approach in transplanted DA neurons in 6-OHDA rat PD model, behavioral dyskinesia scoring","journal":"Neuron","confidence":"Medium","confidence_rationale":"Tier 2 — elegant DREADD epistasis in vivo; single study but clean genetic/pharmacological design","pmids":["27161524"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Double in situ hybridization with multiple neuronal and interneuronal markers across brain regions","journal":"Neuroscience","confidence":"High","confidence_rationale":"Tier 2 — systematic double-ISH mapping with multiple cell-type markers; defines cellular substrate for 5-HT6R function","pmids":["26424380"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Immunostaining of primary cilia, 5-HT6 overexpression/knockdown in primary hippocampal neurons, Morris water maze, Y-maze, fear conditioning in APP/PS1 mice","journal":"Alzheimer's research & therapy","confidence":"Medium","confidence_rationale":"Tier 2 — direct imaging of ciliary localization with loss/gain-of-function in primary neurons plus in vivo cognitive rescue; single lab","pmids":["28931427"],"is_preprint":false},{"year":2019,"finding":"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).","method":"HTR6 knockout/knockdown, LTP electrophysiology, dendritic morphology imaging, mTORC1 pathway analysis in hippocampal neurons","journal":"PLoS biology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic loss-of-function with multiple cellular readouts (LTP, morphology, signaling); single lab but orthogonal methods","pmids":["30883547"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Mutagenesis of IC3 and CT regions, chimeric receptor constructs, live-cell imaging of ciliary localization, interaction studies with TULP3 and RABL2","journal":"Life science alliance","confidence":"High","confidence_rationale":"Tier 1 — systematic mutagenesis with functional ciliary targeting readout and identification of trafficking adapter interactions","pmids":["33372037"],"is_preprint":false},{"year":2021,"finding":"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.","method":"5-HT6R knockout mouse model, behavioral testing, immunofluorescence for neuronal morphology, electrophysiology for neuronal excitability, Shh pathway analysis","journal":"Aging cell","confidence":"Medium","confidence_rationale":"Tier 2 — genetic knockout with multiple orthogonal cellular phenotypic readouts; single lab","pmids":["33960602"],"is_preprint":false},{"year":2008,"finding":"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.","method":"5-HT6R loss-of-function mutant mice, high-fat diet feeding paradigm, body weight and composition analysis","journal":"Brain research","confidence":"Medium","confidence_rationale":"Tier 2 — genetic loss-of-function with clear metabolic phenotype; single lab","pmids":["18755168"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Viral-mediated gene transfer for region-specific 5-HT6R overexpression, behavioral testing (instrumental learning vs. Morris water maze), pharmacological rescue","journal":"Neuropsychopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — targeted gain-of-function with pharmacological rescue and appropriate controls; single lab","pmids":["17192775"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Viral-mediated gene transfer for NAc-specific 5-HT6R overexpression, conditioned place preference, locomotor sensitization, selective 5-HT6 antagonist pharmacology","journal":"Biological psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 — region-specific gain-of-function and pharmacological loss-of-function with dissociable behavioral outcomes; single lab","pmids":["17631868"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Scintillation Proximity Assay (SPA)/antibody-immunocapture of [35S]GTPγS binding to specific Gα subunits in HEK293 stable expression system","journal":"European journal of pharmacology","confidence":"High","confidence_rationale":"Tier 1 — direct G-protein selectivity assay with broad panel of ligands in defined recombinant system","pmids":["18511034"],"is_preprint":false}],"current_model":"HTR6 (5-HT6R) is a Gs-coupled GPCR that constitutively and agonist-dependently activates adenylyl cyclase/cAMP signaling; it is localized almost exclusively in the CNS (on dendrites and primary cilia of striatal, cortical, and hippocampal neurons) where it tonically suppresses cholinergic neurotransmission, modulates GABAergic and glutamatergic transmission, and engages developmental signaling through constitutive interactions with Cdk5 (phosphorylating Ser350 to drive neurite outgrowth via Cdc42) and neurofibromin (whose PH domain is required for constitutive Gs signaling); its signaling is further regulated by Fyn kinase (binding the C-terminal tail via SH3 domain to activate ERK1/2) and SNX14 (a dual negative regulator that sequesters Gαs and promotes receptor degradation), while ciliary targeting requires redundant sequences in both IC3 and the C-terminal tail acting through TULP3 and RABL2 adaptors."},"narrative":{"teleology":[{"year":1993,"claim":"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","pmids":["8389146","8522988","9225298"],"confidence":"High","gaps":["Exclusive Gαs coupling was not formally demonstrated until 2008","No structural basis for G-protein selectivity"]},{"year":1995,"claim":"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","pmids":["7616396","8788511","9884085"],"confidence":"High","gaps":["Mechanism by which HTR6 on non-cholinergic neurons suppresses ACh release was not identified","Direct measurement of acetylcholine levels was not performed"]},{"year":1997,"claim":"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","pmids":["9037500"],"confidence":"High","gaps":["Ciliary localization was not recognized until later studies","Distribution across cortical layers and interneuron subtypes was not assessed"]},{"year":2001,"claim":"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","pmids":["11406289"],"confidence":"High","gaps":["Whether constitutive activity occurs at endogenous expression levels in neurons was not shown","Structural basis of constitutive activity beyond the BBXXB motif was unknown"]},{"year":2006,"claim":"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","pmids":["17189269"],"confidence":"High","gaps":["Physiological consequences of Fyn-dependent ERK signaling in neurons were not determined","Whether Fyn engagement is constitutive or agonist-dependent was not resolved"]},{"year":2007,"claim":"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","pmids":["17625499","21619890","17428998"],"confidence":"High","gaps":["Direct versus indirect mechanisms of GABAergic modulation were not fully resolved","Cell-type specificity of electrophysiological effects was not mapped onto HTR6-expressing subtypes"]},{"year":2007,"claim":"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","pmids":["17192775","17631868"],"confidence":"Medium","gaps":["Downstream signaling pathways mediating region-specific behavioral effects were not identified","Results are from gain-of-function; knockout confirmation in each region was lacking"]},{"year":2008,"claim":"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","pmids":["18511034"],"confidence":"High","gaps":["Non-G-protein signaling (e.g., β-arrestin) was not assessed","Whether exclusive Gαs coupling holds in native neuronal membranes was not tested"]},{"year":2014,"claim":"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","pmids":["24880860"],"confidence":"High","gaps":["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"]},{"year":2015,"claim":"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","pmids":["25795301"],"confidence":"High","gaps":["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"]},{"year":2015,"claim":"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","pmids":["26424380"],"confidence":"High","gaps":["Protein-level confirmation of cell-type expression was not provided","Expression in non-neuronal cells (e.g., glia) was not systematically examined"]},{"year":2016,"claim":"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","pmids":["27791021"],"confidence":"High","gaps":["Whether neurofibromin modulates agonist-stimulated versus only constitutive signaling was not dissected","Structural basis of the HTR6–NF1 PH domain interaction was not determined"]},{"year":2017,"claim":"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","pmids":["28931427"],"confidence":"Medium","gaps":["Whether signaling outputs differ between ciliary and non-ciliary pools of HTR6 was unknown","Mechanism linking ciliary HTR6 to AIS morphology was not identified"]},{"year":2020,"claim":"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","pmids":["33372037"],"confidence":"High","gaps":["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"]},{"year":2021,"claim":"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","pmids":["33960602"],"confidence":"Medium","gaps":["Whether cognitive phenotypes are developmental or reflect ongoing signaling loss was not dissected","Cell-type-specific contributions to the knockout phenotype were not resolved"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Low","gaps":["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":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,3,7,24]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[17,19,20]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,7,8,10,14,24]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[4,9,11,16]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[12,20]}],"complexes":[],"partners":["FYN","CDK5","SNX14","NF1","TULP3","RABL2"],"other_free_text":[]},"mechanistic_narrative":"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]."},"prefetch_data":{"uniprot":{"accession":"P50406","full_name":"5-hydroxytryptamine receptor 6","aliases":["Serotonin receptor 6"],"length_aa":440,"mass_kda":47.0,"function":"G-protein coupled receptor for 5-hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone and a mitogen (PubMed:35714614, PubMed:36989299, PubMed:37327704, PubMed:8522988). Also has a high affinity for tricyclic psychotropic drugs (By similarity). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of downstream effectors (PubMed:35714614). HTR6 is coupled to G(s) G alpha proteins and mediates activation of adenylate cyclase activity (PubMed:35714614, PubMed:37327704). Controls pyramidal neurons migration during corticogenesis, through the regulation of CDK5 activity (By similarity). Is an activator of mTOR signaling (PubMed:23027611)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P50406/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HTR6","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/HTR6","total_profiled":1310},"omim":[{"mim_id":"601109","title":"5-@HYDROXYTRYPTAMINE RECEPTOR 6; HTR6","url":"https://www.omim.org/entry/601109"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in single","driving_tissues":[{"tissue":"brain","ntpm":7.0}],"url":"https://www.proteinatlas.org/search/HTR6"},"hgnc":{"alias_symbol":["5-HT6","5-HT6R"],"prev_symbol":[]},"alphafold":{"accession":"P50406","domains":[{"cath_id":"1.20.1070.10","chopping":"27-168_185-230_255-335","consensus_level":"medium","plddt":89.6884,"start":27,"end":335}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P50406","model_url":"https://alphafold.ebi.ac.uk/files/AF-P50406-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P50406-F1-predicted_aligned_error_v6.png","plddt_mean":72.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HTR6","jax_strain_url":"https://www.jax.org/strain/search?query=HTR6"},"sequence":{"accession":"P50406","fasta_url":"https://rest.uniprot.org/uniprotkb/P50406.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P50406/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P50406"}},"corpus_meta":[{"pmid":"8389146","id":"PMC_8389146","title":"A novel rat serotonin (5-HT6) receptor: molecular cloning, localization and stimulation of cAMP accumulation.","date":"1993","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/8389146","citation_count":333,"is_preprint":false},{"pmid":"8522988","id":"PMC_8522988","title":"Cloning, characterization, and chromosomal localization of a human 5-HT6 serotonin receptor.","date":"1996","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8522988","citation_count":305,"is_preprint":false},{"pmid":"9037500","id":"PMC_9037500","title":"Immuno-localization of serotonin 5-HT6 receptor-like material in the rat central nervous system.","date":"1997","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/9037500","citation_count":256,"is_preprint":false},{"pmid":"19086256","id":"PMC_19086256","title":"A role for the 5-HT(1A), 5-HT4 and 5-HT6 receptors in learning and memory.","date":"2008","source":"Trends in pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/19086256","citation_count":234,"is_preprint":false},{"pmid":"14965245","id":"PMC_14965245","title":"5-ht6 receptors.","date":"2004","source":"Current drug targets. CNS and neurological disorders","url":"https://pubmed.ncbi.nlm.nih.gov/14965245","citation_count":220,"is_preprint":false},{"pmid":"18625457","id":"PMC_18625457","title":"5-HT6 receptor antagonists as novel cognitive enhancing agents for Alzheimer's disease.","date":"2008","source":"Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/18625457","citation_count":202,"is_preprint":false},{"pmid":"16005519","id":"PMC_16005519","title":"5-HT6 receptors: a novel target for cognitive enhancement.","date":"2005","source":"Pharmacology & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/16005519","citation_count":193,"is_preprint":false},{"pmid":"11489457","id":"PMC_11489457","title":"A role for 5-ht6 receptors in retention of spatial learning in the Morris water maze.","date":"2001","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/11489457","citation_count":164,"is_preprint":false},{"pmid":"17625499","id":"PMC_17625499","title":"Neuropharmacological profile of novel and selective 5-HT6 receptor agonists: WAY-181187 and WAY-208466.","date":"2007","source":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/17625499","citation_count":159,"is_preprint":false},{"pmid":"7616396","id":"PMC_7616396","title":"Determination of the role of the 5-ht6 receptor in the rat brain: a study using antisense oligonucleotides.","date":"1995","source":"The Journal of pharmacology and experimental therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/7616396","citation_count":148,"is_preprint":false},{"pmid":"18068807","id":"PMC_18068807","title":"Selective 5-HT6 receptor ligands: progress in the development of a novel pharmacological approach to the treatment of obesity and related metabolic disorders.","date":"2007","source":"Pharmacology & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/18068807","citation_count":144,"is_preprint":false},{"pmid":"11702084","id":"PMC_11702084","title":"5-HT6 receptor antagonists enhance retention of a water maze task in the rat.","date":"2001","source":"Psychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/11702084","citation_count":127,"is_preprint":false},{"pmid":"24850589","id":"PMC_24850589","title":"Serotonin 5-HT6 receptor antagonists for the treatment of cognitive deficiency in Alzheimer's disease.","date":"2014","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24850589","citation_count":123,"is_preprint":false},{"pmid":"17189269","id":"PMC_17189269","title":"The novel cellular mechanism of human 5-HT6 receptor through an interaction with Fyn.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17189269","citation_count":123,"is_preprint":false},{"pmid":"17428998","id":"PMC_17428998","title":"Biochemical and behavioral evidence for antidepressant-like effects of 5-HT6 receptor stimulation.","date":"2007","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/17428998","citation_count":120,"is_preprint":false},{"pmid":"15846482","id":"PMC_15846482","title":"5-HT6 receptor antagonists improve performance in an attentional set shifting task in rats.","date":"2005","source":"Psychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/15846482","citation_count":101,"is_preprint":false},{"pmid":"24880860","id":"PMC_24880860","title":"Cdk5 induces constitutive activation of 5-HT6 receptors to promote neurite growth.","date":"2014","source":"Nature chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/24880860","citation_count":99,"is_preprint":false},{"pmid":"20043816","id":"PMC_20043816","title":"Double-blind, controlled phase II study of a 5-HT6 receptor antagonist, SB-742457, in Alzheimer's disease.","date":"2010","source":"Current Alzheimer research","url":"https://pubmed.ncbi.nlm.nih.gov/20043816","citation_count":98,"is_preprint":false},{"pmid":"13680084","id":"PMC_13680084","title":"Reversal of a cholinergic-induced deficit in a rodent model of recognition memory by the selective 5-HT6 receptor antagonist, Ro 04-6790.","date":"2003","source":"Psychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/13680084","citation_count":98,"is_preprint":false},{"pmid":"16640790","id":"PMC_16640790","title":"Serotonin 5-HT2A and 5-HT6 receptors in the prefrontal cortex of Alzheimer and normal aging patients.","date":"2006","source":"BMC neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/16640790","citation_count":98,"is_preprint":false},{"pmid":"20884998","id":"PMC_20884998","title":"Potential role of the 5-HT6 receptor in depression and anxiety: an overview of preclinical data.","date":"2010","source":"Pharmacological reports : PR","url":"https://pubmed.ncbi.nlm.nih.gov/20884998","citation_count":96,"is_preprint":false},{"pmid":"20569520","id":"PMC_20569520","title":"Lu AE58054, a 5-HT6 antagonist, reverses cognitive impairment induced by subchronic phencyclidine in a novel object recognition test in rats.","date":"2010","source":"The international journal of neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/20569520","citation_count":94,"is_preprint":false},{"pmid":"10323584","id":"PMC_10323584","title":"Investigation of stretching behaviour induced by the selective 5-HT6 receptor antagonist, Ro 04-6790, in rats.","date":"1999","source":"British journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/10323584","citation_count":87,"is_preprint":false},{"pmid":"17922111","id":"PMC_17922111","title":"Pro-cognitive effects of 5-HT6 receptor antagonists in the social recognition procedure in rats: implication of the frontal cortex.","date":"2007","source":"Psychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/17922111","citation_count":86,"is_preprint":false},{"pmid":"12975483","id":"PMC_12975483","title":"An assessment of the effects of serotonin 6 (5-HT6) receptor antagonists in rodent models of learning.","date":"2003","source":"The Journal of pharmacology and experimental therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/12975483","citation_count":82,"is_preprint":false},{"pmid":"11406289","id":"PMC_11406289","title":"Cloning of the mouse 5-HT6 serotonin receptor and mutagenesis studies of the third cytoplasmic loop.","date":"2001","source":"Brain research. Molecular brain research","url":"https://pubmed.ncbi.nlm.nih.gov/11406289","citation_count":82,"is_preprint":false},{"pmid":"23607787","id":"PMC_23607787","title":"5-HT6 receptors and Alzheimer's disease.","date":"2013","source":"Alzheimer's research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/23607787","citation_count":80,"is_preprint":false},{"pmid":"28931427","id":"PMC_28931427","title":"Serotonin 5-HT6 receptors affect cognition in a mouse model of Alzheimer's disease by regulating cilia function.","date":"2017","source":"Alzheimer's research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/28931427","citation_count":78,"is_preprint":false},{"pmid":"9225298","id":"PMC_9225298","title":"Functional and radioligand binding characterization of rat 5-HT6 receptors stably expressed in HEK293 cells.","date":"1997","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/9225298","citation_count":74,"is_preprint":false},{"pmid":"29848076","id":"PMC_29848076","title":"The role of 5 HT6-receptor antagonists in Alzheimer's disease: an update.","date":"2018","source":"Expert opinion on investigational drugs","url":"https://pubmed.ncbi.nlm.nih.gov/29848076","citation_count":72,"is_preprint":false},{"pmid":"27791021","id":"PMC_27791021","title":"Physical interaction between neurofibromin and serotonin 5-HT6 receptor promotes receptor constitutive activity.","date":"2016","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/27791021","citation_count":72,"is_preprint":false},{"pmid":"10836139","id":"PMC_10836139","title":"5-ht6 receptors as emerging targets for drug discovery.","date":"2000","source":"Annual review of pharmacology and toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/10836139","citation_count":70,"is_preprint":false},{"pmid":"15974573","id":"PMC_15974573","title":"A three-dimensional pharmacophore model for 5-hydroxytryptamine6 (5-HT6) receptor antagonists.","date":"2005","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15974573","citation_count":70,"is_preprint":false},{"pmid":"18622410","id":"PMC_18622410","title":"Effects of 5-HT6 receptor antagonism and cholinesterase inhibition in models of cognitive impairment in the rat.","date":"2008","source":"British journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/18622410","citation_count":68,"is_preprint":false},{"pmid":"9884085","id":"PMC_9884085","title":"Involvement of 5-HT6 receptors in nigro-striatal function in rodents.","date":"1998","source":"British journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/9884085","citation_count":67,"is_preprint":false},{"pmid":"12112397","id":"PMC_12112397","title":"5-HT6 receptor binding sites in schizophrenia and following antipsychotic drug administration: autoradiographic studies with [125I]SB-258585.","date":"2002","source":"Synapse (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/12112397","citation_count":67,"is_preprint":false},{"pmid":"21414329","id":"PMC_21414329","title":"Influence of social isolation in the rat on serotonergic function and memory--relevance to models of schizophrenia and the role of 5-HT₆ receptors.","date":"2011","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/21414329","citation_count":67,"is_preprint":false},{"pmid":"11163544","id":"PMC_11163544","title":"Lack of association between the T-->C 267 serotonin 5-HT6 receptor gene (HTR6) polymorphism and prediction of response to clozapine in schizophrenia.","date":"2001","source":"Schizophrenia research","url":"https://pubmed.ncbi.nlm.nih.gov/11163544","citation_count":65,"is_preprint":false},{"pmid":"17192775","id":"PMC_17192775","title":"Increased expression of 5-HT6 receptors in the rat dorsomedial striatum impairs instrumental learning.","date":"2006","source":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/17192775","citation_count":64,"is_preprint":false},{"pmid":"20217056","id":"PMC_20217056","title":"Antidepressant and anxiolytic effects of selective 5-HT6 receptor agonists in rats.","date":"2010","source":"Psychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/20217056","citation_count":64,"is_preprint":false},{"pmid":"26099069","id":"PMC_26099069","title":"Therapeutic Potential of 5-HT6 Receptor Agonists.","date":"2015","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26099069","citation_count":63,"is_preprint":false},{"pmid":"20166958","id":"PMC_20166958","title":"5-HT6 receptor antagonists as potential therapeutics for cognitive impairment.","date":"2010","source":"Current topics in medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20166958","citation_count":63,"is_preprint":false},{"pmid":"27100049","id":"PMC_27100049","title":"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.","date":"2016","source":"ACS chemical neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/27100049","citation_count":60,"is_preprint":false},{"pmid":"26044973","id":"PMC_26044973","title":"5-HT6 Receptor Antagonists: Potential Efficacy for the Treatment of Cognitive Impairment in Schizophrenia.","date":"2015","source":"Current pharmaceutical design","url":"https://pubmed.ncbi.nlm.nih.gov/26044973","citation_count":59,"is_preprint":false},{"pmid":"19549510","id":"PMC_19549510","title":"Dimebolin is a 5-HT6 antagonist with acute cognition enhancing activities.","date":"2009","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/19549510","citation_count":57,"is_preprint":false},{"pmid":"19589055","id":"PMC_19589055","title":"The serotonin 5-HT6 receptor: a viable drug target for treating cognitive deficits in Alzheimer's disease.","date":"2009","source":"Expert review of neurotherapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/19589055","citation_count":54,"is_preprint":false},{"pmid":"26424380","id":"PMC_26424380","title":"Distribution of serotonin receptor 5-HT6 mRNA in rat neuronal subpopulations: A double in situ hybridization study.","date":"2015","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/26424380","citation_count":53,"is_preprint":false},{"pmid":"27161524","id":"PMC_27161524","title":"DREADD Modulation of Transplanted DA Neurons Reveals a Novel Parkinsonian Dyskinesia Mechanism Mediated by the Serotonin 5-HT6 Receptor.","date":"2016","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/27161524","citation_count":52,"is_preprint":false},{"pmid":"18729016","id":"PMC_18729016","title":"5-HT6 receptor antagonists: prospects for the treatment of cognitive disorders including dementia.","date":"2008","source":"Current opinion in drug discovery & development","url":"https://pubmed.ncbi.nlm.nih.gov/18729016","citation_count":52,"is_preprint":false},{"pmid":"12813582","id":"PMC_12813582","title":"Role of 5-HT6 receptors in memory formation.","date":"2001","source":"Drug news & perspectives","url":"https://pubmed.ncbi.nlm.nih.gov/12813582","citation_count":50,"is_preprint":false},{"pmid":"18691131","id":"PMC_18691131","title":"Serotonin 5-HT6 receptor antagonists for the treatment of Alzheimer's disease.","date":"2008","source":"Current topics in medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18691131","citation_count":49,"is_preprint":false},{"pmid":"19302808","id":"PMC_19302808","title":"Procognitive 5-HT6 antagonists in the rat forced swimming test: potential therapeutic utility in mood disorders associated with Alzheimer's disease.","date":"2009","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/19302808","citation_count":48,"is_preprint":false},{"pmid":"21329783","id":"PMC_21329783","title":"5-HT6 receptor memory and amnesia: behavioral pharmacology--learning and memory processes.","date":"2011","source":"International review of neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/21329783","citation_count":47,"is_preprint":false},{"pmid":"7845473","id":"PMC_7845473","title":"5-Hydroxytryptamine receptors with a 5-HT6 receptor-like profile stimulating adenylyl cyclase activity in pig caudate membranes.","date":"1994","source":"Naunyn-Schmiedeberg's archives of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/7845473","citation_count":47,"is_preprint":false},{"pmid":"21499701","id":"PMC_21499701","title":"The 5-HT6 receptor agonist EMD 386088 produces antidepressant and anxiolytic effects in rats after intrahippocampal administration.","date":"2011","source":"Psychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/21499701","citation_count":47,"is_preprint":false},{"pmid":"23336058","id":"PMC_23336058","title":"Activation of 5-HT6 receptors modulates sleep-wake activity and hippocampal theta oscillation.","date":"2012","source":"ACS chemical neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/23336058","citation_count":46,"is_preprint":false},{"pmid":"16055331","id":"PMC_16055331","title":"2-Alkyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles as novel 5-HT6 receptor agonists.","date":"2005","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/16055331","citation_count":46,"is_preprint":false},{"pmid":"25590789","id":"PMC_25590789","title":"5-HT6 Receptor: A New Player Controlling the Development of Neural Circuits.","date":"2015","source":"ACS chemical neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/25590789","citation_count":46,"is_preprint":false},{"pmid":"24698823","id":"PMC_24698823","title":"Memory formation and memory alterations: 5-HT6 and 5-HT7 receptors, novel alternative.","date":"2014","source":"Reviews in the neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/24698823","citation_count":46,"is_preprint":false},{"pmid":"14741325","id":"PMC_14741325","title":"Risperidone response and 5-HT6 receptor gene variance: genetic association analysis with adjustment for nongenetic confounders.","date":"2004","source":"Schizophrenia research","url":"https://pubmed.ncbi.nlm.nih.gov/14741325","citation_count":46,"is_preprint":false},{"pmid":"8788511","id":"PMC_8788511","title":"Effects of altered 5-ht6 expression in the rat: functional studies using antisense oligonucleotides.","date":"1996","source":"Behavioural brain research","url":"https://pubmed.ncbi.nlm.nih.gov/8788511","citation_count":45,"is_preprint":false},{"pmid":"10624811","id":"PMC_10624811","title":"Association analysis of the 5-HT6 receptor polymorphism C267T in Alzheimer's disease.","date":"1999","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/10624811","citation_count":44,"is_preprint":false},{"pmid":"17267053","id":"PMC_17267053","title":"Memory consolidation and amnesia modify 5-HT6 receptors expression in rat brain: an autoradiographic study.","date":"2007","source":"Behavioural brain research","url":"https://pubmed.ncbi.nlm.nih.gov/17267053","citation_count":42,"is_preprint":false},{"pmid":"17631868","id":"PMC_17631868","title":"Increased expression of 5-HT6 receptors in the nucleus accumbens blocks the rewarding but not psychomotor activating properties of cocaine.","date":"2007","source":"Biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/17631868","citation_count":40,"is_preprint":false},{"pmid":"10427606","id":"PMC_10427606","title":"Effects of clozapine and haloperidol on 5-HT6 receptor mRNA levels in rat brain.","date":"1999","source":"Schizophrenia research","url":"https://pubmed.ncbi.nlm.nih.gov/10427606","citation_count":40,"is_preprint":false},{"pmid":"26548316","id":"PMC_26548316","title":"Investigational drugs targeting 5-HT6 receptors for the treatment of Alzheimer's disease.","date":"2015","source":"Expert opinion on investigational drugs","url":"https://pubmed.ncbi.nlm.nih.gov/26548316","citation_count":39,"is_preprint":false},{"pmid":"19422883","id":"PMC_19422883","title":"Role of peripheral and spinal 5-HT6 receptors according to the rat formalin test.","date":"2009","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/19422883","citation_count":38,"is_preprint":false},{"pmid":"19159187","id":"PMC_19159187","title":"Indene-based scaffolds. 2. An indole-indene switch: discovery of novel indenylsulfonamides as 5-HT6 serotonin receptor agonists.","date":"2009","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19159187","citation_count":38,"is_preprint":false},{"pmid":"21989804","id":"PMC_21989804","title":"The effects of PRX-07034, a novel 5-HT6 antagonist, on cognitive flexibility and working memory in rats.","date":"2011","source":"Psychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/21989804","citation_count":38,"is_preprint":false},{"pmid":"22367167","id":"PMC_22367167","title":"5-HT6 receptor blockade differentially affects scopolamine-induced deficits of working memory, recognition memory and aversive learning in mice.","date":"2012","source":"Psychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/22367167","citation_count":37,"is_preprint":false},{"pmid":"27326337","id":"PMC_27326337","title":"N1-Azinylsulfonyl-1H-indoles: 5-HT6 Receptor Antagonists with Procognitive and Antidepressant-Like Properties.","date":"2016","source":"ACS medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/27326337","citation_count":37,"is_preprint":false},{"pmid":"21619890","id":"PMC_21619890","title":"Activation of 5-HT6 receptors inhibits corticostriatal glutamatergic transmission.","date":"2011","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/21619890","citation_count":36,"is_preprint":false},{"pmid":"26441657","id":"PMC_26441657","title":"5-HT6 receptor agonism facilitates emotional learning.","date":"2015","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/26441657","citation_count":35,"is_preprint":false},{"pmid":"16143522","id":"PMC_16143522","title":"Bicyclic heteroarylpiperazines as selective brain penetrant 5-HT6 receptor antagonists.","date":"2005","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/16143522","citation_count":35,"is_preprint":false},{"pmid":"18511034","id":"PMC_18511034","title":"Actions of novel agonists, antagonists and antipsychotic agents at recombinant rat 5-HT6 receptors: a comparative study of coupling to G alpha s.","date":"2008","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/18511034","citation_count":35,"is_preprint":false},{"pmid":"18755168","id":"PMC_18755168","title":"Reduced sensitivity to diet-induced obesity in mice carrying a mutant 5-HT6 receptor.","date":"2008","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/18755168","citation_count":35,"is_preprint":false},{"pmid":"21866910","id":"PMC_21866910","title":"N'-(arylsulfonyl)pyrazoline-1-carboxamidines as novel, neutral 5-hydroxytryptamine 6 receptor (5-HT₆R) antagonists with unique structural features.","date":"2011","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21866910","citation_count":34,"is_preprint":false},{"pmid":"10206228","id":"PMC_10206228","title":"Association study of the 5-HT6 receptor gene in schizophrenia.","date":"1999","source":"American journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10206228","citation_count":34,"is_preprint":false},{"pmid":"26419385","id":"PMC_26419385","title":"Idalopirdine - a small molecule antagonist of 5-HT6 with therapeutic potential against obesity.","date":"2015","source":"Metabolic brain disease","url":"https://pubmed.ncbi.nlm.nih.gov/26419385","citation_count":33,"is_preprint":false},{"pmid":"25034463","id":"PMC_25034463","title":"5-HT6 Receptor Recruitment of mTOR Modulates Seizure Activity in Epilepsy.","date":"2014","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/25034463","citation_count":33,"is_preprint":false},{"pmid":"27266998","id":"PMC_27266998","title":"Design, synthesis, and pharmacological evaluation of multitarget-directed ligands with both serotonergic subtype 4 receptor (5-HT4R) partial agonist and 5-HT6R antagonist activities, as potential treatment of Alzheimer's disease.","date":"2016","source":"European journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27266998","citation_count":32,"is_preprint":false},{"pmid":"15357994","id":"PMC_15357994","title":"Possible differences in modes of agonist and antagonist binding at human 5-HT6 receptors.","date":"2004","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/15357994","citation_count":32,"is_preprint":false},{"pmid":"19443217","id":"PMC_19443217","title":"Synthesis and biological evaluation of novel gamma-carboline analogues of Dimebon as potent 5-HT6 receptor antagonists.","date":"2009","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/19443217","citation_count":32,"is_preprint":false},{"pmid":"30883547","id":"PMC_30883547","title":"Serotonin receptor HTR6-mediated mTORC1 signaling regulates dietary restriction-induced memory enhancement.","date":"2019","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/30883547","citation_count":31,"is_preprint":false},{"pmid":"24501158","id":"PMC_24501158","title":"The procognitive effects of 5-HT6 receptor ligands in animal models of schizophrenia.","date":"2014","source":"Reviews in the neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/24501158","citation_count":31,"is_preprint":false},{"pmid":"18195455","id":"PMC_18195455","title":"Study into a possible mechanism responsible for the antidepressant-like activity of the selective 5-HT6 receptor antagonist SB-399885 in rats.","date":"2007","source":"Pharmacological reports : PR","url":"https://pubmed.ncbi.nlm.nih.gov/18195455","citation_count":31,"is_preprint":false},{"pmid":"15482912","id":"PMC_15482912","title":"1-(2-Aminoethyl)-3-(arylsulfonyl)-1H-indoles as novel 5-HT6 receptor ligands.","date":"2004","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/15482912","citation_count":31,"is_preprint":false},{"pmid":"18596685","id":"PMC_18596685","title":"Selective 5-HT6 receptor blockade improves spatial recognition memory and reverses age-related deficits in spatial recognition memory in the mouse.","date":"2008","source":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/18596685","citation_count":31,"is_preprint":false},{"pmid":"9928244","id":"PMC_9928244","title":"The putative 5-ht6 receptor: localization and function.","date":"1998","source":"Annals of the New York Academy of Sciences","url":"https://pubmed.ncbi.nlm.nih.gov/9928244","citation_count":30,"is_preprint":false},{"pmid":"20166945","id":"PMC_20166945","title":"The medicinal chemistry of 5-HT6 receptor ligands with a focus on arylsulfonyltryptamine analogs.","date":"2010","source":"Current topics in medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20166945","citation_count":29,"is_preprint":false},{"pmid":"18053713","id":"PMC_18053713","title":"Discovery of 3-aryl-3-methyl-1H-quinoline-2,4-diones as a new class of selective 5-HT6 receptor antagonists.","date":"2007","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/18053713","citation_count":29,"is_preprint":false},{"pmid":"21443908","id":"PMC_21443908","title":"Serotonin 5-HT6 receptor blockade reverses the age-related deficits of recognition memory and working memory in mice.","date":"2011","source":"Behavioural brain research","url":"https://pubmed.ncbi.nlm.nih.gov/21443908","citation_count":29,"is_preprint":false},{"pmid":"25795301","id":"PMC_25795301","title":"SNX14 is a bifunctional negative regulator for neuronal 5-HT6 receptor signaling.","date":"2015","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/25795301","citation_count":28,"is_preprint":false},{"pmid":"33372037","id":"PMC_33372037","title":"HTR6 and SSTR3 ciliary targeting relies on both IC3 loops and C-terminal tails.","date":"2020","source":"Life science alliance","url":"https://pubmed.ncbi.nlm.nih.gov/33372037","citation_count":27,"is_preprint":false},{"pmid":"23157629","id":"PMC_23157629","title":"Serotonin receptors of type 6 (5-HT6): from neuroscience to clinical pharmacology.","date":"2013","source":"Current medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23157629","citation_count":27,"is_preprint":false},{"pmid":"25557493","id":"PMC_25557493","title":"Novel 5-HT6 receptor antagonists/D2 receptor partial agonists targeting behavioral and psychological symptoms of dementia.","date":"2014","source":"European journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25557493","citation_count":27,"is_preprint":false},{"pmid":"26886442","id":"PMC_26886442","title":"AVN-211, Novel and Highly Selective 5-HT6 Receptor Small Molecule Antagonist, for the Treatment of Alzheimer's Disease.","date":"2016","source":"Molecular pharmaceutics","url":"https://pubmed.ncbi.nlm.nih.gov/26886442","citation_count":27,"is_preprint":false},{"pmid":"12523486","id":"PMC_12523486","title":"In the search for selective ligands of 5-HT5, 5-HT6 and 5-HT7 serotonin receptors.","date":"2002","source":"Polish journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/12523486","citation_count":27,"is_preprint":false},{"pmid":"33960602","id":"PMC_33960602","title":"5-HT6R null mutatrion induces synaptic and cognitive defects.","date":"2021","source":"Aging cell","url":"https://pubmed.ncbi.nlm.nih.gov/33960602","citation_count":26,"is_preprint":false},{"pmid":"15050637","id":"PMC_15050637","title":"1,2,3,4-tetrahydrocarbazoles as 5-HT6 serotonin receptor ligands.","date":"2004","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/15050637","citation_count":26,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":46720,"output_tokens":5996,"usd":0.11505},"stage2":{"model":"claude-opus-4-6","input_tokens":9599,"output_tokens":3697,"usd":0.21063},"total_usd":0.32568,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1993,\n      \"finding\": \"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.\",\n      \"method\": \"Transient transfection in COS-7 cells with cAMP measurement\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — functional reconstitution in heterologous expression system; foundational paper replicated by multiple subsequent studies\",\n      \"pmids\": [\"8389146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"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.\",\n      \"method\": \"Heterologous expression, cAMP assay, radioligand binding, chromosomal mapping\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — functional reconstitution with pharmacological characterization; replicated across labs\",\n      \"pmids\": [\"8522988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"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.\",\n      \"method\": \"Immunohistochemistry and electron microscopy with affinity-purified antibodies against the C-terminal domain\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization by IHC/EM with functional context; antibody specificity validated\",\n      \"pmids\": [\"9037500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"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.\",\n      \"method\": \"Stable expression in HEK293 cells, radioligand binding ([3H]-LSD, [3H]-5-HT), cAMP accumulation assay\",\n      \"journal\": \"Neuropharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted functional assay with multiple agonists/antagonists in stable cell line\",\n      \"pmids\": [\"9225298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"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.\",\n      \"method\": \"Antisense oligonucleotide knockdown in vivo, radioligand binding, behavioral pharmacology with muscarinic and dopaminergic antagonists\",\n      \"journal\": \"The Journal of pharmacology and experimental therapeutics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic (antisense) loss-of-function with pharmacological rescue; replicated by independent labs\",\n      \"pmids\": [\"7616396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"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.\",\n      \"method\": \"Phosphorothioate antisense oligonucleotides, radioligand binding, behavioral observation\",\n      \"journal\": \"Behavioural brain research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — independent replication of antisense knockdown approach with specific receptor binding controls\",\n      \"pmids\": [\"8788511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"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.\",\n      \"method\": \"In vivo pharmacology with selective 5-HT6 antagonist in 6-OHDA lesion model; behavioral readout of cholinergic vs dopaminergic manipulation\",\n      \"journal\": \"British journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean pharmacological epistasis in vivo; single lab but internally consistent\",\n      \"pmids\": [\"9884085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"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.\",\n      \"method\": \"Site-directed mutagenesis of third cytoplasmic loop, cAMP-responsive reporter gene assay in transiently transfected cells\",\n      \"journal\": \"Brain research. Molecular brain research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structure-function mutagenesis with functional cAMP readout\",\n      \"pmids\": [\"11406289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid, GST pulldown, co-immunoprecipitation, immunocytochemistry/immunohistochemistry, ERK1/2 phosphorylation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal biochemical methods (Y2H + GST pulldown + reciprocal Co-IP) plus functional downstream signaling assay\",\n      \"pmids\": [\"17189269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"In vivo microdialysis in multiple brain regions, pharmacological blockade with GABA-A antagonist bicuculline, ex vivo hippocampal slice glutamate release assay\",\n      \"journal\": \"Neuropsychopharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo microdialysis with pharmacological dissection in multiple brain regions, replicated across brain areas\",\n      \"pmids\": [\"17625499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Pharmacological manipulation with selective agonist/antagonist, Western blotting for phosphoproteins in brain slices and in vivo, in situ hybridization for c-fos\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple phosphoprotein targets validated in both ex vivo and in vivo preparations with selective pharmacological tools\",\n      \"pmids\": [\"17428998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Whole-cell patch-clamp electrophysiology in striatal and cortical neurons, paired-pulse analysis, miniature EPSC recordings, pharmacological validation\",\n      \"journal\": \"Neuropharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct electrophysiological recordings with receptor-specific pharmacological controls and multiple analytical approaches\",\n      \"pmids\": [\"21619890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Proteomic co-purification, co-immunoprecipitation, site-directed mutagenesis (S350A), siRNA knockdown, neurite outgrowth assay, inverse agonist pharmacology\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution with mutagenesis, proteomic identification of partner, validated in primary neurons with multiple orthogonal approaches\",\n      \"pmids\": [\"24880860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, internalization assay, cAMP measurement, PKA phosphorylation assay, GTPase activity assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Co-IP, KD, functional cAMP, trafficking assay) in single study; mechanistically detailed\",\n      \"pmids\": [\"25795301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, PH domain expression rescue, CREB phosphorylation in Nf1+/- mice, in vivo inverse agonist treatment\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple biochemical and genetic approaches including mouse model; mechanistically linked constitutive activity to specific protein-protein interaction domain\",\n      \"pmids\": [\"27791021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Chemogenetic (DREADD) approach in transplanted DA neurons in 6-OHDA rat PD model, behavioral dyskinesia scoring\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — elegant DREADD epistasis in vivo; single study but clean genetic/pharmacological design\",\n      \"pmids\": [\"27161524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Double in situ hybridization with multiple neuronal and interneuronal markers across brain regions\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — systematic double-ISH mapping with multiple cell-type markers; defines cellular substrate for 5-HT6R function\",\n      \"pmids\": [\"26424380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Immunostaining of primary cilia, 5-HT6 overexpression/knockdown in primary hippocampal neurons, Morris water maze, Y-maze, fear conditioning in APP/PS1 mice\",\n      \"journal\": \"Alzheimer's research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct imaging of ciliary localization with loss/gain-of-function in primary neurons plus in vivo cognitive rescue; single lab\",\n      \"pmids\": [\"28931427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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).\",\n      \"method\": \"HTR6 knockout/knockdown, LTP electrophysiology, dendritic morphology imaging, mTORC1 pathway analysis in hippocampal neurons\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function with multiple cellular readouts (LTP, morphology, signaling); single lab but orthogonal methods\",\n      \"pmids\": [\"30883547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Mutagenesis of IC3 and CT regions, chimeric receptor constructs, live-cell imaging of ciliary localization, interaction studies with TULP3 and RABL2\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — systematic mutagenesis with functional ciliary targeting readout and identification of trafficking adapter interactions\",\n      \"pmids\": [\"33372037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"5-HT6R knockout mouse model, behavioral testing, immunofluorescence for neuronal morphology, electrophysiology for neuronal excitability, Shh pathway analysis\",\n      \"journal\": \"Aging cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout with multiple orthogonal cellular phenotypic readouts; single lab\",\n      \"pmids\": [\"33960602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"5-HT6R loss-of-function mutant mice, high-fat diet feeding paradigm, body weight and composition analysis\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function with clear metabolic phenotype; single lab\",\n      \"pmids\": [\"18755168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Viral-mediated gene transfer for region-specific 5-HT6R overexpression, behavioral testing (instrumental learning vs. Morris water maze), pharmacological rescue\",\n      \"journal\": \"Neuropsychopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — targeted gain-of-function with pharmacological rescue and appropriate controls; single lab\",\n      \"pmids\": [\"17192775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Viral-mediated gene transfer for NAc-specific 5-HT6R overexpression, conditioned place preference, locomotor sensitization, selective 5-HT6 antagonist pharmacology\",\n      \"journal\": \"Biological psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — region-specific gain-of-function and pharmacological loss-of-function with dissociable behavioral outcomes; single lab\",\n      \"pmids\": [\"17631868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Scintillation Proximity Assay (SPA)/antibody-immunocapture of [35S]GTPγS binding to specific Gα subunits in HEK293 stable expression system\",\n      \"journal\": \"European journal of pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct G-protein selectivity assay with broad panel of ligands in defined recombinant system\",\n      \"pmids\": [\"18511034\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HTR6 (5-HT6R) is a Gs-coupled GPCR that constitutively and agonist-dependently activates adenylyl cyclase/cAMP signaling; it is localized almost exclusively in the CNS (on dendrites and primary cilia of striatal, cortical, and hippocampal neurons) where it tonically suppresses cholinergic neurotransmission, modulates GABAergic and glutamatergic transmission, and engages developmental signaling through constitutive interactions with Cdk5 (phosphorylating Ser350 to drive neurite outgrowth via Cdc42) and neurofibromin (whose PH domain is required for constitutive Gs signaling); its signaling is further regulated by Fyn kinase (binding the C-terminal tail via SH3 domain to activate ERK1/2) and SNX14 (a dual negative regulator that sequesters Gαs and promotes receptor degradation), while ciliary targeting requires redundant sequences in both IC3 and the C-terminal tail acting through TULP3 and RABL2 adaptors.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"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].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"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.\",\n      \"evidence\": \"Transient transfection in COS-7 and HEK293 cells with cAMP measurement and radioligand binding; replicated with human ortholog and pharmacological profiling\",\n      \"pmids\": [\"8389146\", \"8522988\", \"9225298\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Exclusive Gαs coupling was not formally demonstrated until 2008\", \"No structural basis for G-protein selectivity\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"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.\",\n      \"evidence\": \"Intracerebroventricular antisense oligonucleotides in rats with behavioral pharmacology (atropine rescue) and radioligand binding\",\n      \"pmids\": [\"7616396\", \"8788511\", \"9884085\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which HTR6 on non-cholinergic neurons suppresses ACh release was not identified\", \"Direct measurement of acetylcholine levels was not performed\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Immunohistochemistry and electron microscopy localized HTR6 protein to dendritic processes in striatum and hippocampus, defining its subcellular distribution for the first time.\",\n      \"evidence\": \"Affinity-purified C-terminal antibodies with IHC and EM in rat brain\",\n      \"pmids\": [\"9037500\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ciliary localization was not recognized until later studies\", \"Distribution across cortical layers and interneuron subtypes was not assessed\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"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.\",\n      \"evidence\": \"Site-directed mutagenesis with cAMP-responsive reporter in JEG-3 and COS-7 cells\",\n      \"pmids\": [\"11406289\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether constitutive activity occurs at endogenous expression levels in neurons was not shown\", \"Structural basis of constitutive activity beyond the BBXXB motif was unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"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.\",\n      \"evidence\": \"Yeast two-hybrid, GST pulldown, reciprocal co-immunoprecipitation in cell lines and rat brain, ERK1/2 phosphorylation assay\",\n      \"pmids\": [\"17189269\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological consequences of Fyn-dependent ERK signaling in neurons were not determined\", \"Whether Fyn engagement is constitutive or agonist-dependent was not resolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vivo microdialysis in multiple brain regions, patch-clamp electrophysiology in striatal MSNs and cortical pyramidal neurons, selective pharmacological tools\",\n      \"pmids\": [\"17625499\", \"21619890\", \"17428998\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct versus indirect mechanisms of GABAergic modulation were not fully resolved\", \"Cell-type specificity of electrophysiological effects was not mapped onto HTR6-expressing subtypes\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Region-specific viral overexpression demonstrated that striatal HTR6 impairs instrumental learning while nucleus accumbens HTR6 selectively blocks cocaine reward, establishing circuit-level functional specificity.\",\n      \"evidence\": \"Viral gene transfer for regional overexpression, instrumental learning, conditioned place preference, pharmacological rescue with 5-HT6 antagonist\",\n      \"pmids\": [\"17192775\", \"17631868\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream signaling pathways mediating region-specific behavioral effects were not identified\", \"Results are from gain-of-function; knockout confirmation in each region was lacking\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"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.\",\n      \"evidence\": \"Scintillation proximity assay with Gα-specific antibodies in HEK293 stable expression system with broad ligand panel\",\n      \"pmids\": [\"18511034\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Non-G-protein signaling (e.g., β-arrestin) was not assessed\", \"Whether exclusive Gαs coupling holds in native neuronal membranes was not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"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.\",\n      \"evidence\": \"Proteomic co-purification, co-immunoprecipitation, S350A mutagenesis, siRNA knockdown, neurite outgrowth assay in NG108-15 and primary neurons\",\n      \"pmids\": [\"24880860\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-immunoprecipitation, siRNA knockdown, internalization assay, cAMP measurement, PKA phosphorylation and GTPase activity assays\",\n      \"pmids\": [\"25795301\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"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.\",\n      \"evidence\": \"Double in situ hybridization with multiple neuronal and interneuronal markers across brain regions\",\n      \"pmids\": [\"26424380\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Protein-level confirmation of cell-type expression was not provided\", \"Expression in non-neuronal cells (e.g., glia) was not systematically examined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-immunoprecipitation, siRNA knockdown, PH domain rescue, CREB phosphorylation in Nf1+/- mice, inverse agonist treatment in vivo\",\n      \"pmids\": [\"27791021\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether neurofibromin modulates agonist-stimulated versus only constitutive signaling was not dissected\", \"Structural basis of the HTR6–NF1 PH domain interaction was not determined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"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.\",\n      \"evidence\": \"Immunostaining for ciliary markers, overexpression/knockdown in primary hippocampal neurons, behavioral rescue in APP/PS1 mice\",\n      \"pmids\": [\"28931427\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether signaling outputs differ between ciliary and non-ciliary pools of HTR6 was unknown\", \"Mechanism linking ciliary HTR6 to AIS morphology was not identified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"IC3/CT mutagenesis, chimeric receptor constructs, live-cell ciliary imaging, interaction studies with TULP3 and RABL2\",\n      \"pmids\": [\"33372037\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"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.\",\n      \"evidence\": \"Constitutive knockout mouse, behavioral testing, immunofluorescence, electrophysiology, Shh pathway analysis\",\n      \"pmids\": [\"33960602\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether cognitive phenotypes are developmental or reflect ongoing signaling loss was not dissected\", \"Cell-type-specific contributions to the knockout phenotype were not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 3, 7, 24]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [17, 19, 20]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 7, 8, 10, 14, 24]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [4, 9, 11, 16]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [12, 20]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"FYN\",\n      \"CDK5\",\n      \"SNX14\",\n      \"NF1\",\n      \"TULP3\",\n      \"RABL2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}