Affinage

HTR7

5-hydroxytryptamine receptor 7 · UniProt P34969

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

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HTR7 (5-HT7) is a serotonin-activated G-protein-coupled receptor that couples to Gs to stimulate adenylyl cyclase and cAMP production, governing neuronal plasticity, thermoregulation, circadian and sleep physiology, gut motility, immune polarization, nociception, and itch (PMID:9303561, PMID:9298538, PMID:12529502). The receptor exists as multiple C-terminal splice variants (h5-HT7a/b/d) that are all positively coupled to adenylyl cyclase, and it displays constitutive (agonist-independent) cAMP activity revealed by inverse agonists such as methiothepin (PMID:9303561, PMID:11906971). Beyond classical Gs/cAMP signaling, 5-HT7R couples to Gα12 to activate Rho-family GTPases, providing a parallel cytoskeletal signaling arm (PMID:25324743). Through these branches the receptor drives neurite/axonal elongation, dendritic spine formation, and synaptogenesis via downstream effectors including mTOR, CDK5, Cdc42, ERK, and the actin regulator cofilin (PMID:28122114, PMID:25814944). The cAMP signal bifurcates functionally: a PKA branch that constrains spinal phrenic motor plasticity and an EPAC→mTORC1 branch that drives phrenic motor facilitation, the latter also requiring new TrkB synthesis and PI3K/AKT signaling (PMID:21242254, PMID:23850591, PMID:26269554). 5-HT7R activity upregulates TrkB expression and phosphorylation (PMID:25426041), and its constitutive, G-protein-independent activity drives CDK5-dependent Tau hyperphosphorylation, neurotoxicity, and memory impairment (PMID:32841723). The receptor forms homodimers (highest affinity) and 5-HT1A/5-HT7 heterodimers that suppress 5-HT1A-Gi signaling and GIRK currents while enhancing MAPK activation (PMID:22357950). In the periphery and immune system it promotes M2 anti-inflammatory macrophage polarization, protects against intestinal inflammation via CD11c+ myeloid cells, and triggers serotonergic itch by opening TRPA1 (PMID:23355731, PMID:25072499, PMID:26074006). Receptor output is negatively modulated by direct binding of S100B, which dampens cAMP accumulation, and its expression is post-transcriptionally suppressed by miR-29a via 3'UTR binding (PMID:26499172, PMID:31292861).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1994 High

    Established that 5-HT7 receptor signaling functionally modulates neuronal currents through the cAMP/PKA cascade, defining its core transduction mechanism in native neurons.

    Evidence Whole-cell voltage-clamp in rat SCN neurons with selective agonists/antagonists, forskolin, cAMP analogs, and PKA inhibitor

    PMID:7965836

    Open questions at the time
    • Did not identify the receptor isoform or Gs subunit directly
    • Restricted to GABAA current modulation in one nucleus
  2. 1997 High

    Demonstrated that the receptor is encoded as multiple C-terminal splice variants all positively coupled to adenylyl cyclase, establishing Gs coupling at the molecular level and broad tissue expression.

    Evidence Molecular cloning and heterologous expression (NIH-3T3, HEK293) with radioligand binding and cAMP functional assays plus tissue mRNA analysis

    PMID:9298538 PMID:9303561

    Open questions at the time
    • Functional differences between splice variants not resolved
    • No structural information on the receptor
  3. 1997 High

    Identified 5-HT7 as the principal mediator of serotonergic suppression of SCN photic responses, linking receptor function to circadian physiology.

    Evidence Single-unit electrophysiology in hamster SCN slices with selective 5-HT7 vs 5-HT1A antagonists

    PMID:9175892

    Open questions at the time
    • Downstream signaling to clock machinery not defined
  4. 2002 High

    Revealed that the receptor possesses constitutive (agonist-independent) adenylyl cyclase activity, expanding its mechanism to ligand-independent signaling demonstrable by inverse agonism.

    Evidence Adenylyl cyclase and inverse agonism profiling in transfected HEK293 membranes across all three splice variants

    PMID:11906971

    Open questions at the time
    • Physiological consequences of constitutive activity not yet shown in this study
  5. 2003 High

    Used genetic knockout to assign 5-HT-induced hypothermia and intestinal peristalsis inhibition to 5-HT7, establishing in vivo physiological roles and an allosteric lipid modulator (oleamide).

    Evidence 5-HT7 knockout mice with thermoregulatory challenge; guinea-pig ileum peristalsis organ-bath assays with SB-269970

    PMID:12529502 PMID:12711620

    Open questions at the time
    • Signaling pathway linking receptor to thermoregulation/motility not defined
    • Oleamide mechanism remains independent of receptor
  6. 2004 High

    Dissected the dose-dependent contributions of 5-HT7 versus 5-HT1A to hypothermia, showing 5-HT7 dominates at physiologically relevant agonist concentrations.

    Evidence Combined knockout and selective antagonist dose-response thermoregulation in mice

    PMID:15033384

    Open questions at the time
    • Receptor circuitry mediating temperature drop not mapped
  7. 2005 High

    Connected 5-HT7 to antidepressant-like behavior, REM sleep regulation, spinal nociceptive anatomy, and enteric peristalsis, broadening its behavioral and peripheral physiology.

    Evidence Knockout/antagonist behavioral and sleep EEG studies; spinal cord immunoEM localization; ileal peristalsis with confocal localization

    PMID:16018977 PMID:16082681 PMID:16285955

    Open questions at the time
    • Molecular signaling underlying behavioral phenotypes not established
    • Spinal localization study lacked functional validation in same work
  8. 2008 High

    Correlated 5-HT7 Gs/cAMP intrinsic efficacy with antinociception, directly tying the receptor's signaling output to a behavioral pain outcome.

    Evidence Parallel in vitro cAMP assays in HEK-293F (human receptor) and in vivo capsaicin hypersensitivity with selective agonists/antagonists

    PMID:19118950

    Open questions at the time
    • Site of antinociceptive action (central vs peripheral) not fully resolved
  9. 2009 High

    Linked 5-HT7 to hippocampus-dependent spatial memory and to plastic neuronal remodeling, while excluding adult neurogenesis as the mechanism.

    Evidence Knockout/antagonist behavioral paradigms with BrdU; adolescent rat methylphenidate study with striatal neurite assays

    PMID:19243449 PMID:19447277

    Open questions at the time
    • Molecular signaling for memory role not defined
    • Methylphenidate-receptor link is correlative in vivo
  10. 2011 High

    Defined opposing spinal cAMP branches and synaptic circuit actions, showing 5-HT7-driven phrenic motor facilitation requires TrkB/PI3K and that it modulates hippocampal inhibitory transmission.

    Evidence Intrathecal pharmacology with TrkB siRNA/k252a/PI3K inhibitors and phrenic electrophysiology; whole-cell patch-clamp in rat hippocampal slices

    PMID:21242254 PMID:22204801

    Open questions at the time
    • Source of new TrkB independent of BDNF unexplained
    • Presynaptic vs postsynaptic receptor populations not genetically resolved
  11. 2012 High

    Established that 5-HT7 forms homodimers and 5-HT1A/5-HT7 heterodimers that reshape signaling, suppressing 5-HT1A-Gi/GIRK output while enhancing MAPK.

    Evidence FRET dimerization affinity, Gi functional/GIRK recordings, internalization and MAPK assays in heterologous cells and hippocampal neurons

    PMID:22357950

    Open questions at the time
    • Structural basis of dimer interface unknown
    • In vivo behavioral consequences of heterodimerization not tested here
  12. 2013 Medium

    Extended 5-HT7 function to immune and hepatic biology, mediating M2 macrophage polarization and cAMP/PKA-CREB/AKT-driven IGF-1 secretion in hepatocytes.

    Evidence Human macrophage polarization with selective antagonists; isolated rat hepatocyte biochemistry with antagonist reversal

    PMID:23355731 PMID:23578138

    Open questions at the time
    • Receptor-proximal signaling in macrophages not detailed
    • Single-lab studies without genetic confirmation
  13. 2014 Medium

    Identified a second signaling arm (Gα12/Rho), an S100B negative regulator, and TrkB upregulation, diversifying the receptor's effector landscape beyond cAMP.

    Evidence Review synthesis of G12/Rho coupling; Co-IP and cAMP assays for S100B in HeLa and astrocytes with transgenic mice; Western blots of TrkB/phospho-TrkB across cell lines with Gs/G12 inhibitors

    PMID:25324743 PMID:25426041 PMID:26499172

    Open questions at the time
    • G12/Rho coupling cited from review, primary methods not detailed
    • S100B interaction structure unknown
    • TrkB phosphorylation mechanism not fully mapped
  14. 2015 High

    Mechanistically resolved 5-HT7-driven structural plasticity (spinogenesis, neurite/axon elongation) through CDK5/Cdc42/mTOR/ERK and cofilin, and separated the spinal cAMP signal into PKA-constraining and EPAC-mTORC1-facilitating branches; also established cerebellar plasticity, itch via TRPA1, and intestinal anti-inflammatory roles.

    Evidence Knockout/agonist neuron cultures with effector inhibitors and microfluidic axon assays; intrathecal EPAC/PKA/mTORC1 pharmacology and phrenic electrophysiology; cerebellar slice electrophysiology; HTR7/TRPA1 double knockout itch models; DSS colitis with bone marrow chimera

    PMID:25072499 PMID:25814944 PMID:26074006 PMID:26269554 PMID:26482421 PMID:28122114

    Open questions at the time
    • How cAMP selectively routes to PKA vs EPAC not defined
    • Direct receptor-TRPA1 coupling mechanism unresolved
  15. 2019 High

    Established miR-29a as a post-transcriptional brake on receptor expression that limits 5-HT7-dependent neurite remodeling via ERK during hippocampal development.

    Evidence Luciferase 3'UTR reporter, miR-29a overexpression with neurite morphometry and ERK inhibition, in vivo developmental expression profiling

    PMID:31292861

    Open questions at the time
    • Upstream regulators of miR-29a not identified
  16. 2020 High

    Demonstrated that constitutive, G-protein-independent 5-HT7 activity physically engages CDK5 to drive Tau hyperphosphorylation and neurotoxicity, and confirmed conserved cAMP-dependent learning function via the Drosophila ortholog.

    Evidence Co-IP, Tau[R406W] mouse model, constitutive-activity blockade, prefrontal shRNA knockdown with LTP and memory tests; Drosophila d5-HT7 null and MB-specific rescue olfactory conditioning

    PMID:32841723 PMID:33277559

    Open questions at the time
    • Structural basis of G-protein-independent CDK5 coupling unknown
    • Relevance to human tauopathy not directly tested
  17. 2022 High

    Linked 5-HT7 activation in hippocampal CA1 to depressive-like behavior through an MMP-9-dependent pathway, with corroborating elevated MMP-9 in human depressed hippocampus.

    Evidence LP-211 agonist with MMP-9 inhibitor, behavioral tests, dendritic spine imaging, chronic stress model, and human post-mortem MMP-9 activity assays

    PMID:35294881

    Open questions at the time
    • Signaling steps connecting receptor to MMP-9 induction not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the receptor's cAMP output is selectively partitioned between PKA and EPAC branches, and the structural determinants of its G-protein-independent CDK5 coupling and dimerization, remain unresolved.
  • No structural model of the receptor or its dimer/effector interfaces
  • Mechanism of branch selection between PKA and EPAC unknown
  • No direct disease-causing mutation established in the corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0009975 cyclase activity 4 GO:0060089 molecular transducer activity 4 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-112316 Neuronal System 4 R-HSA-168256 Immune System 2
Partners
CDK5HTR1AS100BTRKBTRPA1
Complex memberships
5-HT1A/5-HT7 heterodimer5-HT7 homodimer

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 5-HT7 receptor activation in rat suprachiasmatic nucleus neurons inhibits GABA-activated current (IGABA) via a cAMP-coupled signaling mechanism; the effect was blocked by ritanserin (a 5-HT7 antagonist) but not by pindolol (5-HT1A/B antagonist), and was mimicked by forskolin and 8-bromo-cAMP, with H-8 (PKA inhibitor) reducing the 5-HT effect, indicating 5-HT7 receptor couples to cAMP/PKA to modulate GABAA receptor currents. Whole-cell voltage-clamp recordings in rat SCN neurons with selective agonists, antagonists, and PKA inhibitors The Journal of physiology High 7965836
1997 5-HT7 receptors mediate serotonin's suppression of light-evoked (photic) responses in hamster suprachiasmatic nucleus neurons; effects of 5-HT, 8-OH-DPAT, and 5-CT were blocked by 5-HT7-active antagonists (ritanserin, clozapine) but not by selective 5-HT1A antagonists (WAY100635, p-MPPI) or the 5-HT1A/B/D antagonist cyanopindolol, establishing the 5-HT7 subtype as the principal mediator of serotonergic modulation of SCN photic responses. Single-unit electrophysiology in hamster SCN slices with pharmacological dissection using selective 5-HT7 and 5-HT1A antagonists; regional specificity confirmed in hippocampus and cerebellum controls Brain research High 9175892
1997 Two human 5-HT7 splice variants (h5-HT7a and h5-HT7b), differing in their intracellular C-terminal tail length, are both functionally expressed and positively coupled to adenylyl cyclase in NIH-3T3 cells; both variants are expressed in roughly equal amounts in various human brain regions. Molecular cloning, expression in NIH-3T3 cells, cAMP functional assay, Southern blot, and brain region mRNA analysis FEBS letters High 9303561
1997 A truncated human 5-HT7 splice variant (h5-HT7b) was cloned, stably expressed in HEK293 cells, and shown to exhibit the same pharmacological profile and positive coupling to adenylyl cyclase as the long form (h5-HT7a); the receptor mRNA is found in brain, small intestine, and aorta. cDNA library cloning, stable HEK293 expression, radioligand binding ([3H]-5-CT), cAMP stimulation assay, RT-PCR British journal of pharmacology High 9298538
2002 All three human 5-HT7 splice variants (h5-HT7a, h5-HT7b, h5-HT7d) display constitutive adenylyl cyclase activation; certain antagonists (e.g., methiothepin) act as inverse agonists by reducing basal cAMP, an effect blocked by the neutral antagonist mesulergine, demonstrating receptor-level constitutive activity independent of agonist stimulation. Stably and transiently transfected HEK293 cell membranes, adenylyl cyclase assay, inverse agonism profiling with 8 antagonists British journal of pharmacology High 11906971
2003 5-HT-induced hypothermia is mediated by the 5-HT7 receptor: both 5-HT and 5-CT failed to induce hypothermia in 5-HT7 knockout mice at physiological doses. Oleamide, a lipid that allosterically interacts with 5-HT7, induced hypothermia equally in knockout and wild-type mice, indicating an independent/additional mechanism, and showed additive or greater-than-additive effects with 5-HT. 5-HT7 receptor knockout mice, body temperature measurement, pharmacological challenge with 5-HT, 5-CT, and oleamide Proceedings of the National Academy of Sciences of the United States of America High 12529502
2004 Both 5-HT7 and 5-HT1A receptors contribute to 8-OH-DPAT-induced hypothermia; at lower doses, hypothermia in wild-type mice is fully blocked by the selective 5-HT7 antagonist SB-269970 and is absent in 5-HT7 knockout mice, demonstrating that 5-HT7 is the dominant receptor at physiologically relevant concentrations while 5-HT1A mediates effects at higher doses. 5-HT7 knockout and wild-type mice, selective antagonists (SB-269970, WAY-100135), body temperature measurement across dose ranges European journal of pharmacology High 15033384
2005 5-HT7 receptor knockout mice display antidepressant-like behavior (decreased immobility in forced swim and tail suspension tests) and reduced REM sleep, mirroring effects of the selective 5-HT7 antagonist SB-269970; citalopram (SSRI) decreased immobility in both 5-HT7+/+ and 5-HT7−/− mice, indicating it utilizes an independent mechanism. 5-HT7 knockout mice, forced swim test, tail suspension test, sleep EEG recording, selective antagonist SB-269970, SSRI citalopram Biological psychiatry High 16018977
2005 5-HT7 receptors are localized presynaptically (on peptidergic primary afferent terminals and intrinsic axons, ~60% of labeling in lamina I) and postsynaptically (on peptidergic cell bodies and dendrites) in the rat dorsal spinal cord, and also in astrocytes (~17–20%), providing morphological basis for 5-HT7 involvement in nociceptive processing. Immunocytochemistry and electron microscopy on rat lumbar spinal cord The Journal of comparative neurology Medium 16082681
2005 5-HT7 receptors mediate inhibition of peristalsis in the guinea-pig ileum: the selective antagonist SB-269970-A concentration-dependently antagonized the 5-HT- or 5-CT-induced increase in the threshold required to trigger peristalsis and could restore blocked peristalsis. Isolated guinea-pig ileum peristalsis assay, selective 5-HT7 antagonist SB-269970-A and methiothepin, 5-HT2/3/4 receptor blockade as background British journal of pharmacology Medium 12711620
2005 5-HT7 receptors expressed on myenteric neurons (including descending/inhibitory neurons containing nNOS/VIP and after-hyperpolarizing neurons) modulate circular muscle accommodation during peristalsis in the guinea-pig ileum; SB-269970 increased threshold pressure and reduced accommodation. Immunohistochemistry, confocal microscopy, isolated ileal peristalsis assay with SB-269970 Gastroenterology Medium 16285955
2008 5-HT7 receptor agonists (AS-19, E-55888) dose-dependently reduced capsaicin-induced mechanical hypersensitivity in mice; the effect was blocked by 5-HT7 antagonists but not by 5-HT1A antagonist WAY-100635. The order of antinociceptive efficacy matched their in vitro efficacy to stimulate cAMP in HEK-293F cells expressing the human 5-HT7 receptor, establishing a direct correlation between 5-HT7 Gs/cAMP intrinsic efficacy and antinociception. In vitro cAMP assay in HEK-293F cells (human 5-HT7 receptor), radioligand binding, in vivo capsaicin mechanical hypersensitivity model with selective agonists and antagonists Pain High 19118950
2009 5-HT7 receptor-deficient mice show selective impairment in allocentric (hippocampus-dependent) spatial memory but intact egocentric (striatum-dependent) memory; identical hippocampal neurogenesis (BrdU) in knockout and wild-type mice indicates the spatial memory role is independent of adult neurogenesis. 5-HT7 knockout mice, novel location/object test, Barnes maze, BrdU immunohistochemistry; pharmacological confirmation with SB-269970 in C57BL/6J mice Behavioural brain research High 19447277
2011 Spinal 5-HT7 receptor activation by intrathecal AS-19 elicits long-lasting phrenic motor facilitation (PMF >120 min) via a signaling pathway requiring new TrkB synthesis and activity (blocked by k252a and TrkB siRNA) and downstream PI3K/AKT activation, but not BDNF synthesis — a mechanism distinct from 5-HT2 receptor-dependent PMF. Intrathecal agonist/antagonist injections in anesthetized rats, TrkB siRNA, k252a (TrkB inhibitor), PI3K and MEK pathway inhibitors, phrenic nerve electrophysiology The Journal of physiology High 21242254
2011 5-HT7 receptor activation in the hippocampal CA1 area increases the frequency (but not amplitude) of spontaneous IPSCs in pyramidal neurons by two mechanisms: (1) enhancement of excitatory glutamatergic input to GABAergic interneurons (likely via presynaptic 5-HT7 receptors, partially TTX- and kynurenic acid-sensitive) and (2) direct excitation of interneurons increasing GABA release (TTX-resistant component). Whole-cell patch-clamp recordings in rat hippocampal slices, 5-CT + WAY-100635 (to isolate 5-HT7), TTX, kynurenic acid, selective 5-HT7 antagonist Journal of physiology and pharmacology High 22204801
2012 5-HT1A and 5-HT7 receptors form heterodimers (and respective homodimers) both in vitro and in vivo; 5-HT7-5-HT7 homodimers have the highest affinity for complex formation, followed by 5-HT7-5-HT1A heterodimers, then 5-HT1A-5-HT1A homodimers. Heterodimerization decreases 5-HT1A-mediated Gi protein activation and GIRK channel activity without affecting 5-HT7 signaling, promotes 5-HT1A receptor internalization, enhances 5-HT1A-mediated MAPK activation, and is physiologically relevant in hippocampal neurons. FRET-based assays (homo/heterodimer affinity), Gi functional assay, GIRK channel recordings in heterologous system and hippocampal neurons, internalization assay, MAPK assay; 5-HT7 expression tracked developmentally Journal of cell science High 22357950
2013 HTR7 (5-HT7 receptor) mediates serotonin-induced macrophage polarization toward M2 (anti-inflammatory) state: 5-HT7 alone mediates inhibition of LPS-induced proinflammatory cytokine release, and together with 5-HT2B mediates upregulation of M2-associated genes; blockade of 5-HT7 (and 5-HT2B) during monocyte-to-macrophage differentiation preferentially reduced M2 polarization markers. Human macrophage culture, selective receptor antagonists (5-HT7 and 5-HT2B), cytokine ELISA, gene expression analysis, in vitro polarization assay Journal of immunology Medium 23355731
2013 5-HT7R activation in hepatocytes stimulates cAMP/PKA activity, phospho-CREB, and pERK/pAKT signaling, leading to IGF-1 synthesis and secretion; all effects were reversed by the 5-HT7 antagonist SB269970, demonstrating a functional 5-HT7 receptor coupled to cAMP/PKA and CREB/AKT in hepatocytes. Isolated rat hepatocytes, PCR/sequencing/Western blot for receptor expression, ELISA and cAMP/PKA assay, phospho-protein Western blots, antagonist reversal Cancer science Medium 23578138
2013 Spinal 5-HT7 receptor activation constrains acute intermittent hypoxia (AIH)-induced phrenic long-term facilitation (pLTF) via PKA: intrathecal 5-HT7 antagonist (SB-269970) or PKA inhibitor (KT-5720) both enhanced pLTF, while PKA activation (8-br-cAMP) blunted pLTF, identifying a Gs/PKA signaling branch that negatively regulates 5-HT2-dependent spinal motor plasticity. Intrathecal injections in anesthetized rats, selective 5-HT7 antagonist, PKA inhibitor and activator, phrenic nerve electrophysiology Neuroscience High 23850591
2014 5-HT7 receptor is critically involved in acute and chronic intestinal inflammation: expressed on CD11c/CD86-positive myeloid cells in the large intestine, 5-HT7R expression increased after colitis induction; genetic ablation or pharmacological blockade worsened colitis severity, while receptor stimulation was anti-inflammatory; bone marrow chimera experiments demonstrated that 5-HT7R on hematopoietic (CD11c+) cells mediates this effect. 5-HT7R knockout mice, DSS acute/chronic colitis model, pharmacological agonist/antagonist treatment, bone marrow chimera, MRI, histology, immunophenotyping Inflammatory bowel diseases High 25072499
2014 S100B, a Ca2+-binding protein, physically interacts with the 5-HT7 receptor and negatively regulates 5-HT7-mediated cAMP accumulation in transfected HeLa cells and mouse cortical astrocytes; S100B overexpression causes brain-region-specific dysregulation of cAMP and depressive-like behavior in female mice, reversible by 5-HT7 blockade. Co-immunoprecipitation/interaction assay, cAMP accumulation in transfected HeLa cells and primary astrocytes, S100B transgenic mice, forced swim test, pharmacological blockade with SB269970 European neuropsychopharmacology Medium 26499172
2015 5-HT7R activation promotes formation of dendritic spines and synaptogenesis in postnatal cortical and striatal neurons via CDK5 and small GTPase Cdc42 as downstream effectors; neurons from 5-HT7R knockout mice or pharmacologically blocked receptors have decreased spine numbers, indicating constitutive 5-HT7R activity contributes to spinogenesis. Primary cortical/striatal neuron cultures, selective agonist LP-211, 5-HT7R knockout neurons, antagonist treatment, confocal imaging of dendritic spines, CDK5 and Cdc42 inhibitors Journal of neurochemistry High 28122114
2015 5-HT7R activation stimulates neurite/axonal elongation through multiple signaling pathways: mTOR, Rho GTPase Cdc42, CDK5, and ERK, which converge on actin cytoskeleton reorganization; LP-211 treatment altered expression profile of cofilin (actin-binding protein), and axonal elongation was confirmed using microfluidic chambers separating axons from soma/dendrites. Primary cortical/hippocampal/striatal neuron cultures, selective agonist LP-211, pharmacological inhibitors of mTOR/Cdc42/CDK5/ERK, 2D-Western blot for cofilin, microfluidic chamber assay for axonal elongation, actin polymerization drugs Frontiers in behavioral neuroscience High 25814944
2015 HTR7 is a key mediator of serotonergic acute and chronic itch: HTR7 activation promotes opening of the ion channel TRPA1, triggering itch behaviors; acute itch from serotonin or SSRI required both HTR7 and TRPA1; in a mouse model of atopic dermatitis, mice lacking HTR7 or TRPA1 showed reduced scratching and skin lesion severity. Genetic screen across mouse strains for itch co-regulated transcripts, HTR7 and TRPA1 knockout mice, serotonin/SSRI-induced itch behavioral assay, atopic dermatitis model Neuron High 26074006
2015 Spinal 5-HT7 receptor-induced phrenic motor facilitation is mediated by EPAC (exchange protein activated by cAMP), not PKA: EPAC inhibitor (ESI-05) abolished 5-HT7 agonist-induced PMF, while PKA inhibitor (KT-5720) did not; direct EPAC activation was sufficient to elicit PMF; mTORC1 is required downstream, as intrathecal rapamycin abolished both 5-HT7- and EPAC-induced PMF, establishing a 5-HT7 → cAMP → EPAC → mTORC1 pathway for spinal motor plasticity. Intrathecal agonist injections in anesthetized rats, selective EPAC inhibitor (ESI-05), PKA inhibitor (KT-5720), EPAC activator (8-pCPT-2'-Me-cAMP), mTORC1 inhibitor (rapamycin), phrenic nerve electrophysiology Journal of neurophysiology High 26269554
2015 5-HT7R activation induces cerebellar long-term depression (LTD) at the parallel fiber-Purkinje cell synapse via a postsynaptic PKC-MAPK signaling pathway; a 5-HT7R antagonist abolished standard parallel fiber-induced LTD, and a 5-HT7R agonist impaired LTP induced by 1 Hz stimulation, demonstrating 5-HT7R as a bidirectional regulator of cerebellar synaptic plasticity. Patch-clamp recordings in cerebellar slices of adult mice, selective 5-HT7R agonist LP-211, antagonist, PKC and MAPK inhibitors Neuropharmacology High 26482421
2020 5-HT7R physically interacts with CDK5, and constitutive (G-protein-independent) 5-HT7R activity is required for Tau hyperphosphorylation and formation of highly bundled Tau structures (HBTS) via CDK5; 5-HT7R-mediated CDK5 activation induces neuronal death, reduced LTP, and impaired memory in a Tau[R406W] mouse model; blockade of constitutive 5-HT7R activity prevented Tau hyperphosphorylation and neurotoxicity, and 5-HT7R knockdown in prefrontal cortex abrogated LTP deficits and memory impairments. Co-immunoprecipitation (5-HT7R–CDK5 interaction), Tau[R406W] overexpression mouse model, pharmacological blockade of constitutive 5-HT7R activity, 5-HT7R shRNA knockdown in prefrontal cortex, LTP recording, behavioral memory tests, CDK5 activity assays Progress in neurobiology High 32841723
2022 5-HT7R activation in the hippocampal CA1 region induces depressive-like behavior in an MMP-9-dependent manner: acute LP-211 (5-HT7R agonist) administration induced depressive-like behavior in mice, accompanied by dendritic spine elongation and decreased spine density; pharmacological modulation of 5-HT7R downstream effectors during chronic unpredictable stress similarly activated the 5-HT7R/MMP-9 pathway in CA1; post mortem human brain samples from depressed individuals revealed increased MMP-9 enzymatic activity in the hippocampus. 5-HT7R agonist LP-211 in mice, MMP-9 inhibitor, behavioral tests, dendritic spine imaging, chronic unpredictable stress model, MMP-9 enzymatic activity assay in human post mortem hippocampal tissue Cell reports High 35294881
2014 5-HT7R is coupled to Gα12 protein in addition to Gs, and Gα12-mediated signaling activates small GTPases of the Rho family, providing a second major signaling arm for 5-HT7R independent of cAMP. Intracellular signaling assays (review synthesis of primary data cited in this review paper; primary data from other labs) Frontiers in behavioral neuroscience Medium 25324743
2019 miR-29a post-transcriptionally regulates 5-HT7R expression by binding its 3'UTR (confirmed by luciferase assay), downregulating 5-HT7R mRNA in hippocampal neurons; miR-29a overexpression impairs 5-HT7R-dependent neurite elongation and remodeling via inhibition of ERK signaling; in vivo, upregulation of miR-29a during hippocampal development parallels downregulation of 5-HT7R. Luciferase 3'UTR reporter assay, miR-29a overexpression in hippocampal neurons, neurite morphometry, ERK pathway inhibition, in vivo developmental expression profiling Molecular neurobiology High 31292861
2014 5-HT7R activation increases expression and basal phosphorylation (at Tyr816) of full-length TrkB in cortical neurons, SH-SY5Y cells, and RGC-5 cells; the effect involves both Gαs and Gα12 downstream pathways depending on the cell system, and occurs within 30 min of receptor activation. Primary cerebral cortical cultures, SH-SY5Y and RGC-5 cell lines, selective 5-HT7R agonist LP-12, Western blot for TrkB expression and phospho-TrkB (Tyr816), pathway inhibitors for Gαs and Gα12 Frontiers in behavioral neuroscience Medium 25426041
2009 Methylphenidate administration to adolescent rats produced a marked increase in 5-HT7 (Htr7) receptor expression in the nucleus accumbens and increased synaptic contacts; a selective Htr7 antagonist fully counteracted MPH-reduced impulsive behavior and enhanced impulsivity when administered alone; 5-HT7 agonist-induced activation in striatal neuron primary cultures significantly increased neurite length, suggesting 5-HT7 mediates plastic remodeling of neuronal morphology. Adolescent rat MPH treatment, Htr7 expression analysis, behavioral impulsivity assay, selective Htr7 antagonist, striatal neuron primary culture with agonist, neurite length measurement Genes, brain, and behavior Medium 19243449
2020 The Drosophila ortholog of 5-HT7 (d5-HT7), expressed specifically in mushroom body (MB) neurons, is required for olfactory associative learning in larvae; d5-HT7 mediates learning via cAMP-dependent signaling; spatio-temporal restriction of d5-HT7 expression to the MB neurons was sufficient to rescue olfactory learning deficits in d5-HT7 null larvae. Drosophila d5-HT7 null mutants, tissue-specific rescue with MB-specific expression of d5-HT7, olfactory conditioning assay, cAMP-PKA pathway dissection Scientific reports Medium 33277559

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Functional, molecular and pharmacological advances in 5-HT7 receptor research. Trends in pharmacological sciences 269 15559250
2005 5-HT7 receptor inhibition and inactivation induce antidepressantlike behavior and sleep pattern. Biological psychiatry 223 16018977
1995 Characterization and distribution of putative 5-ht7 receptors in guinea-pig brain. British journal of pharmacology 212 7647964
2009 The 5-HT7 receptor and disorders of the nervous system: an overview. Psychopharmacology 207 19649616
2013 Serotonin skews human macrophage polarization through HTR2B and HTR7. Journal of immunology (Baltimore, Md. : 1950) 191 23355731
2004 8-OH-DPAT acts on both 5-HT1A and 5-HT7 receptors to induce hypothermia in rodents. European journal of pharmacology 165 15033384
2012 Heterodimerization of serotonin receptors 5-HT1A and 5-HT7 differentially regulates receptor signalling and trafficking. Journal of cell science 164 22357950
2000 5-HT7 receptors: current knowledge and future prospects. Trends in pharmacological sciences 162 10664612
2010 Serotonin 5-HT7 receptor agents: Structure-activity relationships and potential therapeutic applications in central nervous system disorders. Pharmacology & therapeutics 160 20923682
2015 HTR7 Mediates Serotonergic Acute and Chronic Itch. Neuron 147 26074006
2003 No hypothermic response to serotonin in 5-HT7 receptor knockout mice. Proceedings of the National Academy of Sciences of the United States of America 137 12529502
2011 Role of the 5-HT7 receptor in the central nervous system: from current status to future perspectives. Molecular neurobiology 134 21424680
2013 Multiple roles of serotonin in pain control mechanisms--implications of 5-HT₇ and other 5-HT receptor types. European journal of pharmacology 130 23500207
2018 Review: 5-HT1, 5-HT2, 5-HT3 and 5-HT7 Receptors and their Role in the Modulation of Pain Response in the Central Nervous System. Current neuropharmacology 128 28901281
2015 The role of the serotonin receptor subtypes 5-HT1A and 5-HT7 and its interaction in emotional learning and memory. Frontiers in pharmacology 127 26300776
2004 5-HT7 receptors. Current drug targets. CNS and neurological disorders 125 14965246
1997 5-HT7 receptors mediate serotonergic effects on light-sensitive suprachiasmatic nucleus neurons. Brain research 120 9175892
2008 5-HT7 receptor activation inhibits mechanical hypersensitivity secondary to capsaicin sensitization in mice. Pain 114 19118950
2009 The 5-HT7 receptor is involved in allocentric spatial memory information processing. Behavioural brain research 112 19447277
1997 Cloning, expression and pharmacology of a truncated splice variant of the human 5-HT7 receptor (h5-HT7b). British journal of pharmacology 107 9298538
2005 Pre- and postsynaptic localization of the 5-HT7 receptor in rat dorsal spinal cord: immunocytochemical evidence. The Journal of comparative neurology 99 16082681
2015 Targeting the Serotonin 5-HT7 Receptor in the Search for Treatments for CNS Disorders: Rationale and Progress to Date. CNS drugs 98 25721336
2014 Interplay between serotonin 5-HT1A and 5-HT7 receptors in depressive disorders. CNS neuroscience & therapeutics 94 24935787
2014 5-HT7 receptors as modulators of neuronal excitability, synaptic transmission and plasticity: physiological role and possible implications in autism spectrum disorders. Frontiers in cellular neuroscience 93 25221471
2013 The serotonin 5-HT7 receptors: two decades of research. Experimental brain research 88 24042216
2002 The human 5-HT7 serotonin receptor splice variants: constitutive activity and inverse agonist effects. British journal of pharmacology 86 11906971
2014 Cellular mechanisms of the 5-HT7 receptor-mediated signaling. Frontiers in behavioral neuroscience 85 25324743
2005 Pronociceptive role of peripheral and spinal 5-HT7 receptors in the formalin test. Pain 78 16098671
2011 Spinal 5-HT7 receptor activation induces long-lasting phrenic motor facilitation. The Journal of physiology 77 21242254
2017 Serotonin 5-HT7 receptor increases the density of dendritic spines and facilitates synaptogenesis in forebrain neurons. Journal of neurochemistry 74 28122114
2014 Serotonin 5-HT7 receptor is critically involved in acute and chronic inflammation of the gastrointestinal tract. Inflammatory bowel diseases 71 25072499
2002 5-HT7 receptors are involved in mediating 5-HT-induced activation of rat primary afferent neurons. Life sciences 71 12215375
2008 (Phenylpiperazinyl-butyl)oxindoles as selective 5-HT7 receptor antagonists. Journal of medicinal chemistry 69 18361484
2007 The 5-HT7 receptor: role in novel object discrimination and relation to novelty-seeking behavior. Neuroscience 68 17869441
2002 Localization of 5-HT2A, 5-HT3, 5-HT5A and 5-HT7 receptor-like immunoreactivity in the rat cerebellum. Journal of chemical neuroanatomy 68 12084412
2001 Acute restraint stress increases 5-HT7 receptor mRNA expression in the rat hippocampus. Neuroscience letters 66 11514061
1994 Inhibition by 5-HT7 receptor stimulation of GABAA receptor-activated current in cultured rat suprachiasmatic neurones. The Journal of physiology 64 7965836
2005 5-HT7 receptors modulate peristalsis and accommodation in the guinea pig ileum. Gastroenterology 63 16285955
2009 Methylphenidate to adolescent rats drives enduring changes of accumbal Htr7 expression: implications for impulsive behavior and neuronal morphology. Genes, brain, and behavior 61 19243449
2007 The 5-HT7 receptor influences stereotypic behavior in a model of obsessive-compulsive disorder. Neuroscience letters 60 17267119
2014 Novel arylsulfonamide derivatives with 5-HT₆/5-HT₇ receptor antagonism targeting behavioral and psychological symptoms of dementia. Journal of medicinal chemistry 59 24805037
2015 Activation of 5-HT7 receptor stimulates neurite elongation through mTOR, Cdc42 and actin filaments dynamics. Frontiers in behavioral neuroscience 57 25814944
2008 Effects of SB-269970, a 5-HT7 receptor antagonist, in mouse models predictive of antipsychotic-like activity. Behavioural pharmacology 54 18332680
1997 Role of 5-ht7 receptors in the long-lasting hypotensive response induced by 5-hydroxytryptamine in the rat. British journal of pharmacology 54 9179401
2014 Serotonergic 5-HT7 receptors and cognition. Reviews in the neurosciences 51 24486730
2013 Spinal 5-HT7 receptors and protein kinase A constrain intermittent hypoxia-induced phrenic long-term facilitation. Neuroscience 51 23850591
2002 [3H]-SB-269970 radiolabels 5-HT7 receptors in rodent, pig and primate brain tissues. Neuropharmacology 51 11750917
2012 5-HT1A and 5-HT7 receptor crosstalk in the regulation of emotional memory: implications for effects of selective serotonin reuptake inhibitors. Neuropharmacology 50 22801295
2007 5-HT7 receptor antagonists as a new class of antidepressants. Drug news & perspectives 49 18301795
2011 5-HT7 receptors modulate GABAergic transmission in rat hippocampal CA1 area. Journal of physiology and pharmacology : an official journal of the Polish Physiological Society 48 22204801
1997 Expression of 5-HT7 receptor mRNA in rat brain during postnatal development. Neuroscience letters 48 9178857
2022 Activation of the 5-HT7 receptor and MMP-9 signaling module in the hippocampal CA1 region is necessary for the development of depressive-like behavior. Cell reports 46 35294881
2014 Memory formation and memory alterations: 5-HT6 and 5-HT7 receptors, novel alternative. Reviews in the neurosciences 46 24698823
2009 Synthesis of new serotonin 5-HT7 receptor ligands. Determinants of 5-HT7/5-HT1A receptor selectivity. Journal of medicinal chemistry 46 19326916
2004 Functional expression of the serotonin 5-HT7 receptor in human glioblastoma cell lines. British journal of pharmacology 46 15339860
1995 Assignment of the 5HT7 receptor gene (HTR7) to chromosome 10q and exclusion of genetic linkage with Tourette syndrome. Genomics 46 7601444
2015 Spinal 5-HT7 receptors induce phrenic motor facilitation via EPAC-mTORC1 signaling. Journal of neurophysiology 45 26269554
2014 The role of serotonin 5-HT7 receptor in regulating sleep and wakefulness. Reviews in the neurosciences 45 24681431
2015 The 5-HT7 receptor as a potential target for treating drug and alcohol abuse. Frontiers in neuroscience 44 25628528
2015 The 5-HT7 receptor triggers cerebellar long-term synaptic depression via PKC-MAPK. Neuropharmacology 43 26482421
2012 5-HT1A and 5-HT7 receptors contribute to lurasidone-induced dopamine efflux. Neuroreport 42 22415605
2007 5-HT7, neurogenesis and antidepressants: a promising therapeutic axis for treating depression. Clinical and experimental pharmacology & physiology 42 17439430
2003 5-Hydroxytryptamine7 (5-HT7) receptor immunoreactivity-positive 'stigmoid body'-like structure in developing rat brains. International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience 42 12711351
2021 Current Limitations and Candidate Potential of 5-HT7 Receptor Antagonism in Psychiatric Pharmacotherapy. Frontiers in psychiatry 41 33679481
2014 Selective agonists for serotonin 7 (5-HT7) receptor and their applications in preclinical models: an overview. Reviews in the neurosciences 41 24622785
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2013 Serotonin and the 5-HT7 receptor: the link between hepatocytes, IGF-1 and small intestinal neuroendocrine tumors. Cancer science 40 23578138
2015 S100B interacts with the serotonin 5-HT7 receptor to regulate a depressive-like behavior. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology 38 26499172
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2003 5-HT7 receptors mediate the inhibitory effect of 5-HT on peristalsis in the isolated guinea-pig ileum. British journal of pharmacology 37 12711620
2013 Modulation of 5-HT7 receptor: effect on object recognition performances in mice. Psychopharmacology 36 23995300
2010 Selective inhibition of 5-HT7 receptor reduces CGRP release in an experimental model for migraine. Headache 36 20236348
2009 Memory time-course: mRNA 5-HT1A and 5-HT7 receptors. Behavioural brain research 36 19447286
2015 Spatial memory deficit across aging: current insights of the role of 5-HT7 receptors. Frontiers in behavioral neuroscience 35 25642173
2015 Involvement of 5-HT₇ receptors in vortioxetine's modulation of circadian rhythms and episodic memory in rodents. Neuropharmacology 34 25446573
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2004 5-HT7, but not 5-HT2B, receptors mediate hypotension in vagosympathectomized rats. European journal of pharmacology 34 15476750
2000 Presence of a 5-HT7 receptor positively coupled to adenylate cyclase activation in human granulosa-lutein cells. The Journal of clinical endocrinology and metabolism 34 10720076
2012 5-HT7 receptor activation attenuates thermal hyperalgesia in streptozocin-induced diabetic mice. Pharmacology, biochemistry, and behavior 33 22609798
2009 Therapeutic potential of 5-HT7 receptors in mood disorders. Current drug targets 33 19702552
2004 Evidence for 5-HT2B and 5-HT7 receptor-mediated relaxation in pulmonary arteries of weaned pigs. Naunyn-Schmiedeberg's archives of pharmacology 33 15726452
2021 Modulation of Serotonin Receptors in Neurodevelopmental Disorders: Focus on 5-HT7 Receptor. Molecules (Basel, Switzerland) 32 34199418
2014 5-HT7 receptor signaling: improved therapeutic strategy in gut disorders. Frontiers in behavioral neuroscience 32 25565996
2007 5-HT7 receptor-mediated dilatation in the middle meningeal artery of anesthetized rats. European journal of pharmacology 32 17316605
1999 Physical mapping of the serotonin 5-HT(7) receptor gene (HTR7) to chromosome 10 and pseudogene (HTR7P) to chromosome 12, and testing of linkage disequilibrium between HTR7 and autistic disorder. American journal of medical genetics 31 10490701
2007 Comparison of 5-HT4 and 5-HT7 receptor expression and function in the circular muscle of the human colon. Life sciences 30 17258778
2003 Pharmacological characterization of a serotonin receptor (5-HT7) stimulating cAMP production in human corneal epithelial cells. Investigative ophthalmology & visual science 30 14578406
2020 Serotonin receptor 5-HT7 in Drosophila mushroom body neurons mediates larval appetitive olfactory learning. Scientific reports 29 33277559
2019 The microRNA-29a Modulates Serotonin 5-HT7 Receptor Expression and Its Effects on Hippocampal Neuronal Morphology. Molecular neurobiology 29 31292861
2015 The critical role of spinal 5-HT7 receptors in opioid and non-opioid type stress-induced analgesia. European journal of pharmacology 29 25917322
2014 5-HT7 receptor activation promotes an increase in TrkB receptor expression and phosphorylation. Frontiers in behavioral neuroscience 29 25426041
2007 Expression and role of 5-HT7 receptor in brain and intestine in rats with irritable bowel syndrome. Chinese medical journal 29 18167178
2015 Distribution of 5-HT3, 5-HT4, and 5-HT7 Receptors Along the Human Colon. Journal of neurogastroenterology and motility 28 26130632
2007 Novel quinazolinone derivatives as 5-HT7 receptor ligands. Bioorganic & medicinal chemistry 28 18083580
2006 Ontogenetic distribution of 5-HT2C, 5-HT5A, and 5-HT7 receptors in the rat hippocampus. Gene expression 28 16572590
2020 Amelioration of Tau pathology and memory deficits by targeting 5-HT7 receptor. Progress in neurobiology 27 32841723
2002 In the search for selective ligands of 5-HT5, 5-HT6 and 5-HT7 serotonin receptors. Polish journal of pharmacology 27 12523486
2004 Aminotriazine 5-HT7 antagonists. Bioorganic & medicinal chemistry letters 26 15261279
2002 SB-258741: a 5-HT7 receptor antagonist of potential clinical interest. CNS drug reviews 26 12070528

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