Affinage

NTRK2

BDNF/NT-3 growth factors receptor · UniProt Q16620

Length
822 aa
Mass
92.0 kDa
Annotated
2026-06-10
100 papers in source corpus 31 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NTRK2 (TrkB) is a brain-enriched transmembrane glycoprotein receptor tyrosine kinase that transduces neurotrophin signals to control neuronal survival, synaptic plasticity, and circuit-level behavior (PMID:2555172, PMID:8264643). It is activated by BDNF and by NT-4/NT-4, which engage partially distinct extracellular contact residues, triggering receptor autophosphorylation and recruitment of downstream effectors (PMID:1375038). Ligand binding bifurcates into parallel cascades whose physiological outputs are separable: phosphorylation of a PLCγ docking site drives CaMKIV/CREB activation required for hippocampal LTP, whereas a distinct Shc docking site couples to MAPK, and a PI3K/Akt arm supports survival and anti-apoptotic signaling (PMID:12367511, PMID:15329723). Through these outputs TrkB is essential for presynaptic maturation and synaptogenesis of hippocampal connections (PMID:9736654), oligodendrocyte myelin ensheathment (PMID:23486965), and the integrity of prefrontal parvalbumin interneuron network dynamics (PMID:33593856); at the circuit level it acts in paraventricular hypothalamic neurons to suppress appetite (PMID:32265438) and in postsynaptic CA1 neurons to mediate ketamine's rapid antidepressant effect via dynamin1-dependent activation (PMID:34407417). TrkB receptor availability is shaped by its truncated, kinase-deficient isoforms (TrkB.T1/TrkB-Shc), which act as dominant-negative modulators of full-length receptor responsiveness and can signal independently to drive glycine transporter internalization and tumor-promoting PI3K/Akt-STAT3 output (PMID:8978665, PMID:31678045, PMID:32532995), and by Slitrk5-directed recycling through Rab11 endosomes (PMID:26004511). Beyond canonical neurotrophins, TrkB is transactivated by oxytocin GPCR signaling (PMID:35721318) and is directly bound at its transmembrane domain by antidepressants and psychedelics, which allosterically potentiate BDNF signaling in a cholesterol-sensitive manner (PMID:33606976, PMID:37280397). TrkB function also extends to ovarian follicle and oocyte survival via PI3K-AKT (PMID:24877631), senescent-cell survival via an autocrine BDNF loop activating ERK5/BCL2L2 (PMID:36266274), and bone homeostasis (PMID:35973996), and TrkB kinase activity is an antiseizure target (PMID:24903749).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 1989 High

    Established the molecular identity of TrkB as a nervous-system-enriched receptor tyrosine kinase, defining the protein class whose ligands and signaling would later be dissected.

    Evidence cDNA cloning and glycoprotein reconstitution with in situ hybridization

    PMID:2555172

    Open questions at the time
    • Did not identify the activating ligand
    • No downstream signaling defined
  2. 1992 High

    Identified NT-4 as a TrkB ligand and showed via Cys345Ser mutagenesis that NT-4 and BDNF use partially distinct contact residues, revealing ligand-selective receptor engagement.

    Evidence Radioligand displacement, tyrosine phosphorylation, transformation/differentiation assays, site-directed mutagenesis

    PMID:1375038

    Open questions at the time
    • Did not map the full ligand-binding interface
    • NT-3 contribution not addressed here
  3. 1994 Medium

    Connected TrkB activation to a defined set of downstream effectors (PLCγ1, ERK1/2, PI3K) and survival/differentiation outputs, framing TrkB as a multi-pathway survival receptor.

    Evidence Phospho-immunoblots and downstream activation/survival assays in BDNF-expressing neuroblastoma cells

    PMID:8264643

    Open questions at the time
    • Single cell line, single lab
    • Did not establish which pathway controls which phenotype
  4. 1996 Medium

    Showed truncated TrkB isoforms act as dominant-negative receptors, establishing that the catalytic/non-catalytic isoform ratio tunes BDNF responsiveness.

    Evidence Isoform co-expression and survival assays in primary sympathetic neurons

    PMID:8978665

    Open questions at the time
    • Mechanism of dominant-negative action not resolved
    • Single lab
  5. 1998 High

    Demonstrated in vivo that TrkB is required for presynaptic maturation and synaptogenesis, moving TrkB from in vitro signaling to organ-level neural circuit development.

    Evidence Knockout mouse analysis with tract tracing, EM, and immunocytochemistry

    PMID:9736654

    Open questions at the time
    • Cell-autonomous vs network effects not separated
    • Did not link a specific signaling arm to the phenotype
  6. 2002 High

    Genetically separated the PLCγ and Shc docking pathways, assigning hippocampal LTP/CaMKIV/CREB to PLCγ and MAPK activation to Shc, establishing parallel TrkB signaling routes with distinct functions.

    Evidence Docking-site knockin mice with LTP electrophysiology and BDNF-stimulated signaling assays

    PMID:12367511

    Open questions at the time
    • PI3K arm not addressed in this design
    • Behavioral consequences not fully mapped
  7. 2004 High

    Showed TrkB/PI3K-Akt suppresses anoikis and drives metastasis, extending TrkB survival signaling to non-neural epithelial and oncogenic contexts.

    Evidence Genome-wide anoikis-suppression screen with pathway inhibition and mouse metastasis model

    PMID:15329723

    Open questions at the time
    • Ligand dependence in tumors not fully defined
    • Did not address isoform contributions
  8. 2009 Medium

    Established a peripheral reproductive role for TrkB in ovarian follicle assembly via induction of FSH receptor, broadening TrkB function beyond the nervous system.

    Evidence Ntrk2 knockout mouse follicle counts, FSHR expression, NT-4 treatment

    PMID:19357131

    Open questions at the time
    • Downstream signaling to FSHR not defined
    • Single lab
  9. 2012 Medium

    Defined excitotoxic regulation of TrkB by calpain cleavage and TrkB-T1 upregulation, and a ligand-trafficking control by TrkB-Shc, mechanistically linking isoform balance to neuronal death.

    Evidence Calpain cleavage and lentiviral rescue in neurons (22258407); overexpression immunoblots in CHOK1 cells (22425982)

    PMID:22258407 PMID:22425982

    Open questions at the time
    • TrkB-Shc work limited to overexpression in non-neuronal cells, single method
    • Endogenous relevance of the degradation mechanism unconfirmed
  10. 2013 High

    Extended TrkB function to oligodendrocyte myelination and identified RARα as a transcriptional activator of the TrkB promoter, addressing how TrkB output and expression are regulated.

    Evidence Oligodendrocyte-specific conditional knockout with EM/myelin readouts (23486965); promoter transactivation/ChIP assay (23960204)

    PMID:23486965 PMID:23960204

    Open questions at the time
    • RARα finding is single-lab, single-method, not replicated
    • Signaling arm mediating myelination not pinpointed
  11. 2014 High

    Showed gonadotropin-induced oocyte NTRK2.FL-AKT signaling is required for oocyte survival, with cooperative BDNF/kisspeptin input via NTRK2.T1 and KISS1R, defining a reproductive survival pathway.

    Evidence Oocyte-specific Ntrk2 knockout, gonadotropin stimulation, PI3K-AKT assays, cell-line co-expression

    PMID:24877631

    Open questions at the time
    • Mechanism of NTRK2.T1/KISS1R cooperativity not structurally defined
    • Single lab
  12. 2015 Medium

    Resolved post-translational control of TrkB trafficking: Slitrk5 directs ligand-dependent recycling via Rab11, while truncated TrkB-T1 drives glycine transporter internalization through Rho-GTPase, expanding the non-kinase roles of TrkB.

    Evidence Reciprocal Co-IP, super-resolution imaging, recycling assays, Slitrk5 KO (26004511); glycine transport, pharmacology and RNAi in astrocytes (26200505)

    PMID:26004511 PMID:26200505

    Open questions at the time
    • Glycine transporter work is single lab
    • How TrkB-T1 engages Rho-GTPase mechanistically not resolved
  13. 2015 Medium

    Demonstrated TrkB kinase activity sustains neuromuscular junction presynaptic terminals, particularly with aging, linking kinase function to peripheral synapse maintenance.

    Evidence Chemical-genetic kinase inhibition (TrkBF616A + 1NMPP1) with NMJ morphometry

    PMID:26517952

    Open questions at the time
    • Downstream effectors at NMJ not identified
    • Single lab
  14. 2018 Medium

    Identified TrkB signaling within oxytocin neurons as a developmental driver of oxytocin expression and maternal behavior, embedding TrkB in social/behavioral circuits.

    Evidence OXT-neuron-specific TrkB conditional knockout with behavioral and TRAP RNA-seq readouts

    PMID:30192229

    Open questions at the time
    • Signaling arm mediating oxytocin regulation not defined
    • Single lab
  15. 2018 Medium

    Showed corticostriatal TrkB-ERK signaling is required to balance goal-directed versus habitual behaviors, mapping TrkB kinase output onto defined action-selection circuits.

    Evidence Region-specific truncated TrkB overexpression with phospho-ERK assays and operant behavior

    PMID:29540698

    Open questions at the time
    • Dominant-negative overexpression may have off-target effects
    • Single lab
  16. 2019 Medium

    Used spatial optogenetic activation to show local TrkB signaling initiates actin waves and specifies axonal identity, revealing a cell-biological role in neuronal polarization.

    Evidence Opto-cytTrkB activation with live actin imaging, Rac1 assays, ankyrinG staining

    PMID:31678045

    Open questions at the time
    • Endogenous spatial ligand cues not addressed
    • Single lab
  17. 2020 High

    Established TrkB as a key node in PVH appetite circuits and showed truncated TrkB.T1 can drive ligand-independent glioma growth, linking TrkB to opposite physiological and pathological survival contexts.

    Evidence PVH-specific conditional knockout with chemogenetics/circuit tracing (32265438); PDGF glioma model with Akt/STAT3 assays (32532995)

    PMID:32265438 PMID:32532995

    Open questions at the time
    • Mechanism of TrkB.T1 ligand-independent signaling not fully defined
    • Glioma study single lab/Medium confidence
  18. 2021 High

    Discovered antidepressants directly bind the TrkB transmembrane domain to potentiate BDNF signaling in a cholesterol-sensitive manner, and that postsynaptic CA1 TrkB mediates ketamine's rapid action, redefining TrkB as a direct drug target.

    Evidence MD simulations, binding assays, TMD-motif mutagenesis, in vivo behavior (33606976); CA1/CA3-specific deletion with electrophysiology and dynamin1 dependence (34407417)

    PMID:33606976 PMID:34407417

    Open questions at the time
    • Structural validation of the TMD binding pocket beyond simulation incomplete
    • Generality across antidepressant classes not exhaustively mapped
  19. 2021 Medium

    Showed adult TrkB signaling maintains prefrontal parvalbumin interneuron integrity and γ oscillations, assigning TrkB a continuous role in mature inhibitory network function.

    Evidence Viral dominant-negative trkB in mPFC PV interneurons with LFP recording and behavior

    PMID:33593856

    Open questions at the time
    • Dominant-negative may affect related receptors
    • Single lab
  20. 2022 Medium

    Extended TrkB's reach to senescent-cell survival (autocrine BDNF→ERK5/BCL2L2), oxytocin GPCR transactivation of TrkB at inhibitory synapses, and bone homeostasis, demonstrating broad TrkB signaling versatility.

    Evidence Drug screen + ERK5/BCL2L2 assays in aged mice (36266274); phospho-TrkB assays with oxytocin pharmacology (35721318); TrkB agonist/AEP KO/OVX bone models (35973996)

    PMID:35721318 PMID:35973996 PMID:36266274

    Open questions at the time
    • Oxytocin and bone findings each single lab
    • Cross-talk mechanism of GPCR transactivation not structurally defined
  21. 2023 High

    Showed psychedelics (LSD, psilocin) bind TrkB with ~1000-fold higher affinity than antidepressants at a partially overlapping TMD site, and that their plasticity/antidepressant effects are TrkB-dependent but 5-HT2A-independent, dissociating two drug-receptor axes.

    Evidence Radioligand binding, MD simulations, TMD mutagenesis, and in vivo behavioral assays separating TrkB from 5-HT2A

    PMID:37280397

    Open questions at the time
    • Co-crystal structure of psychedelic-bound TrkB not reported
    • Relationship to clinical efficacy untested
  22. 2024 Medium

    Linked cortical BDNF-TrkB-CREB signaling in layer 5 neurons to sleep slow-wave activity, placing TrkB synaptic-strength control upstream of a defined sleep electrophysiological output.

    Evidence Pharmacology/optogenetics with EEG, transcriptomics and proteomics in layer 5 neurons

    PMID:39046880

    Open questions at the time
    • Mechanistic role of the enriched ubiquitin/proteasome subunits not established
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How distinct extracellular vs transmembrane binding modes (neurotrophins, RNA aptamer C4-3, antidepressants, psychedelics, GPCR transactivation) are integrated into graded, context-specific TrkB output across diverse cell types remains unresolved.
  • No unified structural model coupling TMD allostery to kinase activation
  • Cell-type determinants of isoform ratio and signaling-arm selection not defined
  • How non-neuronal TrkB roles (bone, senescence, ovary, tumor) are gated remains open

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0048018 receptor ligand activity 2 GO:0060089 molecular transducer activity 2 GO:0098772 molecular function regulator activity 2 GO:0140657 ATP-dependent activity 1
Localization
GO:0005886 plasma membrane 3 GO:0005768 endosome 1
Pathway
R-HSA-112316 Neuronal System 4 R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-1474165 Reproduction 2
Partners
BDNFKISS1RNTF4SLITRK5

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1989 trkB encodes a novel glycoprotein receptor tyrosine kinase (gp145trkB) with a 145 kDa molecular weight (93 kDa polypeptide backbone), expressed preferentially in brain and nervous system tissues, identifying it as a cell surface receptor in the tyrosine kinase family. cDNA cloning, glycoprotein synthesis from biologically active cDNA, in situ hybridization The EMBO journal High 2555172
1992 The trkB tyrosine kinase receptor serves as a functional receptor for neurotrophin-4 (NT-4/XNT-4): XNT-4 displaces 125I-BDNF from gp145trkB, induces tyrosine phosphorylation, causes NIH 3T3 transformation when co-expressed with gp145trkB, and induces PC12 neuronal differentiation. Mutation of extracellular Cys-345 to Ser abolishes XNT-4 activation but not BDNF activation, indicating partially distinct binding domains for NT-4 and BDNF on TrkB. Radioligand displacement assay (125I-BDNF), tyrosine phosphorylation assay, NIH 3T3 transformation assay, PC12 differentiation assay, site-directed mutagenesis (Cys345Ser) Neuron High 1375038
1994 In neuroblastoma cells (SMS-KCN) co-expressing TrkB and BDNF, exogenous BDNF induces tyrosine phosphorylation of TrkB and activates downstream phospholipase C-γ1, ERK1/2, and PI3K; BDNF also induces immediate-early genes c-FOS and NGFI-A and promotes cell survival and neurite outgrowth, constituting an autocrine/paracrine survival loop. Tyrosine phosphorylation assay (immunoblot), downstream kinase activation assays, immediate-early gene expression, cell survival and neurite outgrowth assays Molecular and cellular biology Medium 8264643
1996 Non-catalytic (truncated) TrkB isoforms act as dominant-negative receptors: co-expression of non-catalytic TrkB with catalytic TrkB in NGF-dependent sympathetic neurons substantially reduces BDNF-mediated survival signaling, demonstrating that the relative levels of catalytic vs. non-catalytic TrkB isoforms modulate BDNF responsiveness. Plasmid injection into neurons, survival assay, manipulation of TrkB isoform expression ratios The EMBO journal Medium 8978665
1998 TrkB is required for maturation and synaptogenesis of hippocampal connections in vivo: trkB(-/-) mice show reduced axon collaterals (21-49%), decreased axonal varicosity density, lower synaptic contact density, altered presynaptic bouton ultrastructure (decreased synaptic vesicle density), and reduced expression of v-SNARE and t-SNARE synaptic proteins, demonstrating TrkB is essential for presynaptic development. Lipophilic tracer injections, biocytin fills, electron microscopy, immunocytochemistry, knockout mouse analysis The Journal of neuroscience High 9736654
2002 TrkB mediates hippocampal LTP via recruitment of PLCγ and subsequent phosphorylation of CaMKIV and CREB: mice with targeted mutation in the PLCγ docking site of TrkB (trkB(PLC/PLC)) show impaired hippocampal LTP and strongly reduced CaMKIV/CREB phosphorylation upon BDNF stimulation, while MAPK activation is retained. Mice with mutated Shc docking site (trkB(SHC/SHC)) retain LTP but show impaired MAPK activation, indicating parallel signaling pathways. Targeted knockin mutagenesis (PLCγ and Shc docking site mutations), electrophysiology (LTP recording), BDNF-stimulated signaling assays (pCaMKIV, pCREB, pMAPK) in primary neurons Neuron High 12367511
2004 TrkB suppresses anoikis (detachment-induced apoptosis) in non-malignant epithelial cells by activating the PI3K/PKB (Akt) pathway, enabling cell survival and proliferation in suspension and promoting metastasis in mice. TrkB-expressing cells formed rapidly growing tumors that infiltrated lymphatics and blood vessels. Genome-wide functional screen for anoikis suppression, PI3K/Akt pathway inhibition assays, mouse tumor formation and metastasis assays Nature High 15329723
2009 NTRK2 (TrkB) and NTRK1 receptors are required for timely primordial follicle assembly and early follicular development in the mouse ovary; Ntrk2(-/-) mice show reduced follicle assembly and decreased FSH receptor (FSHR) expression. NT-4 (NTF4) exposure increases Fshr gene expression and cyclin D2 formation, indicating TrkB signaling induces functional FSHR to facilitate subsequent follicle development. Knockout mouse analysis (Ntrk2(-/-)), follicle counting, FSHR expression assay, NTF4 treatment of ovaries, cyclin D2 formation assay Reproduction (Cambridge, England) Medium 19357131
2012 Excitotoxicity causes neuronal death via imbalance of TrkB isoforms: calpain cleaves full-length TrkB (TrkB-FL) producing a truncated form similar to inactive TrkB-T1, while mRNA of TrkB-T1 is upregulated. Restoring TrkB-FL/TrkB-T1 balance via lentiviral TrkB-T1 interference and TrkB-FL overexpression protects neurons from excitotoxic death. Calpain cleavage assay, Western blot, RT-PCR, lentiviral gene delivery (TrkB-T1 knockdown + TrkB-FL overexpression), excitotoxicity neuronal survival assay, stroke patient tissue analysis Cell death & disease Medium 22258407
2012 TrkB-Shc truncated isoform reduces phosphorylated full-length TrkB (TrkB-TK+) protein levels in response to BDNF, suggesting TrkB-Shc promotes degradation of activated TrkB-TK+ complexes to prevent TrkB overactivation; conversely, TrkB-Shc protein stability is increased following BDNF exposure. Transient overexpression in CHOK1 cells, BDNF stimulation, immunoblot for phospho-TrkB and TrkB isoform protein levels Biochemical and biophysical research communications Low 22425982
2013 Oligodendrocyte-specific TrkB deletion disrupts myelination: conditional TrkB knockout in oligodendrocytes reduces myelin protein expression and myelin thickness in CNS white matter tracts during development without affecting the number of mature oligodendrocytes or myelinated axons, demonstrating a direct role for TrkB in myelin ensheathment. TrkB deletion in oligodendroglia also increases OPC proliferation, an effect dependent on TrkC and p75 expression. Conditional knockout mice (oligodendrocyte-specific TrkB deletion), myelin protein expression assay, electron microscopy for myelin thickness, OPC density quantification, in vitro TrkB knockdown in OPCs The Journal of neuroscience High 23486965
2013 Retinoic acid receptor α (RARα) binds to and transactivates the TrkB promoter via a putative retinoic acid response element, providing a transcriptional mechanism by which retinoid signaling upregulates TrkB expression. In vitro transcription/promoter binding assay, chromatin immunoprecipitation/reporter assay for RARα binding to TrkB promoter Cerebral cortex Low 23960204
2014 Oocyte-specific deletion of Ntrk2 causes post-pubertal oocyte death and infertility. Oocytes lacking NTRK2 fail to activate PI3K-AKT signaling in response to gonadotropins. The preovulatory gonadotropin surge rapidly induces full-length NTRK2 (NTRK2.FL) expression in oocytes, and BDNF + kisspeptin act cooperatively (via oocyte NTRK2.T1 and KISS1R) to mediate gonadotropin-induced NTRK2.FL upregulation, establishing NTRK2-AKT as the survival pathway activated at the onset of reproductive cyclicity. Oocyte-specific conditional knockout (Ntrk2), gonadotropin stimulation assays, PI3K-AKT activation assays, cell line co-expression of NTRK2.T1 + KISS1R with BDNF/kisspeptin stimulation Endocrinology High 24877631
2015 Slitrk5 directly interacts with TrkB receptors and mediates BDNF-dependent TrkB trafficking: under basal conditions Slitrk5 preferentially binds PTPδ, but upon BDNF stimulation, Slitrk5 shifts to cis-interactions with TrkB. Absence of Slitrk5 reduces ligand-dependent TrkB recycling and alters BDNF responsiveness. Slitrk5 recruits the Rab11 effector Rab11-FIP3 to direct TrkB to Rab11-positive recycling endosomes. Co-immunoprecipitation, structured illumination microscopy, receptor recycling assays, Rab11-FIP3 pulldown, Slitrk5 knockout mouse analysis Developmental cell High 26004511
2015 BDNF acting via truncated TrkB-T1 (not full-length TrkB-FL) promotes internalization of glycine transporters GlyT1 and GlyT2 in astrocytes through Rho-GTPase signaling: BDNF decreases Vmax but not Km of glycine transport (consistent with transporter internalization); dynasore (dynamin/clathrin inhibitor) prevents this effect; Rho-family blocker (toxin B) and TrkB-T knockdown abolish it, while PLCγ, PI3K, and MAPK inhibitors do not. Radiolabeled glycine transport assay ([3H]glycine), pharmacological inhibitors, RNAi (TrkB-T knockdown), immunofluorescence for transporter endosomal localization Glia Medium 26200505
2019 Local TrkB activation at neurite ends initiates actin waves and specifies axonal fate: optogenetic activation (Opto-cytTrkB) of TrkB signaling in the distal neurite triggers F-actin wave generation from the somato-neuritic area toward the neurite end; TrkB signaling connects distally activated Rac1 to proximal signaling pathways; local TrkB activation relocates the axon initial segment organizer ankyrinG and confers axonal identity to the stimulated neurite. Optogenetics (Opto-cytTrkB), live imaging of actin waves, immunostaining for ankyrinG, Rac1 activity assays Cell chemical biology Medium 31678045
2020 A truncated NTRK2 splice variant TrkB.T1 (kinase-deficient) enhances PDGF-driven gliomas in vivo and augments PDGF-induced Akt and STAT3 signaling in vitro in a ligand-independent fashion; next-generation sequencing broadly implicates TrkB.T1 in PI3K signaling cascades. In vivo glioma model (PDGF-driven), in vitro Akt/STAT3 signaling assays, next-generation sequencing, splice variant characterization Nature communications Medium 32532995
2020 TrkB-expressing paraventricular hypothalamic (PVH) neurons suppress appetite through multiple neurocircuits: selective Ntrk2 deletion in PVH causes severe hyperphagic obesity; PVHTrkB neurons project to both VMH and LPBN; Ntrk2 deletion in either projection causes hyperphagia and obesity; BDNF increases firing of PVHTrkB neurons, demonstrating TrkB as a key regulator of PVH appetite circuits. Conditional Ntrk2 knockout (PVH-specific), chemogenetic activation/inhibition (DREADD), axonal projection tracing, electrophysiology, BDNF stimulation Nature communications High 32265438
2021 Both typical and fast-acting antidepressants directly bind to the transmembrane domain (TMD) of TrkB dimers, facilitating synaptic TrkB localization and its activation by BDNF. The TMD of TrkB has a cholesterol-sensing function mediating synaptic effects of cholesterol. Mutation of the TrkB antidepressant-binding motif impairs cellular, behavioral, and plasticity-promoting responses to antidepressants in vitro and in vivo. Atomistic molecular dynamics simulations defined the binding site at the TMD of TrkB dimers. Molecular dynamics simulations, radioligand binding assays, site-directed mutagenesis of antidepressant-binding motif, synaptic localization assays, in vitro and in vivo behavioral/plasticity assays Cell High 33606976
2021 Postsynaptic TrkB in CA1 neurons is required for ketamine-induced synaptic potentiation and rapid antidepressant action: deletion of TrkB only in CA1 (postsynaptic) but not CA3 (presynaptic) eliminates ketamine-induced synaptic potentiation; ketamine elicits dynamin1-dependent TrkB activation and downstream signaling. Region-specific BDNF/TrkB deletion (CA3 vs CA1), electrophysiology (synaptic potentiation), dynamin1 dependence assay, behavioral antidepressant assay Cell reports High 34407417
2022 BDNF and TrkB form an autocrine loop in senescent cells: senescent cells express high TrkB (NTRK2) and secrete BDNF (SASP factor); TrkB activation by BDNF promotes senescent cell survival by activating ERK5 and elevating BCL2L2; TrkB inhibition selectively triggers apoptosis of senescent cells and reduces senescent cell accumulation in aged mouse organs. Drug library screen, TrkB inhibitor treatment, BDNF ablation, ERK5/BCL2L2 signaling assays, apoptosis assays, in vivo aged mouse organ analysis Nature communications High 36266274
2022 Oxytocin rapidly transactivates TrkB receptors in primary cortical neurons and in acute brain slices, increasing TrkB tyrosine phosphorylation via the oxytocin GPCR (not the vasopressin receptor). TrkB transactivation by oxytocin enhances gephyrin clustering, suggesting a mechanism for oxytocin modulation of inhibitory synapses. Immunoblot for phospho-TrkB, acute brain slice preparation (bath application), primary cortical culture, receptor pharmacology, gephyrin clustering immunostaining Frontiers in molecular neuroscience Medium 35721318
2022 TrkB activation via BDNF/TrkB signaling activates Akt which phosphorylates and inhibits asparagine endopeptidase (AEP); TrkB agonist R13 increases osteoprotegerin (OPG) through TrkB→CREB activation, blocking trabecular bone loss; TrkB also inhibits the C/EBPβ/AEP pathway to suppress RANKL-induced osteoclastogenesis. TrkB agonist (R13/7,8-DHF) treatment, ovariectomy (OVX) mouse model, AEP knockout mice, AEP phosphorylation assays, OPG/RANKL measurement, osteoclastogenesis assay (RAW264.7), CREB activation assay Nature communications Medium 35973996
2023 LSD and psilocin directly bind to TrkB with affinities ~1,000-fold higher than other antidepressants, binding at distinct but partially overlapping sites within the TMD of TrkB dimers relative to antidepressant binding sites. Psychedelic effects on neurotrophic signaling, plasticity, and antidepressant-like behavior depend on TrkB binding and promotion of endogenous BDNF signaling but are independent of 5-HT2A receptor activation; LSD-induced head twitching is dependent on 5-HT2A and independent of TrkB. Radioligand binding assays, molecular dynamics simulations, TrkB-binding site mutagenesis, neurotrophic signaling assays, plasticity assays, in vivo behavioral assays in mice (antidepressant-like behavior, head twitch response) Nature neuroscience High 37280397
2024 Cortical BDNF-TrkB-CREB signaling in layer 5 pyramidal neurons regulates sleep slow-wave activity (SWA): pharmacological and optogenetic perturbations show TrkB activation is required for SWA buildup; TrkB activation enriches ubiquitin and proteasome subunits (by proteomic analysis); BDNF effects on synaptic strength increase SWA independently of neuronal firing per se. Pharmacology (TrkB inhibitor), optogenetic perturbations, EEG (SWA measurement), RNA sequencing/transcriptomics, proteomics, mathematical modeling, layer 5 cell-specific analysis Cell reports Medium 39046880
2018 BDNF-TrkB signaling in oxytocin (OXT) neurons is required for maternal behavior: ablation of TrkB selectively in OXT neurons partially recapitulates maternal care impairments seen in BDNF-deficient females; BDNF signaling through TrkB in OXT neurons regulates oxytocin expression during development. OXT neuron-specific TrkB conditional knockout, maternal behavior assessment, oxytocin expression analysis, translating ribosome affinity purification (TRAP) RNA-seq eLife Medium 30192229
2021 Adult TrkB signaling in parvalbumin (PV) interneurons of the medial prefrontal cortex is essential for maintenance of PV interneuron integrity, local network dynamics, and γ oscillations: viral dominant-negative trkB expression in mPFC PV interneurons reduces PV inhibition, increases broadband LFP activity, and increases aggression, demonstrating that adult BDNF/trkB signaling sustains PV interneuron function. Viral vector (dominant-negative trkB), immunohistochemistry, local field potential (LFP) recording, behavioral assays The Journal of neuroscience Medium 33593856
2018 Overexpression of truncated (inactive) TrkB in the orbitofrontal cortex or dorsomedial striatum interferes with TrkB phosphorylation and ERK42/44 phosphorylation, abolishing goal-directed action selection. In the dorsolateral striatum, truncated TrkB overexpression blocks habit formation, demonstrating that corticostriatal TrkB-ERK signaling is necessary for balancing goal-directed versus habitual behaviors. Viral-mediated truncated TrkB overexpression in specific brain regions, immunoblot for phospho-TrkB and phospho-ERK, operant conditioning behavioral assays Scientific reports Medium 29540698
2015 TrkB kinase activity at neuromuscular junctions (NMJ) is required for presynaptic terminal maintenance: inhibition of TrkB kinase activity in TrkBF616A mice reduces presynaptic terminal volume (~20%) and motor end-plate area (~10%); in early old age, TrkB kinase inhibition significantly reduces NMJ pre/postsynaptic overlap and increases denervated NMJs (~20%). Chemical-genetic TrkB kinase inhibition (TrkBF616A + 1NMPP1), confocal microscopy of NMJ morphology, quantification of denervation Experimental gerontology Medium 26517952
2014 TrkB kinase activity inhibition suppresses kindled seizures: inducible conditional TrkB knockout reduces behavioral seizure severity; chemical-genetic TrkB kinase inhibition (TrkBF616A + 1NMPP1) reversibly elevates focal electrographic and generalized seizure thresholds in kindled mice, establishing TrkB kinase as an antiseizure target. Inducible conditional TrkB knockout (Act-CreER TrkBflox/flox), chemical-genetic approach (TrkBF616A + 1NMPP1), kindling model, electrographic seizure threshold measurement Epilepsia High 24903749
2012 RNA aptamer C4-3 binds the extracellular domain of TrkB with high affinity (Kd ~2 nM), acts as a partial TrkB agonist, exhibits neuroprotective effects in cortical neurons, and activates TrkB upon hippocampal infusion in mice, demonstrating the extracellular domain as a functional binding/activation site. Recombinant protein binding assays (Kd measurement), cell-based signaling assays, cortical neuron neuroprotection assay, in vivo TrkB activation (hippocampal infusion) Molecular pharmacology Medium 22752556

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 TrkB signalling pathways in LTP and learning. Nature reviews. Neuroscience 841 19927149
2013 Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma. Nature genetics 649 23817572
2010 Postsynaptic BDNF-TrkB signaling in synapse maturation, plasticity, and disease. Developmental neurobiology 571 20186705
1989 trkB, a novel tyrosine protein kinase receptor expressed during mouse neural development. The EMBO journal 560 2555172
2021 Antidepressant drugs act by directly binding to TRKB neurotrophin receptors. Cell 512 33606976
2004 Suppression of anoikis and induction of metastasis by the neurotrophic receptor TrkB. Nature 487 15329723
2002 Mechanism of TrkB-mediated hippocampal long-term potentiation. Neuron 374 12367511
1994 Expression and function of TRK-B and BDNF in human neuroblastomas. Molecular and cellular biology 343 8264643
2023 Psychedelics promote plasticity by directly binding to BDNF receptor TrkB. Nature neuroscience 340 37280397
1992 The trkB tyrosine protein kinase is a receptor for neurotrophin-4. Neuron 294 1375038
1998 TrkB and TrkC signaling are required for maturation and synaptogenesis of hippocampal connections. The Journal of neuroscience : the official journal of the Society for Neuroscience 207 9736654
2013 TrkB receptor signalling: implications in neurodegenerative, psychiatric and proliferative disorders. International journal of molecular sciences 200 23670594
2012 Truncated TrkB: beyond a dominant negative receptor. Cytokine & growth factor reviews 165 22341689
2016 Neuroprotection, Growth Factors and BDNF-TrkB Signalling in Retinal Degeneration. International journal of molecular sciences 160 27657046
2011 The CREB1-BDNF-NTRK2 pathway in depression: multiple gene-cognition-environment interactions. Biological psychiatry 131 21215389
2013 Oligodendroglial expression of TrkB independently regulates myelination and progenitor cell proliferation. The Journal of neuroscience : the official journal of the Society for Neuroscience 124 23486965
1997 Expression of TrkA, TrkB and TrkC in human neuroblastomas. Journal of neuro-oncology 120 9049830
2010 Increased BDNF levels and NTRK2 gene association suggest a disruption of BDNF/TrkB signaling in autism. Genes, brain, and behavior 107 20662941
2005 Biological effects of TrkA and TrkB receptor signaling in neuroblastoma. Cancer letters 100 15921851
1996 Expression and function of TrkB variants in developing sensory neurons. The EMBO journal 99 8978665
1993 BDNF and trkB mRNA expression in the hippocampal formation of aging rats. Neurobiology of aging 91 8487914
2012 BDNF-TrkB signaling and neuroprotection in schizophrenia. Asian journal of psychiatry 90 23380313
2018 Targeting the BDNF/TrkB pathway for the treatment of tumors. Oncology letters 86 30675270
2021 A synaptic locus for TrkB signaling underlying ketamine rapid antidepressant action. Cell reports 84 34407417
1995 Cloning and chromosomal localization of the human TRK-B tyrosine kinase receptor gene (NTRK2). Genomics 81 7789988
2012 Imbalance of neurotrophin receptor isoforms TrkB-FL/TrkB-T1 induces neuronal death in excitotoxicity. Cell death & disease 80 22258407
2020 Function and Mechanisms of Truncated BDNF Receptor TrkB.T1 in Neuropathic Pain. Cells 77 32403409
2015 Slitrk5 Mediates BDNF-Dependent TrkB Receptor Trafficking and Signaling. Developmental cell 77 26004511
2019 Targeting BDNF/TrkB pathways for preventing or suppressing epilepsy. Neuropharmacology 73 31377199
2017 Therapeutic Potentials of BDNF/TrkB in Breast Cancer; Current Status and Perspectives. Journal of cellular biochemistry 72 28230291
2014 Neurotrophin receptor TrkB promotes lung adenocarcinoma metastasis. Proceedings of the National Academy of Sciences of the United States of America 71 24982195
2014 Loss of Ntrk2/Kiss1r signaling in oocytes causes premature ovarian failure. Endocrinology 66 24877631
2017 Isoflurane produces antidepressant effects and induces TrkB signaling in rodents. Scientific reports 65 28798343
2014 BDNF and its TrkB receptor in human fracture healing. Annals of anatomy = Anatomischer Anzeiger : official organ of the Anatomische Gesellschaft 65 24984919
2013 Abnormal retinoid and TrkB signaling in the prefrontal cortex in mood disorders. Cerebral cortex (New York, N.Y. : 1991) 64 23960204
2009 NTRK1 and NTRK2 receptors facilitate follicle assembly and early follicular development in the mouse ovary. Reproduction (Cambridge, England) 64 19357131
2005 The neurotrophic receptor TrkB in anoikis resistance and metastasis: a perspective. Cancer research 63 16103047
2008 Genetic association of neurotrophic tyrosine kinase receptor type 2 (NTRK2) With Alzheimer's disease. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 61 17918233
2022 TrkB Truncated Isoform Receptors as Transducers and Determinants of BDNF Functions. Frontiers in neuroscience 60 35321093
2008 Association studies of the BDNF and the NTRK2 gene polymorphisms with prophylactic lithium response in bipolar patients. Pharmacogenomics 60 19018715
2016 Sulforaphane epigenetically enhances neuronal BDNF expression and TrkB signaling pathways. Molecular nutrition & food research 58 27735126
2015 Norepinephrine Protects against Amyloid-β Toxicity via TrkB. Journal of Alzheimer's disease : JAD 58 25208620
2018 Brain derived neurotrophic factor (BDNF), its tyrosine kinase receptor B (TrkB) and nicotine. Neurotoxicology 55 29499216
2020 Human BDNF/TrkB variants impair hippocampal synaptogenesis and associate with neurobehavioural abnormalities. Scientific reports 53 32493978
2008 Gene-gene interactions among CHRNA4, CHRNB2, BDNF, and NTRK2 in nicotine dependence. Biological psychiatry 52 18534558
2020 TrkB-expressing paraventricular hypothalamic neurons suppress appetite through multiple neurocircuits. Nature communications 49 32265438
2004 Interaction of BDNF/TrkB signaling with NMDA receptor in learning and memory. Drug news & perspectives 49 15514702
2021 The Emerging Role of BDNF/TrkB Signaling in Cardiovascular Diseases. Life (Basel, Switzerland) 47 33477900
2011 BDNF-TrkB signalling in fear learning: from genetics to neural networks. Reviews in the neurosciences 44 21639804
2020 A kinase-deficient NTRK2 splice variant predominates in glioma and amplifies several oncogenic signaling pathways. Nature communications 43 32532995
2018 BDNF-TrkB signaling in oxytocin neurons contributes to maternal behavior. eLife 43 30192229
2012 Prelimbic BDNF and TrkB signaling regulates consolidation of both appetitive and aversive emotional learning. Translational psychiatry 43 23250006
2015 BDNF, via truncated TrkB receptor, modulates GlyT1 and GlyT2 in astrocytes. Glia 41 26200505
2022 A TrkB agonist prodrug prevents bone loss via inhibiting asparagine endopeptidase and increasing osteoprotegerin. Nature communications 39 35973996
2018 Prefrontal cortical trkB, glucocorticoids, and their interactions in stress and developmental contexts. Neuroscience and biobehavioral reviews 38 30477984
2015 Role of TrkB kinase activity in aging diaphragm neuromuscular junctions. Experimental gerontology 36 26517952
2012 RNA aptamer-based functional ligands of the neurotrophin receptor, TrkB. Molecular pharmacology 36 22752556
2024 TrkB transmembrane domain: bridging structural understanding with therapeutic strategy. Trends in biochemical sciences 34 38433044
2022 The BDNF/TrkB Neurotrophin System in the Sensory Organs of Zebrafish. International journal of molecular sciences 34 35269763
2008 Targeting TrkB neurotrophin receptor to treat depression. Expert opinion on therapeutic targets 34 18479217
2017 Regulation of actions and habits by ventral hippocampal trkB and adolescent corticosteroid exposure. PLoS biology 33 29186135
2015 TrkB Promotes Breast Cancer Metastasis via Suppression of Runx3 and Keap1 Expression. Molecules and cells 33 26657794
2013 The interaction of BDNF and NTRK2 gene increases the susceptibility of paranoid schizophrenia. PloS one 33 24069289
2019 TrkB agonistic antibodies superior to BDNF: Utility in treating motoneuron degeneration. Neurobiology of disease 32 31470106
2013 Neurotrophic tyrosine kinase receptor type 2 (NTRK2) gene associated with treatment response to mood stabilizers in patients with bipolar I disorder. Journal of molecular neuroscience : MN 32 23315174
2019 TrkB neurotrophin receptor at the core of antidepressant effects, but how? Cell and tissue research 31 30637517
2022 A BDNF-TrkB autocrine loop enhances senescent cell viability. Nature communications 30 36266274
2024 BDNF-TrkB Signaling in Mitochondria: Implications for Neurodegenerative Diseases. Molecular neurobiology 29 39030441
2022 The MBNL1/circNTRK2/PAX5 pathway regulates aerobic glycolysis in glioblastoma cells by encoding a novel protein NTRK2-243aa. Cell death & disease 29 36064939
2020 Cholinergic neuroplasticity in asthma driven by TrkB signaling. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 29 32277855
1999 Compartmental expression of trkB receptor protein in the developing striatum. Neuroscience 28 10077331
2021 ERRγ ligand HPB2 upregulates BDNF-TrkB and enhances dopaminergic neuronal phenotype. Pharmacological research 27 33434621
2020 LMP1 promotes nasopharyngeal carcinoma metastasis through NTRK2-mediated anoikis resistance. American journal of cancer research 26 32775002
2018 Partial TrkB receptor activation suppresses cortical epileptogenesis through actions on parvalbumin interneurons. Neurobiology of disease 26 29408225
2011 Expression of TrkB and BDNF in human cochlea-an immunohistochemical study. Cell and tissue research 26 21739244
2014 The truncated TrkB receptor influences mammalian sleep. American journal of physiology. Regulatory, integrative and comparative physiology 25 25502751
2020 Individual differences in stereotypy and neuron subtype translatome with TrkB deletion. Molecular psychiatry 24 32366954
2024 BDNF-TrkB signaling orchestrates the buildup process of local sleep. Cell reports 23 39046880
2022 Enhanced BDNF and TrkB Activation Enhance GABA Neurotransmission in Cerebellum in Hyperammonemia. International journal of molecular sciences 23 36233065
2021 Adult trkB Signaling in Parvalbumin Interneurons is Essential to Prefrontal Network Dynamics. The Journal of neuroscience : the official journal of the Society for Neuroscience 23 33593856
2015 The neurotrophic receptor Ntrk2 directs lymphoid tissue neovascularization during Leishmania donovani infection. PLoS pathogens 23 25710496
2022 Circular RNA_0006014 promotes breast cancer progression through sponging miR-885-3p to regulate NTRK2 and PIK3/AKT pathway. Aging 22 35383130
2018 P2X4R silence suppresses glioma cell growth through BDNF/TrkB/ATF4 signaling pathway. Journal of cellular biochemistry 22 30362154
2024 Rethinking the role of TRKB in the action of antidepressants and psychedelics. Trends in neurosciences 21 39304417
2022 Transactivation of TrkB Receptors by Oxytocin and Its G Protein-Coupled Receptor. Frontiers in molecular neuroscience 21 35721318
2020 Local TrkB signaling: themes in development and neural plasticity. Cell and tissue research 21 32936344
2008 Expression and localisation of BDNF, NT4 and TrkB in proliferative vitreoretinopathy. Experimental eye research 21 18405896
2005 Association study of neurotrophic tyrosine kinase receptor type 2 (NTRK2) and childhood-onset mood disorders. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 21 15389758
2020 Effects of palmatine on BDNF/TrkB-mediated trigeminal neuralgia. Scientific reports 20 32193501
2020 TrkB agonists prevent postischemic emergence of refractory neonatal seizures in mice. JCI insight 20 32427585
2014 Antiseizure effects of TrkB kinase inhibition. Epilepsia 20 24903749
2024 Genetic Dissection of BDNF and TrkB Expression in Glial Cells. Biomolecules 19 38254691
2022 Tropomyosin receptor kinase B (TrkB) signalling: targeted therapy in neurogenic tumours. The journal of pathology. Clinical research 19 36533776
2021 Stress Diminishes BDNF-stimulated TrkB Signaling, TrkB-NMDA Receptor Linkage and Neuronal Activity in the Rat Brain. Neuroscience 19 34298123
2019 Locally Activating TrkB Receptor Generates Actin Waves and Specifies Axonal Fate. Cell chemical biology 19 31678045
2017 Variations in COMT and NTRK2 Influence Symptom Burden in Women Undergoing Breast Cancer Treatment. Biological research for nursing 19 28205449
2012 Evidence that truncated TrkB isoform, TrkB-Shc can regulate phosphorylated TrkB protein levels. Biochemical and biophysical research communications 19 22425982
2020 Optical Activation of TrkB Signaling. Journal of molecular biology 18 32422149
2018 Bidirectional coordination of actions and habits by TrkB in mice. Scientific reports 18 29540698
2016 Prenatal Cocaine Exposure Upregulates BDNF-TrkB Signaling. PloS one 18 27494324

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