Tropomyosin receptor kinase B (TrkB), [5] [6] [7] also known as tyrosine receptor kinase B, or BDNF/NT-3 growth factors receptor or neurotrophic tyrosine kinase, receptor, type 2 is a protein that in humans is encoded by the NTRK2 gene. [8] TrkB is a receptor for brain-derived neurotrophic factor (BDNF). [9] [10]
Tropomyosin receptor kinase B is the high-affinity catalytic receptor for several "neurotrophins", small protein growth factors that induce the survival and differentiation of distinct cell populations. The neurotrophins that activate TrkB are: BDNF (Brain Derived Neurotrophic Factor), neurotrophin-4 (NT-4), and neurotrophin-3 (NT-3). [11] [12] As such, TrkB mediates the multiple effects of these neurotrophic factors, which include neuronal differentiation and survival.
The TrkB receptor is part of the large family of receptor tyrosine kinases. A tyrosine kinase is an enzyme capable of adding a phosphate group to certain tyrosines on target proteins or substrates. A receptor tyrosine kinase is a tyrosine kinase located at the cellular membrane, and is activated by the binding of a ligand to the receptor's extracellular domain. Other examples of tyrosine kinase receptors include the insulin receptor, the IGF1 receptor, the MuSK protein receptor, the Vascular Endothelial Growth Factor (or VEGF) receptor, etc.
Currently, there are three TrkB isoforms in the mammalian CNS. The full-length isoform (TK+) is a typical tyrosine kinase receptor and transduces the BDNF signal via Ras-ERK, PI3K, and PLCγ. In contrast, two truncated isoforms (TK-: T1 and T2) possess the same extracellular domain, transmembrane domain, and first 12 intracellular amino acid sequences as TK+. However, the C-terminal sequences are isoform-specific (11 and 9 amino acids, respectively).
BDNF binding initiates TrkB dimerization and trans-autophosphorylation, revealing binding sites for PLCγ and Shc proteins. When PLCγ binds to TrkB, PIP2 is hydrolyzed into IP3 and DAG. IP3 binds to the endoplasmic reticulum, inducing calcium release, while DAG stimulates Protein Kinase C (PKC). PKC activation is implicated in neuronal plasticity and survival, among other effects [13] . Shc binding recruits PI3K, which promotes AKT and MAPK/ERK signaling cascades involved in dendritogenesis, cellular differentiation, and proliferation [14] .
TrkB.T1 isoforms prevent autophosphorylation, limiting full-length TrkB signaling and its associated effects on neuronal plasticity. However, TrkB.T1 has separate signaling pathways in astrocytes and glial cells, regulating calcium influx and cell morphology [15] . Disease states associated with overexpression of TrkB.T1 include ischemia, stroke, spinal cord injury, neurodegenerative disorders, and chronic pain [16] .
TrkB is part of a sub-family of protein kinases which includes also TrkA and TrkC. There are other neurotrophic factors structurally related to BDNF: NGF (for nerve growth factor), NT-3 (for neurotrophin-3) and NT-4 (for neurotrophin-4). While TrkB mediates the effects of BDNF, NT-4 and NT-3, TrkA is bound and thereby activated only by NGF. Further, TrkC binds and is activated by NT-3 [17] .
TrkB binds BDNF and NT-4 more strongly than it binds NT-3. NT-3 has a greater binding affinity for TrkC than TrkB.
Although originally identified as an oncogenic fusion in 1982, [18] only recently has there been a renewed interest in the Trk family as it relates to its role in human cancers because of the identification of NTRK1 (TrkA), NTRK2 (TrkB) and NTRK3 (TrkC) gene fusions and other oncogenic alterations in a number of tumor types. A number of Trk inhibitors are (in 2015) in clinical trials and have shown early promise in shrinking human tumors. [19]
TrkB and its ligand BDNF have been associated to both normal brain function and in the pathology and progression of Alzheimer's disease (AD) and other neurodegenerative disorders. First of all, BDNF/TrkB signalling has been implicated in long-term memory formation, the regulation of long-term potentiation, as well as hippocampal synaptic plasticity. [14] [20] In particular, neuronal activity has been shown to lead to an increase in TrkB mRNA transcription, as well as changes in TrkB protein trafficking, including receptor endocytosis or translocation. [21] Both TrkB and BDNF are downregulated in the brain of early AD patients with mild cognitive impairments, [22] [23] while work in mice has shown that reducing TrkB levels in the brain of AD mouse models leads to a significant increase in memory deficits. [24] In addition, combining the induction of adult hippocampal neurogenesis and increasing BDNF levels lead to an improved cognition, mimicking exercise benefits in AD mouse models. [25] The effect of TrkB/BDNF signalling on AD pathology has been shown to be in part mediated by an increase in δ-secretase levels, via an upregulation of the JAK2/STAT3 pathway and C/EBPβ downstream of TrkB. [26] Additionally, TrkB has been shown to reduce amyloid-β production by APP binding and phosphorylation, while TrkB cleavage by δ-secretase blocks normal TrkB activity. [27] Dysregulation of the TrkB/BDNF pathway has been implicated in other neurological and neurodegenerative conditions, including stroke, Huntington's Disease, Parkinson's Disease, Amyotrophic lateral sclerosis and stress-related disorders. [28] [29] [30]
TrkB activation is implicated in KCC2 downregulation in the CNS [15] . KCC2 cotransports potassium and chloride ions out of the cell. Chloride levels inside the cell remain low, so when GABAA receptors are activated, extracellular chloride can flow into the cell, inducing hyperpolarization. KCC2 downregulation causes intracellular Cl- accumulation, decreasing the electrochemical gradient that is critical for inhibitory GABAA signaling [31] . Altered inhibitory transmission caused by KCC2 downregulation is one mechanism implicated in epilepsy.
In the early 2020s, it was reported that some antidepressants, ketamine, and certain psychedelic drugs including LSD and psilocin interacted directly with TrkB and that this action might be involved in their antidepressant effects. [32] [33] However, subsequent studies with LSD and psilocin failed to reproduce these findings and instead found no interaction of these agents with TrkB. [34]
Entrectinib (formerly RXDX-101) is an investigational drug developed by Ignyta, Inc., which has potential antitumor activity. It is a selective pan-Trk receptor tyrosine kinase inhibitor (TKI) targeting gene fusions in TrkA, TrkB (this gene), and TrkC (respectively, coded by NTRK1, NTRK2, and NTRK3 genes) that is currently in phase 2 clinical testing. [35] In addition, TrkB/BDNF signalling has been the target for developing novel drugs for Alzheimer's Disease, Parkinson's Disease or other neurodegenerative and psychiatric disorders, aiming at either pharmacological modulation of the pathway (e.g. small molecule mimetics) or other means (e.g. exercise induced changes in TrkB signalling). [36] [37] [30]
Antidepressants like fluoxetine, imipramine, and others (micromolar range), dissociatives and related compounds like ketamine (micromolar range) and (2R,6R)-hydroxynorketamine (nanomolar range), and serotonergic psychedelics and related drugs like LSD, psilocin, and lisuride (nanomolar range) have all been reported to act as positive allosteric modulators of TrkB. [32] [33] However, subsequent studies with LSD and psilocin failed to replicate these findings and instead found no interactions of these drugs with TrkB. [34]
TrkB has been shown to interact with:
Another common feature of neurotrophins is that they produce their physiologic effects by means of the tropomyosin receptor kinase (Trk) receptor family (also known as the tyrosine receptor kinase family). ...Trk receptors All neurotrophins bind to a class of highly homologous receptor tyrosine kinases known as Trk receptors, of which three types are known: TrkA, TrkB, and TrkC. These transmembrane receptors are glycoproteins whose molecular masses range from 140 to 145 kDa. Each type of Trk receptor tends to bind specific neurotrophins: TrkA is the receptor for NGF, TrkB the receptor for BDNF and NT-4, and TrkC the receptor for NT-3.However, some overlap in the specificity of these receptors has been noted.
{{cite journal}}: CS1 maint: DOI inactive as of December 2025 (link)Recent studies have suggested that psychedelics such as LSD directly interact with TrkB with high affinity, promoting BDNF-mediated neuroplasticity and antidepressant-like effects via allosteric potentiation of BDNF signaling in active synapses.8 To investigate this, we screened LSD across 450 human kinases, including TrkB, but found no significant interactions between LSD and any tested human kinases. Further experiments in transfected cells revealed no effect of LSD or psilocin on BDNF-mediated activation of a TrkB reporter. We note that similar negative preliminary results, which have not yet been published in a peer-reviewed journal, were recently reported by Boltaev et al.63
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