Biology:Tropomyosin receptor kinase B

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Short description: Protein and coding gene in humans

A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Tropomyosin receptor kinase B (TrkB),[1][2][3] 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.[4] TrkB is a receptor for brain-derived neurotrophic factor (BDNF).[5][6]

Function

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).[6][2] 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.

TrkB signaling

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.[7] Shc binding recruits PI3K, which promotes AKT and MAPK/ERK signaling cascades involved in dendritogenesis, cellular differentiation, and proliferation.[8]

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.[9] Disease states associated with overexpression of TrkB.T1 include ischemia, stroke, spinal cord injury, neurodegenerative disorders, and chronic pain.[10]

Family members

Tropomyosin kinase receptor family members and their endogenous ligands.

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.[11]

TrkB binds BDNF and NT-4 more strongly than it binds NT-3. NT-3 has a greater binding affinity for TrkC than TrkB.

Clinical Implications

Cancer

Although originally identified as an oncogenic fusion in 1982,[12] 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.[13]

Neurodegenerative Diseases

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.[8][14] 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.[15] Both TrkB and BDNF are downregulated in the brain of early AD patients with mild cognitive impairments,[16][17] 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.[18] 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.[19] 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.[20] 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.[21] 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.[22][23][24]

Epilepsy

TrkB activation is implicated in KCC2 downregulation in the CNS.[9] 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.[25] Altered inhibitory transmission caused by KCC2 downregulation is one mechanism implicated in epilepsy.

Depression

In the early 2020s, it was reported that some antidepressants, ketamine, and certain psychedelics, including LSD and psilocin acted as allosteric modulators by binding to the transmembrane domain of TrkB and that this action might be involved in their antidepressant effects.[26][27] However, subsequent studies with LSD and psilocin indicated that these interactions may be highly dependent on the lipid environment of the cell membrane, which may account for inconsistent findings across experimental models.[28]

Drug Targets

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.[29] 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).[30][31][24]

Ligands

Agonists

Antagonists

Positive allosteric modulators

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.[26][27] However, subsequent studies with LSD and psilocin failed to replicate these findings and instead found no interactions of these drugs with TrkB.[28]

Others

Interactions

TrkB has been shown to interact with:

See also

  • Trk receptor

References

  1. ↑ "trkB, a novel tyrosine protein kinase receptor expressed during mouse neural development". The EMBO Journal 8 (12): 3701–3709. December 1989. doi:10.1002/j.1460-2075.1989.tb08545.x. PMID 2555172. 
  2. ↑ 2.0 2.1 "Similarities and differences in the way neurotrophins interact with the Trk receptors in neuronal and nonneuronal cells". Neuron 10 (2): 137–149. February 1993. doi:10.1016/0896-6273(93)90306-c. PMID 7679912. 
  3. ↑ "Chapter 8: Atypical neurotransmitters". Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. 2009. ISBN 978-0-07-148127-4. "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." 
  4. ↑ "Cloning and chromosomal localization of the human TRK-B tyrosine kinase receptor gene (NTRK2)". Genomics 25 (2): 538–546. January 1995. doi:10.1016/0888-7543(95)80055-Q. PMID 7789988. 
  5. ↑ "trkB encodes a functional receptor for brain-derived neurotrophic factor and neurotrophin-3 but not nerve growth factor". Cell 65 (5): 885–893. May 1991. doi:10.1016/0092-8674(91)90395-f. PMID 1710174. 
  6. ↑ 6.0 6.1 "TrkB mediates BDNF/NT-3-dependent survival and proliferation in fibroblasts lacking the low affinity NGF receptor". Cell 66 (2): 405–413. July 1991. doi:10.1016/0092-8674(91)90629-d. PMID 1649703. 
  7. ↑ "The Impact of Kinases in Amyotrophic Lateral Sclerosis at the Neuromuscular Synapse: Insights into BDNF/TrkB and PKC Signaling". Cells 8 (12): 1578. December 2019. doi:10.3390/cells8121578. PMID 31817487. 
  8. ↑ 8.0 8.1 "TrkB signalling pathways in LTP and learning". Nature Reviews. Neuroscience 10 (12): 850–860. December 2009. doi:10.1038/nrn2738. PMID 19927149. 
  9. ↑ 9.0 9.1 "12". Jasper's basic mechanisms of the epilepsies. Contemporary neurology series (5th ed.). New York, NY: Oxford University Press. 2024. ISBN 978-0-19-754946-9. 
  10. ↑ "Function and Mechanisms of Truncated BDNF Receptor TrkB.T1 in Neuropathic Pain" (in en). cells 9 (5). 2020-05-11. doi:10.3390/cell. ISSN 2073-4409. https://www.mdpi.com/2073-4409/9/5/1194. 
  11. ↑ "Trk receptors: mediators of neurotrophin action". Current Opinion in Neurobiology 11 (3): 272–280. June 2001. doi:10.1016/S0959-4388(00)00208-7. PMID 11399424. 
  12. ↑ "Oncogenes in solid human tumours". Nature 300 (5892): 539–542. December 1982. doi:10.1038/300539a0. PMID 7144906. Bibcode: 1982Natur.300..539P. 
  13. ↑ "An Oncogenic NTRK Fusion in a Patient with Soft-Tissue Sarcoma with Response to the Tropomyosin-Related Kinase Inhibitor LOXO-101". Cancer Discovery 5 (10): 1049–1057. October 2015. doi:10.1158/2159-8290.CD-15-0443. PMID 26216294. 
  14. ↑ "Regulation of late-phase LTP and long-term memory in normal and aging hippocampus: role of secreted proteins tPA and BDNF". Ageing Research Reviews. Synaptic Function and Behavior During Normal Ageing 3 (4): 407–430. November 2004. doi:10.1016/j.arr.2004.07.002. PMID 15541709. 
  15. ↑ "Activity-dependent modulation of the BDNF receptor TrkB: mechanisms and implications". Trends in Neurosciences 28 (9): 464–471. September 2005. doi:10.1016/j.tins.2005.07.003. PMID 16040136. 
  16. ↑ "Microarray analysis of hippocampal CA1 neurons implicates early endosomal dysfunction during Alzheimer's disease progression". Biological Psychiatry 68 (10): 885–893. November 2010. doi:10.1016/j.biopsych.2010.05.030. PMID 20655510. 
  17. ↑ "Precursor form of brain-derived neurotrophic factor and mature brain-derived neurotrophic factor are decreased in the pre-clinical stages of Alzheimer's disease". Journal of Neurochemistry 93 (6): 1412–1421. June 2005. doi:10.1111/j.1471-4159.2005.03135.x. PMID 15935057. 
  18. ↑ "TrkB reduction exacerbates Alzheimer's disease-like signaling aberrations and memory deficits without affecting β-amyloidosis in 5XFAD mice". Translational Psychiatry 5 (5): e562. May 2015. doi:10.1038/tp.2015.55. PMID 25942043. 
  19. ↑ "Combined adult neurogenesis and BDNF mimic exercise effects on cognition in an Alzheimer's mouse model". Science 361 (6406). September 2018. doi:10.1126/science.aan8821. PMID 30190379. 
  20. ↑ "Deficiency in BDNF/TrkB Neurotrophic Activity Stimulates δ-Secretase by Upregulating C/EBPβ in Alzheimer's Disease". Cell Reports 28 (3): 655–669.e5. July 2019. doi:10.1016/j.celrep.2019.06.054. PMID 31315045. 
  21. ↑ "TrkB receptor cleavage by delta-secretase abolishes its phosphorylation of APP, aggravating Alzheimer's disease pathologies". Molecular Psychiatry 26 (7): 2943–2963. July 2021. doi:10.1038/s41380-020-00863-8. PMID 32782380. 
  22. ↑ "Neurobiology of BDNF in fear memory, sensitivity to stress, and stress-related disorders". Molecular Psychiatry 25 (10): 2251–2274. October 2020. doi:10.1038/s41380-019-0639-2. PMID 31900428. 
  23. ↑ "The Role of Altered BDNF/TrkB Signaling in Amyotrophic Lateral Sclerosis". Frontiers in Cellular Neuroscience 13. 2019-08-13. doi:10.3389/fncel.2019.00368. PMID 31456666. 
  24. ↑ 24.0 24.1 "Integral Characterization of Defective BDNF/TrkB Signalling in Neurological and Psychiatric Disorders Leads the Way to New Therapies". International Journal of Molecular Sciences 18 (2): 268. January 2017. doi:10.3390/ijms18020268. PMID 28134845. 
  25. ↑ "Downregulation of potassium chloride cotransporter KCC2 after transient focal cerebral ischemia". Stroke 41 (3): e151–e159. March 2010. doi:10.1161/STROKEAHA.109.570424. PMID 20044519. 
  26. ↑ 26.0 26.1 "Antidepressant drugs act by directly binding to TRKB neurotrophin receptors". Cell 184 (5): 1299–1313.e19. March 2021. doi:10.1016/j.cell.2021.01.034. PMID 33606976. 
  27. ↑ 27.0 27.1 "Psychedelics promote plasticity by directly binding to BDNF receptor TrkB". Nature Neuroscience 26 (6): 1032–1041. June 2023. doi:10.1038/s41593-023-01316-5. PMID 37280397. 
  28. ↑ 28.0 28.1 "The polypharmacology of psychedelics reveals multiple targets for potential therapeutics". Neuron 113 (19): 3129–3142.e9. October 2025. doi:10.1016/j.neuron.2025.06.012. PMID 40683247. "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". 
  29. ↑ "Promising entrectinib clinical trial data". ScienceDaily. 18 April 2016. https://www.sciencedaily.com/releases/2016/04/160418092429.htm. 
  30. ↑ "Born to Protect: Leveraging BDNF Against Cognitive Deficit in Alzheimer's Disease". CNS Drugs 34 (3): 281–297. March 2020. doi:10.1007/s40263-020-00705-9. PMID 32052374. 
  31. ↑ "BDNF as a Promising Therapeutic Agent in Parkinson's Disease". International Journal of Molecular Sciences 21 (3): 1170. February 2020. doi:10.3390/ijms21031170. PMID 32050617. 
  32. ↑ "Amitriptyline is a TrkA and TrkB receptor agonist that promotes TrkA/TrkB heterodimerization and has potent neurotrophic activity". Chemistry & Biology 16 (6): 644–656. June 2009. doi:10.1016/j.chembiol.2009.05.010. PMID 19549602. 
  33. ↑ "Neurosteroid dehydroepiandrosterone interacts with nerve growth factor (NGF) receptors, preventing neuronal apoptosis". PLoS Biology 9 (4). April 2011. doi:10.1371/journal.pbio.1001051. PMID 21541365. 
  34. ↑ "Deoxygedunin, a natural product with potent neurotrophic activity in mice". PLOS ONE 5 (7). July 2010. doi:10.1371/journal.pone.0011528. PMID 20644624. Bibcode: 2010PLoSO...511528J. 
  35. ↑ "A synthetic 7,8-dihydroxyflavone derivative promotes neurogenesis and exhibits potent antidepressant effect". Journal of Medicinal Chemistry 53 (23): 8274–8286. December 2010. doi:10.1021/jm101206p. PMID 21073191. 
  36. ↑ "7,8-dihydroxyflavone, a small molecular TrkB agonist, is useful for treating various BDNF-implicated human disorders". Translational Neurodegeneration 5. 2016. doi:10.1186/s40035-015-0048-7. PMID 26740873. 
  37. ↑ "The prodrug of 7,8-dihydroxyflavone development and therapeutic efficacy for treating Alzheimer's disease". Proceedings of the National Academy of Sciences of the United States of America 115 (3): 578–583. January 2018. doi:10.1073/pnas.1718683115. PMID 29295929. Bibcode: 2018PNAS..115..578C. 
  38. ↑ "7,8-Dihydroxyflavone reduces sleep during dark phase and suppresses orexin A but not orexin B in mice". Journal of Psychiatric Research 69: 110–119. October 2015. doi:10.1016/j.jpsychires.2015.08.002. PMID 26343602. 
  39. ↑ 39.0 39.1 "Identification of Novel Positive Allosteric Modulators of Neurotrophin Receptors for the Treatment of Cognitive Dysfunction". Cells 10 (8): 1871. July 2021. doi:10.3390/cells10081871. PMID 34440640. 
  40. ↑ "Novel mechanisms for DHEA action". Journal of Molecular Endocrinology 56 (3): R139–R155. April 2016. doi:10.1530/JME-16-0013. PMID 26908835. 
  41. ↑ "Dehydroepiandrosterone: an ancestral ligand of neurotrophin receptors". Endocrinology 156 (1): 16–23. January 2015. doi:10.1210/en.2014-1596. PMID 25330101. 
  42. ↑ "Interactions between brain-derived neurotrophic factor and the TRKB receptor. Identification of two ligand binding domains in soluble TRKB by affinity separation and chemical cross-linking". The Journal of Biological Chemistry 272 (40): 25296–25303. October 1997. doi:10.1074/jbc.272.40.25296. PMID 9312147. 
  43. ↑ "A discrete domain of the human TrkB receptor defines the binding sites for BDNF and NT-4". Biochemical and Biophysical Research Communications 291 (3): 501–507. March 2002. doi:10.1006/bbrc.2002.6468. PMID 11855816. Bibcode: 2002BBRC..291..501N. 
  44. ↑ "Association of the Src family tyrosine kinase Fyn with TrkB". Journal of Neurochemistry 71 (1): 106–111. July 1998. doi:10.1046/j.1471-4159.1998.71010106.x. PMID 9648856. 
  45. ↑ 45.0 45.1 45.2 "Brain-derived neurotrophic factor promotes interaction of the Nck2 adaptor protein with the TrkB tyrosine kinase receptor". Biochemical and Biophysical Research Communications 294 (5): 1087–1092. June 2002. doi:10.1016/S0006-291X(02)00606-X. PMID 12074588. Bibcode: 2002BBRC..294.1087S. 
  46. ↑ "The signaling adapter FRS-2 competes with Shc for binding to the nerve growth factor receptor TrkA. A model for discriminating proliferation and differentiation". The Journal of Biological Chemistry 274 (14): 9861–9870. April 1999. doi:10.1074/jbc.274.14.9861. PMID 10092678. 
  47. ↑ "Association of the atypical protein kinase C-interacting protein p62/ZIP with nerve growth factor receptor TrkA regulates receptor trafficking and Erk5 signaling". The Journal of Biological Chemistry 278 (7): 4730–4739. February 2003. doi:10.1074/jbc.M208468200. PMID 12471037. 
  48. ↑ "N-Shc and Sck, two neuronally expressed Shc adapter homologs. Their differential regional expression in the brain and roles in neurotrophin and Src signaling". The Journal of Biological Chemistry 273 (12): 6960–6967. March 1998. doi:10.1074/jbc.273.12.6960. PMID 9507002. 

Further reading



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