Tropomyosin receptor kinase B (TrkB),[5][6][7] also known astyrosine receptor kinase B, orBDNF/NT-3 growth factors receptor orneurotrophic tyrosine kinase, receptor, type 2 is aprotein that in humans is encoded by theNTRK2gene.[8] TrkB is a receptor forbrain-derived neurotrophic factor (BDNF).[9][10]
Tropomyosin receptor kinase B is the high affinitycatalytic receptor for several "neurotrophins", which are 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), andneurotrophin-3 (NT-3).[11][12] As such, TrkB mediates the multiple effects of these neurotrophic factors, which includes neuronal differentiation and survival. Research has shown that activation of the TrkB receptor can lead to down regulation of theKCC2 chloride transporter in cells of the CNS.[13] In addition to the role of the pathway in neuronal development, BDNF signaling is also necessary for properastrocyte morphogenesis and maturation, via the astrocytic TrkB.T1 isoform.[14]
The TrkB receptor is part of the large family of receptor tyrosine kinases. A "tyrosinekinase" is an enzyme which is capable of adding a phosphate group to certain tyrosines on target proteins, or "substrates". A receptor tyrosine kinase is a "tyrosine kinase" which is located at the cellular membrane, and is activated by binding of a ligand to the receptor's extracellular domain. Other examples of tyrosine kinase receptors include theinsulin receptor, the IGF1 receptor, theMuSK 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). T1 has the original signaling cascade that is involved in the regulation of cell morphology and calcium influx.
TrkB is part of a sub-family of protein kinases which includes alsoTrkA andTrkC. There are other neurotrophic factors structurally related toBDNF:NGF (for nerve growth factor),NT-3 (for neurotrophin-3) andNT-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.
TrkB binds BDNF and NT-4 more strongly than it binds NT-3. TrkC binds NT-3 more strongly than TrkB does.
Although originally identified as an oncogenic fusion in 1982,[15] 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 ofTrk inhibitors are (in 2015) in clinical trials and have shown early promise in shrinking human tumors.[16]
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.[17][18] 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.[19] Both TrkB and BDNF are downregulated in the brain of early AD patients with mild cognitive impairments,[20][21] 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.[22] In addition, combining the induction of adult hippocampalneurogenesis and increasing BDNF levels lead to an improved cognition, mimicking exercise benefits in AD mouse models.[23] 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.[24] 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.[25] 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.[26][27][28]
Entrectinib (formerly RXDX-101) is an investigational drug developed by Ignyta, Inc., which has potential antitumor activity. It is a selective pan-Trk receptortyrosine kinase inhibitor (TKI) targeting gene fusions inTrkA, TrkB (this gene), andTrkC (respectively, coded byNTRK1, NTRK2, andNTRK3 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][28]
In the early 2020s, it was reported that someantidepressants,ketamine, and certainpsychedelic drugs includingLSD andpsilocin 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]
^Ip NY, Stitt TN, Tapley P, Klein R, Glass DJ, Fandl J, Greene LA, Barbacid M, Yancopoulos GD (February 1993). "Similarities and differences in the way neurotrophins interact with the Trk receptors in neuronal and nonneuronal cells".Neuron.10 (2):137–149.doi:10.1016/0896-6273(93)90306-c.PMID7679912.S2CID46072027.
^Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 8: Atypical neurotransmitters". In Sydor A, Brown RY (eds.).Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical.ISBN978-0-07-148127-4.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.
^Nakagawara A, Liu XG, Ikegaki N, White PS, Yamashiro DJ, Nycum LM, et al. (January 1995). "Cloning and chromosomal localization of the human TRK-B tyrosine kinase receptor gene (NTRK2)".Genomics.25 (2):538–546.doi:10.1016/0888-7543(95)80055-Q.PMID7789988.
^Squinto SP, Stitt TN, Aldrich TH, Valenzuela DM, DiStefano PS, Yancopoulos GD (May 1991). "trkB encodes a functional receptor for brain-derived neurotrophic factor and neurotrophin-3 but not nerve growth factor".Cell.65 (5):885–893.doi:10.1016/0092-8674(91)90395-f.PMID1710174.S2CID28853455.
^Glass DJ, Nye SH, Hantzopoulos P, Macchi MJ, Squinto SP, Goldfarb M, Yancopoulos GD (July 1991). "TrkB mediates BDNF/NT-3-dependent survival and proliferation in fibroblasts lacking the low affinity NGF receptor".Cell.66 (2):405–413.doi:10.1016/0092-8674(91)90629-d.PMID1649703.S2CID43626580.
^Glass DJ, Nye SH, Hantzopoulos P, Macchi MJ, Squinto SP, Goldfarb M, Yancopoulos GD (July 1991). "TrkB mediates BDNF/NT-3-dependent survival and proliferation in fibroblasts lacking the low affinity NGF receptor".Cell.66 (2):405–413.doi:10.1016/0092-8674(91)90629-d.PMID1649703.S2CID43626580.
^Ip NY, Stitt TN, Tapley P, Klein R, Glass DJ, Fandl J, Greene LA, Barbacid M, Yancopoulos GD (February 1993). "Similarities and differences in the way neurotrophins interact with the Trk receptors in neuronal and nonneuronal cells".Neuron.10 (2):137–149.doi:10.1016/0896-6273(93)90306-c.PMID7679912.S2CID46072027.
^"BDNF-induced TrkB activation down-regulates the K+-Cl- cotransporter KCC2 and impairs neuronal Cl- extrusion".PMC2173387.
^Nagappan G, Lu B (September 2005). "Activity-dependent modulation of the BDNF receptor TrkB: mechanisms and implications".Trends in Neurosciences.28 (9):464–471.doi:10.1016/j.tins.2005.07.003.PMID16040136.S2CID7608817.
^Notaras M, van den Buuse M (October 2020). "Neurobiology of BDNF in fear memory, sensitivity to stress, and stress-related disorders".Molecular Psychiatry.25 (10):2251–2274.doi:10.1038/s41380-019-0639-2.PMID31900428.S2CID209540967.
^abJain MK, Gumpper RH, Slocum ST, Schmitz GP, Madsen JS, Tummino TA, Suomivuori CM, Huang XP, Shub L, DiBerto JF, Kim K, DeLeon C, Krumm BE, Fay JF, Keiser M, Hauser AS, Dror RO, Shoichet B, Gloriam DE, Nichols DE, Roth BL (July 2025)."The polypharmacology of psychedelics reveals multiple targets for potential therapeutics"(PDF).Neuron.doi:10.1016/j.neuron.2025.06.012.PMID40683247.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
^Feng P, Akladious AA, Hu Y, Raslan Y, Feng J, Smith PJ (October 2015). "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.doi:10.1016/j.jpsychires.2015.08.002.PMID26343602.
^Naylor RL, Robertson AG, Allen SJ, Sessions RB, Clarke AR, Mason GG, et al. (March 2002). "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.Bibcode:2002BBRC..291..501N.doi:10.1006/bbrc.2002.6468.PMID11855816.
^abcSuzuki S, Mizutani M, Suzuki K, Yamada M, Kojima M, Hatanaka H, Koizumi S (June 2002). "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.Bibcode:2002BBRC..294.1087S.doi:10.1016/S0006-291X(02)00606-X.PMID12074588.
Klein R, Conway D, Parada LF, Barbacid M (May 1990). "The trkB tyrosine protein kinase gene codes for a second neurogenic receptor that lacks the catalytic kinase domain".Cell.61 (4):647–656.doi:10.1016/0092-8674(90)90476-U.PMID2160854.S2CID205020147.
Squinto SP, Stitt TN, Aldrich TH, Davis S, Bianco SM, Radziejewski C, et al. (May 1991). "trkB encodes a functional receptor for brain-derived neurotrophic factor and neurotrophin-3 but not nerve growth factor".Cell.65 (5):885–893.doi:10.1016/0092-8674(91)90395-F.PMID1710174.S2CID28853455.
Soppet D, Escandon E, Maragos J, Middlemas DS, Reid SW, Blair J, et al. (May 1991). "The neurotrophic factors brain-derived neurotrophic factor and neurotrophin-3 are ligands for the trkB tyrosine kinase receptor".Cell.65 (5):895–903.doi:10.1016/0092-8674(91)90396-G.PMID1645620.S2CID37843818.
Squinto SP, Stitt TN, Aldrich TH, Davis S, Bianco SM, Radziejewski C, et al. (May 1991). "trkB encodes a functional receptor for brain-derived neurotrophic factor and neurotrophin-3 but not nerve growth factor".Cell.65 (5):885–893.doi:10.1016/0092-8674(91)90395-F.PMID1710174.S2CID28853455.
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