Tropomyosin receptor kinase B

{{Short description|Protein and coding gene in humans}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox gene}} '''Tropomyosin receptor kinase B''' ('''TrkB'''),<ref>{{cite journal | vauthors = Klein R, Parada LF, Coulier F, Barbacid M | title = trkB, a novel tyrosine protein kinase receptor expressed during mouse neural development | journal = The EMBO Journal | volume = 8 | issue = 12 | pages = 3701–3709 | date = December 1989 | pmid = 2555172 | pmc = 402053 | doi = 10.1002/j.1460-2075.1989.tb08545.x | doi-access = free }}</ref><ref name="Similarities and differences in the">{{cite journal | vauthors = Ip NY, Stitt TN, Tapley P, Klein R, Glass DJ, Fandl J, Greene LA, Barbacid M, Yancopoulos GD | title = Similarities and differences in the way neurotrophins interact with the Trk receptors in neuronal and nonneuronal cells | journal = Neuron | volume = 10 | issue = 2 | pages = 137–149 | date = February 1993 | pmid = 7679912 | doi = 10.1016/0896-6273(93)90306-c | s2cid = 46072027 }}</ref><ref name="Malenka_2009">{{cite book | vauthors = Malenka RC, Nestler EJ, Hyman SE | veditors = Sydor A, Brown RY | chapter = Chapter 8: Atypical neurotransmitters | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | location = New York | year = 2009 | publisher = McGraw-Hill Medical | isbn = 978-0-07-148127-4 | edition = 2nd | quote = 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. }}</ref> 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]].<ref name="Nakagawara_1995">{{cite journal | vauthors = Nakagawara A, Liu XG, Ikegaki N, White PS, Yamashiro DJ, Nycum LM, Biegel JA, Brodeur GM | title = Cloning and chromosomal localization of the human TRK-B tyrosine kinase receptor gene (NTRK2) | journal = Genomics | volume = 25 | issue = 2 | pages = 538–546 | date = January 1995 | pmid = 7789988 | doi = 10.1016/0888-7543(95)80055-Q }}</ref> TrkB is a receptor for [[brain-derived neurotrophic factor]] (BDNF).<ref>{{cite journal | vauthors = Squinto SP, Stitt TN, Aldrich TH, Davis S, Blanco SM, RadzieJewski C, Glass DJ, Masiakowski P, Furth ME, Valenzuela DM, Distefano PS, Yancopoulos GD | title = trkB encodes a functional receptor for brain-derived neurotrophic factor and neurotrophin-3 but not nerve growth factor | journal = Cell | volume = 65 | issue = 5 | pages = 885–893 | date = May 1991 | pmid = 1710174 | doi = 10.1016/0092-8674(91)90395-f | s2cid = 28853455 }}</ref><ref name="TrkB mediates BDNF">{{cite journal | vauthors = Glass DJ, Nye SH, Hantzopoulos P, Macchi MJ, Squinto SP, Goldfarb M, Yancopoulos GD | title = TrkB mediates BDNF/NT-3-dependent survival and proliferation in fibroblasts lacking the low affinity NGF receptor | journal = Cell | volume = 66 | issue = 2 | pages = 405–413 | date = July 1991 | pmid = 1649703 | doi = 10.1016/0092-8674(91)90629-d | s2cid = 43626580 }}</ref>

== Function == Tropomyosin receptor kinase B is the high-affinity [[catalytic receptor]] for several "[[neurotrophin]]s", 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).<ref name="TrkB mediates BDNF"/><ref name="Similarities and differences in the"/> 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 kinase]]s. 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 [[Insulin-like growth factor 1 receptor|IGF1 receptor]], the [[MuSK protein]] receptor, the [[VEGF receptor|Vascular Endothelial Growth Factor (or VEGF) receptor]], etc.

[[Image:TrkB-schema-eng.png|thumb|left|300px|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 [[Phosphoinositide phospholipase C|PLCγ]] binds to TrkB, [[Phosphatidylinositol 4,5-bisphosphate|PIP2]] is hydrolyzed into [[IP3/DAG pathway|IP3]] and [[Diglyceride|DAG]]. IP3 binds to the [[endoplasmic reticulum]], inducing calcium release, while DAG stimulates [[Protein kinase C|Protein Kinase C]] (PKC). PKC activation is implicated in neuronal plasticity and survival, among other effects.<ref>{{cite journal | vauthors = Lanuza MA, Just-Borràs L, Hurtado E, Cilleros-Mañé V, Tomàs M, Garcia N, Tomàs J | title = The Impact of Kinases in Amyotrophic Lateral Sclerosis at the Neuromuscular Synapse: Insights into BDNF/TrkB and PKC Signaling | journal = Cells | volume = 8 | issue = 12 | pages = 1578 | date = December 2019 | pmid = 31817487 | pmc = 6953086 | doi = 10.3390/cells8121578 | doi-access = free }}</ref> Shc binding recruits PI3K, which promotes AKT and MAPK/ERK signaling cascades involved in dendritogenesis, cellular differentiation, and proliferation.<ref name="Minichiello_2009" />

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.<ref name="Harward_2024">{{Cite book | vauthors = Harward SC | veditors = Noebels JL | chapter = 12 | title = Jasper's basic mechanisms of the epilepsies | location = New York, NY | date = 2024 | publisher = Oxford University Press | isbn = 978-0-19-754946-9 | edition = 5th | series = Contemporary neurology series }}</ref> Disease states associated with overexpression of TrkB.T1 include ischemia, stroke, spinal cord injury, neurodegenerative disorders, and chronic pain.<ref>{{Cite journal | vauthors = Cao T, Matyas JJ, Renn CL, Faden AI, Dorsey SG, Wu J | title = Function and Mechanisms of Truncated BDNF Receptor TrkB.T1 in Neuropathic Pain | journal = [[cell (journal)|cells]] | volume = 9 | issue = 5 | date = 2020-05-11 | doi = 10.3390/cell | url = https://www.mdpi.com/2073-4409/9/5/1194 | language = en | doi-broken-date = 3 December 2025 | doi-access = free | issn = 2073-4409 | archive-url = http://web.archive.org/web/20250119113054/https://www.mdpi.com/2073-4409/9/5/1194 | archive-date = 2025-01-19 }}</ref>

== Family members == [[File:Trk Family Members 11212025.jpg|thumb|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]]: [[Nerve growth factor|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.<ref>{{cite journal | vauthors = Patapoutian A, Reichardt LF | title = Trk receptors: mediators of neurotrophin action | journal = Current Opinion in Neurobiology | volume = 11 | issue = 3 | pages = 272–280 | date = June 2001 | pmid = 11399424 | doi = 10.1016/S0959-4388(00)00208-7 }}</ref>

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,<ref>{{cite journal | vauthors = Pulciani S, Santos E, Lauver AV, Long LK, Aaronson SA, Barbacid M | title = Oncogenes in solid human tumours | journal = Nature | volume = 300 | issue = 5892 | pages = 539–542 | date = December 1982 | pmid = 7144906 | doi = 10.1038/300539a0 | s2cid = 30179526 | bibcode = 1982Natur.300..539P }}</ref> 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 inhibitor]]s are (in 2015) in clinical trials and have shown early promise in shrinking human tumors.<ref>{{cite journal | vauthors = Doebele RC, Davis LE, Vaishnavi A, Le AT, Estrada-Bernal A, Keysar S, Jimeno A, Varella-Garcia M, Aisner DL, Li Y, Stephens PJ, Morosini D, Tuch BB, Fernandes M, Nanda N, Low JA | title = An Oncogenic NTRK Fusion in a Patient with Soft-Tissue Sarcoma with Response to the Tropomyosin-Related Kinase Inhibitor LOXO-101 | journal = Cancer Discovery | volume = 5 | issue = 10 | pages = 1049–1057 | date = October 2015 | pmid = 26216294 | pmc = 4635026 | doi = 10.1158/2159-8290.CD-15-0443 }}</ref>

=== 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.<ref name="Minichiello_2009">{{cite journal | vauthors = Minichiello L | title = TrkB signalling pathways in LTP and learning | journal = Nature Reviews. Neuroscience | volume = 10 | issue = 12 | pages = 850–860 | date = December 2009 | pmid = 19927149 | doi = 10.1038/nrn2738 | s2cid = 1383421 }}</ref><ref>{{cite journal | vauthors = Pang PT, Lu B | title = Regulation of late-phase LTP and long-term memory in normal and aging hippocampus: role of secreted proteins tPA and BDNF | journal = Ageing Research Reviews | volume = 3 | issue = 4 | pages = 407–430 | date = November 2004 | pmid = 15541709 | doi = 10.1016/j.arr.2004.07.002 | series = Synaptic Function and Behavior During Normal Ageing | s2cid = 25174502 }}</ref> 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.<ref>{{cite journal | vauthors = Nagappan G, Lu B | title = Activity-dependent modulation of the BDNF receptor TrkB: mechanisms and implications | journal = Trends in Neurosciences | volume = 28 | issue = 9 | pages = 464–471 | date = September 2005 | pmid = 16040136 | doi = 10.1016/j.tins.2005.07.003 | s2cid = 7608817 }}</ref> Both TrkB and BDNF are downregulated in the brain of early AD patients with mild cognitive impairments,<ref>{{cite journal | vauthors = Ginsberg SD, Alldred MJ, Counts SE, Cataldo AM, Neve RL, Jiang Y, Wuu J, Chao MV, Mufson EJ, Nixon RA, Che S | title = Microarray analysis of hippocampal CA1 neurons implicates early endosomal dysfunction during Alzheimer's disease progression | journal = Biological Psychiatry | volume = 68 | issue = 10 | pages = 885–893 | date = November 2010 | pmid = 20655510 | pmc = 2965820 | doi = 10.1016/j.biopsych.2010.05.030 }}</ref><ref>{{cite journal | vauthors = Peng S, Wuu J, Mufson EJ, Fahnestock M | title = 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 = Journal of Neurochemistry | volume = 93 | issue = 6 | pages = 1412–1421 | date = June 2005 | pmid = 15935057 | doi = 10.1111/j.1471-4159.2005.03135.x | s2cid = 770223 | doi-access = free }}</ref> 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.<ref>{{cite journal | vauthors = Devi L, Ohno M | title = TrkB reduction exacerbates Alzheimer's disease-like signaling aberrations and memory deficits without affecting β-amyloidosis in 5XFAD mice | journal = Translational Psychiatry | volume = 5 | issue = 5 | pages = e562 | date = May 2015 | pmid = 25942043 | pmc = 4471286 | doi = 10.1038/tp.2015.55 }}</ref> 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.<ref>{{cite journal | vauthors = Choi SH, Bylykbashi E, Chatila ZK, Lee SW, Pulli B, Clemenson GD, Kim E, Rompala A, Oram MK, Asselin C, Aronson J, Zhang C, Miller SJ, Lesinski A, Chen JW, Kim DY, van Praag H, Spiegelman BM, Gage FH, Tanzi RE | title = Combined adult neurogenesis and BDNF mimic exercise effects on cognition in an Alzheimer's mouse model | journal = Science | volume = 361 | issue = 6406 | date = September 2018 | pmid = 30190379 | pmc = 6149542 | doi = 10.1126/science.aan8821 | article-number = eaan8821 }}</ref> 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.<ref>{{cite journal | vauthors = Wang ZH, Xiang J, Liu X, Yu SP, Manfredsson FP, Sandoval IM, Wu S, Wang JZ, Ye K | title = Deficiency in BDNF/TrkB Neurotrophic Activity Stimulates δ-Secretase by Upregulating C/EBPβ in Alzheimer's Disease | journal = Cell Reports | volume = 28 | issue = 3 | pages = 655–669.e5 | date = July 2019 | pmid = 31315045 | pmc = 6684282 | doi = 10.1016/j.celrep.2019.06.054 }}</ref> 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.<ref>{{cite journal | vauthors = Xia Y, Wang ZH, Liu P, Edgington-Mitchell L, Liu X, Wang XC, Ye K | title = TrkB receptor cleavage by delta-secretase abolishes its phosphorylation of APP, aggravating Alzheimer's disease pathologies | journal = Molecular Psychiatry | volume = 26 | issue = 7 | pages = 2943–2963 | date = July 2021 | pmid = 32782380 | doi = 10.1038/s41380-020-00863-8 | s2cid = 221109220 | doi-access = free }}</ref> 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.<ref>{{cite journal | vauthors = Notaras M, van den Buuse M | title = Neurobiology of BDNF in fear memory, sensitivity to stress, and stress-related disorders | journal = Molecular Psychiatry | volume = 25 | issue = 10 | pages = 2251–2274 | date = October 2020 | pmid = 31900428 | doi = 10.1038/s41380-019-0639-2 | s2cid = 209540967 }}</ref><ref>{{cite journal | vauthors = Pradhan J, Noakes PG, Bellingham MC | title = The Role of Altered BDNF/TrkB Signaling in Amyotrophic Lateral Sclerosis | journal = Frontiers in Cellular Neuroscience | volume = 13 | date = 2019-08-13 | pmid = 31456666 | pmc = 6700252 | doi = 10.3389/fncel.2019.00368 | doi-access = free | article-number = 368 }}</ref><ref name="Tejeda_2017">{{cite journal | vauthors = Tejeda GS, Díaz-Guerra M | title = Integral Characterization of Defective BDNF/TrkB Signalling in Neurological and Psychiatric Disorders Leads the Way to New Therapies | journal = International Journal of Molecular Sciences | volume = 18 | issue = 2 | pages = 268 | date = January 2017 | pmid = 28134845 | pmc = 5343804 | doi = 10.3390/ijms18020268 | doi-access = free }}</ref>

=== Epilepsy === TrkB activation is implicated in [[Chloride potassium symporter 5|KCC2]] downregulation in the CNS.<ref name="Harward_2024" /> KCC2 cotransports potassium and chloride ions out of the cell. Chloride levels inside the cell remain low, so when [[GABAA receptor|GABAA receptors]] are activated, extracellular chloride can flow into the cell, inducing [[Hyperpolarization (biology)|hyperpolarization]]. KCC2 downregulation causes intracellular Cl<big>-</big> accumulation, decreasing the [[electrochemical gradient]] that is critical for inhibitory GABAA signaling.<ref>{{cite journal | vauthors = Jaenisch N, Witte OW, Frahm C | title = Downregulation of potassium chloride cotransporter KCC2 after transient focal cerebral ischemia | journal = Stroke | volume = 41 | issue = 3 | pages = e151–e159 | date = March 2010 | pmid = 20044519 | doi = 10.1161/STROKEAHA.109.570424 }}</ref> Altered inhibitory transmission caused by KCC2 downregulation is one mechanism implicated in [[epilepsy]].

=== Depression === In the early 2020s, it was reported that some [[antidepressant]]s, [[ketamine]], and certain [[psychedelic drug|psychedelic]]s, 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.<ref name="Casarotto_2021">{{cite journal | vauthors = Casarotto PC, Girych M, Fred SM, Kovaleva V, Moliner R, Enkavi G, Biojone C, Cannarozzo C, Sahu MP, Kaurinkoski K, Brunello CA, Steinzeig A, Winkel F, Patil S, Vestring S, Serchov T, Diniz CR, Laukkanen L, Cardon I, Antila H, Rog T, Piepponen TP, Bramham CR, Normann C, Lauri SE, Saarma M, Vattulainen I, Castrén E | title = Antidepressant drugs act by directly binding to TRKB neurotrophin receptors | journal = Cell | volume = 184 | issue = 5 | pages = 1299–1313.e19 | date = March 2021 | pmid = 33606976 | pmc = 7938888 | doi = 10.1016/j.cell.2021.01.034 }}</ref><ref name="Moliner_2023">{{cite journal | vauthors = Moliner R, Girych M, Brunello CA, Kovaleva V, Biojone C, Enkavi G, Antenucci L, Kot EF, Goncharuk SA, Kaurinkoski K, Kuutti M, Fred SM, Elsilä LV, Sakson S, Cannarozzo C, Diniz CR, Seiffert N, Rubiolo A, Haapaniemi H, Meshi E, Nagaeva E, Öhman T, Róg T, Kankuri E, Vilar M, Varjosalo M, Korpi ER, Permi P, Mineev KS, Saarma M, Vattulainen I, Casarotto PC, Castrén E | title = Psychedelics promote plasticity by directly binding to BDNF receptor TrkB | journal = Nature Neuroscience | volume = 26 | issue = 6 | pages = 1032–1041 | date = June 2023 | pmid = 37280397 | pmc = 10244169 | doi = 10.1038/s41593-023-01316-5 | doi-access = free }}</ref> 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.<ref name="Jain_2025">{{cite journal | vauthors = Jain 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 | title = The polypharmacology of psychedelics reveals multiple targets for potential therapeutics | journal = Neuron | volume = 113 | issue = 19 | pages = 3129–3142.e9 | date = October 2025 | pmid = 40683247 | doi = 10.1016/j.neuron.2025.06.012 | quote = 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 }}</ref>

=== 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 [[Tropomyosin receptor kinase A|TrkA]], TrkB (this gene), and [[Tropomyosin receptor kinase C|TrkC]] (respectively, coded by [[Tropomyosin receptor kinase A|NTRK1]], NTRK2, and [[Tropomyosin receptor kinase C|NTRK3]] genes) that is currently in phase 2 clinical testing.<ref>{{cite web | title = Promising entrectinib clinical trial data | date = 18 April 2016 | url = https://www.sciencedaily.com/releases/2016/04/160418092429.htm | work = ScienceDaily }}</ref> 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).<ref>{{cite journal | vauthors = Caffino L, Mottarlini F, Fumagalli F | title = Born to Protect: Leveraging BDNF Against Cognitive Deficit in Alzheimer's Disease | journal = CNS Drugs | volume = 34 | issue = 3 | pages = 281–297 | date = March 2020 | pmid = 32052374 | doi = 10.1007/s40263-020-00705-9 | hdl-access = free | s2cid = 211081340 | hdl = 2434/731220 }}</ref><ref>{{cite journal | vauthors = Palasz E, Wysocka A, Gasiorowska A, Chalimoniuk M, Niewiadomski W, Niewiadomska G | title = BDNF as a Promising Therapeutic Agent in Parkinson's Disease | journal = International Journal of Molecular Sciences | volume = 21 | issue = 3 | pages = 1170 | date = February 2020 | pmid = 32050617 | pmc = 7037114 | doi = 10.3390/ijms21031170 | doi-access = free }}</ref><ref name="Tejeda_2017" />

==Ligands== ===Agonists=== {{Div col|colwidth=20em}} * [[3,7-Dihydroxyflavone]] * [[3,7,8,2'-Tetrahydroxyflavone]] * [[7,3′-Dihydroxyflavone]] * [[7,8,2'-Trihydroxyflavone]] * [[7,8,3'-Trihydroxyflavone]] * [[Amitriptyline]]<ref name="Jang_2009">{{cite journal | vauthors = Jang SW, Liu X, Chan CB, Weinshenker D, Hall RA, Xiao G, Ye K | title = Amitriptyline is a TrkA and TrkB receptor agonist that promotes TrkA/TrkB heterodimerization and has potent neurotrophic activity | journal = Chemistry & Biology | volume = 16 | issue = 6 | pages = 644–656 | date = June 2009 | pmid = 19549602 | pmc = 2844702 | doi = 10.1016/j.chembiol.2009.05.010 }}</ref> * [[BNN-20]]<ref name="Lazaridis_2011">{{cite journal | vauthors = Lazaridis I, Charalampopoulos I, Alexaki VI, Avlonitis N, Pediaditakis I, Efstathopoulos P, Calogeropoulou T, Castanas E, Gravanis A | title = Neurosteroid dehydroepiandrosterone interacts with nerve growth factor (NGF) receptors, preventing neuronal apoptosis | journal = PLoS Biology | volume = 9 | issue = 4 | date = April 2011 | pmid = 21541365 | pmc = 3082517 | doi = 10.1371/journal.pbio.1001051 | doi-access = free | article-number = e1001051 }}</ref> * [[Braegen-02]] * [[Brain-derived neurotrophic factor]] (BDNF) * [[Deoxygedunin]]<ref name="Jang_2010">{{cite journal | vauthors = Jang SW, Liu X, Chan CB, France SA, Sayeed I, Tang W, Lin X, Xiao G, Andero R, Chang Q, Ressler KJ, Ye K | title = Deoxygedunin, a natural product with potent neurotrophic activity in mice | journal = PLOS ONE | volume = 5 | issue = 7 | date = July 2010 | pmid = 20644624 | pmc = 2903477 | doi = 10.1371/journal.pone.0011528 | bibcode = 2010PLoSO...511528J | doi-access = free | article-number = e11528 }}</ref>{{citation needed|date=November 2022}} * [[Diosmetin]] * [[DMAQ-B1]] * [[Eutropoflavin]] (4'-DMA-7,8-DHF)<ref name="Liu_2010">{{cite journal | vauthors = Liu X, Chan CB, Jang SW, Pradoldej S, Huang J, He K, Phun LH, France S, Xiao G, Jia Y, Luo HR, Ye K | title = A synthetic 7,8-dihydroxyflavone derivative promotes neurogenesis and exhibits potent antidepressant effect | journal = Journal of Medicinal Chemistry | volume = 53 | issue = 23 | pages = 8274–8286 | date = December 2010 | pmid = 21073191 | pmc = 3150605 | doi = 10.1021/jm101206p }}</ref> * [[HIOC]] * [[LM22A-4]] * [[N-Acetylserotonin]] (NAS) * [[Neurotrophin-3]] (NT-3) * [[Neurotrophin-4]] (NT-4) * [[Norwogonin]] (5,7,8-THF) * [[R7 (drug)|R7]] ([[prodrug]] of tropoflavin)<ref name="Liu_2016">{{cite journal | vauthors = Liu C, Chan CB, Ye K | title = 7,8-dihydroxyflavone, a small molecular TrkB agonist, is useful for treating various BDNF-implicated human disorders | journal = Translational Neurodegeneration | volume = 5 | date = 2016 | pmid = 26740873 | pmc = 4702337 | doi = 10.1186/s40035-015-0048-7 | doi-access = free | article-number = 2 }}</ref> * [[R13 (drug)|R13]] (BrAD-R13; Braegen-01; prodrug of tropoflavin)<ref name="Chen_2018">{{cite journal | vauthors = Chen C, Wang Z, Zhang Z, Liu X, Kang SS, Zhang Y, Ye K | title = The prodrug of 7,8-dihydroxyflavone development and therapeutic efficacy for treating Alzheimer's disease | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 115 | issue = 3 | pages = 578–583 | date = January 2018 | pmid = 29295929 | pmc = 5777001 | doi = 10.1073/pnas.1718683115 | doi-access = free | bibcode = 2018PNAS..115..578C }}</ref> * [[TDP6]] * [[Tropoflavin]] (7,8-DHF)<ref name="Feng_2015">{{cite journal | vauthors = Feng P, Akladious AA, Hu Y, Raslan Y, Feng J, Smith PJ | title = 7,8-Dihydroxyflavone reduces sleep during dark phase and suppresses orexin A but not orexin B in mice | journal = Journal of Psychiatric Research | volume = 69 | pages = 110–119 | date = October 2015 | pmid = 26343602 | doi = 10.1016/j.jpsychires.2015.08.002 }}</ref> {{Div col end}}

===Antagonists=== {{Div col|colwidth=20em}} * [[ANA-12]] * [[Cyclotraxin B]] * [[Gossypetin]] (3,5,7,8,3',4'-HHF) {{Div col end}}

===Positive allosteric modulators === * [[ACD856]] (nanomolar range)<ref name="Dahlstrom_2021">{{cite journal | vauthors = Dahlström M, Madjid N, Nordvall G, Halldin MM, Vazquez-Juarez E, Lindskog M, Sandin J, Winblad B, Eriksdotter M, Forsell P | title = Identification of Novel Positive Allosteric Modulators of Neurotrophin Receptors for the Treatment of Cognitive Dysfunction | journal = Cells | volume = 10 | issue = 8 | pages = 1871 | date = July 2021 | pmid = 34440640 | pmc = 8391421 | doi = 10.3390/cells10081871 | doi-access = free }}</ref> * [[Ponazuril]] (ACD855) (micromolar range)<ref name="Dahlstrom_2021" />

[[Antidepressant]]s like [[fluoxetine]], [[imipramine]], and others (micromolar range), [[dissociative]]s and related compounds like [[ketamine]] (micromolar range) and [[(2R,6R)-hydroxynorketamine|(2''R'',6''R'')-hydroxynorketamine]] (nanomolar range), and [[serotonergic psychedelic]]s and related drugs like [[LSD]], [[psilocin]], and [[lisuride]] (nanomolar range) have all been reported to act as positive allosteric modulators of TrkB.<ref name="Casarotto_2021" /><ref name="Moliner_2023" /> However, subsequent studies with LSD and psilocin failed to replicate these findings and instead found no interactions of these drugs with TrkB.<ref name="Jain_2025" />

=== Others === * [[Dehydroepiandrosterone]] (DHEA)<ref name="Prough_2016">{{cite journal | vauthors = Prough RA, Clark BJ, Klinge CM | title = Novel mechanisms for DHEA action | journal = Journal of Molecular Endocrinology | volume = 56 | issue = 3 | pages = R139–R155 | date = April 2016 | pmid = 26908835 | doi = 10.1530/JME-16-0013 | doi-access = free }}</ref><ref name="Pediaditakis_2015">{{cite journal | vauthors = Pediaditakis I, Iliopoulos I, Theologidis I, Delivanoglou N, Margioris AN, Charalampopoulos I, Gravanis A | title = Dehydroepiandrosterone: an ancestral ligand of neurotrophin receptors | journal = Endocrinology | volume = 156 | issue = 1 | pages = 16–23 | date = January 2015 | pmid = 25330101 | doi = 10.1210/en.2014-1596 | doi-access = free }}</ref>

== Interactions == TrkB has been shown to [[Protein-protein interaction|interact]] with:

{{div col|colwidth=20em}} * [[Brain-derived neurotrophic factor]] (BDNF),<ref name="Haniu_1997">{{cite journal | vauthors = Haniu M, Montestruque S, Bures EJ, Talvenheimo J, Toso R, Lewis-Sandy S, Welcher AA, Rohde MF | title = 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 | journal = The Journal of Biological Chemistry | volume = 272 | issue = 40 | pages = 25296–25303 | date = October 1997 | pmid = 9312147 | doi = 10.1074/jbc.272.40.25296 | doi-access = free }}</ref><ref name="Naylor_2002">{{cite journal | vauthors = Naylor RL, Robertson AG, Allen SJ, Sessions RB, Clarke AR, Mason GG, Burston JJ, Tyler SJ, Wilcock GK, Dawbarn D | title = A discrete domain of the human TrkB receptor defines the binding sites for BDNF and NT-4 | journal = Biochemical and Biophysical Research Communications | volume = 291 | issue = 3 | pages = 501–507 | date = March 2002 | pmid = 11855816 | doi = 10.1006/bbrc.2002.6468 | bibcode = 2002BBRC..291..501N }}</ref> * [[FYN]],<ref name="Iwasaki_1998">{{cite journal | vauthors = Iwasaki Y, Gay B, Wada K, Koizumi S | title = Association of the Src family tyrosine kinase Fyn with TrkB | journal = Journal of Neurochemistry | volume = 71 | issue = 1 | pages = 106–111 | date = July 1998 | pmid = 9648856 | doi = 10.1046/j.1471-4159.1998.71010106.x | s2cid = 9012343 }}</ref> * [[NCK2]],<ref name="pmid12074588" /> * [[PLCG1]],<ref name="pmid12074588">{{cite journal | vauthors = Suzuki S, Mizutani M, Suzuki K, Yamada M, Kojima M, Hatanaka H, Koizumi S | title = Brain-derived neurotrophic factor promotes interaction of the Nck2 adaptor protein with the TrkB tyrosine kinase receptor | journal = Biochemical and Biophysical Research Communications | volume = 294 | issue = 5 | pages = 1087–1092 | date = June 2002 | pmid = 12074588 | doi = 10.1016/S0006-291X(02)00606-X | bibcode = 2002BBRC..294.1087S }}</ref><ref name="Meakin_1999">{{cite journal | vauthors = Meakin SO, MacDonald JI, Gryz EA, Kubu CJ, Verdi JM | title = The signaling adapter FRS-2 competes with Shc for binding to the nerve growth factor receptor TrkA. A model for discriminating proliferation and differentiation | journal = The Journal of Biological Chemistry | volume = 274 | issue = 14 | pages = 9861–9870 | date = April 1999 | pmid = 10092678 | doi = 10.1074/jbc.274.14.9861 | doi-access = free }}</ref> * [[Sequestosome 1]],<ref name="Geetha_2003">{{cite journal | vauthors = Geetha T, Wooten MW | title = Association of the atypical protein kinase C-interacting protein p62/ZIP with nerve growth factor receptor TrkA regulates receptor trafficking and Erk5 signaling | journal = The Journal of Biological Chemistry | volume = 278 | issue = 7 | pages = 4730–4739 | date = February 2003 | pmid = 12471037 | doi = 10.1074/jbc.M208468200 | doi-access = free }}</ref> and * [[SHC3]].<ref name="pmid12074588" /><ref name="pmid9507002">{{cite journal | vauthors = Nakamura T, Muraoka S, Sanokawa R, Mori N | title = N-Shc and Sck, two neuronally expressed Shc adapter homologs. Their differential regional expression in the brain and roles in neurotrophin and Src signaling | journal = The Journal of Biological Chemistry | volume = 273 | issue = 12 | pages = 6960–6967 | date = March 1998 | pmid = 9507002 | doi = 10.1074/jbc.273.12.6960 | doi-access = free }}</ref> {{Div col end}}

== See also == * [[Trk receptor]]

== References == {{Reflist|33em}}

== Further reading == {{Refbegin|33em}} * {{cite journal | vauthors = Klein R, Conway D, Parada LF, Barbacid M | title = The trkB tyrosine protein kinase gene codes for a second neurogenic receptor that lacks the catalytic kinase domain | journal = Cell | volume = 61 | issue = 4 | pages = 647–656 | date = May 1990 | pmid = 2160854 | doi = 10.1016/0092-8674(90)90476-U | s2cid = 205020147 }} * {{cite journal | vauthors = Squinto SP, Stitt TN, Aldrich TH, Davis S, Blanco SM, RadzieJewski C, Glass DJ, Masiakowski P, Furth ME, Valenzuela DM, Distefano PS, Yancopoulos GD | title = trkB encodes a functional receptor for brain-derived neurotrophic factor and neurotrophin-3 but not nerve growth factor | journal = Cell | volume = 65 | issue = 5 | pages = 885–893 | date = May 1991 | pmid = 1710174 | doi = 10.1016/0092-8674(91)90395-F | s2cid = 28853455 }} * {{cite journal | vauthors = Rose CR, Blum R, Pichler B, Lepier A, Kafitz KW, Konnerth A | title = Truncated TrkB-T1 mediates neurotrophin-evoked calcium signalling in glia cells | journal = Nature | volume = 426 | issue = 6962 | pages = 74–78 | date = November 2003 | pmid = 14603320 | doi = 10.1038/nature01983 | s2cid = 4432074 | bibcode = 2003Natur.426...74R }} * {{cite journal | vauthors = Ohira K, Kumanogoh H, Sahara Y, Homma KJ, Hirai H, Nakamura S, Hayashi M | title = A truncated tropomyosin-related kinase B receptor, T1, regulates glial cell morphology via Rho GDP dissociation inhibitor 1 | journal = The Journal of Neuroscience | volume = 25 | issue = 6 | pages = 1343–1353 | date = February 2005 | pmid = 15703388 | pmc = 6725989 | doi = 10.1523/JNEUROSCI.4436-04.2005 | doi-access = free }} * {{cite journal | vauthors = Yamada K, Nabeshima T | title = Brain-derived neurotrophic factor/TrkB signaling in memory processes | journal = Journal of Pharmacological Sciences | volume = 91 | issue = 4 | pages = 267–270 | date = April 2003 | pmid = 12719654 | doi = 10.1254/jphs.91.267 | doi-access = free }} * {{cite journal | vauthors = Soppet D, Escandon E, Maragos J, Middlemas DS, Reid SW, Blair J, Burton LE, Stanton BR, Kaplan DR, Hunter T, Nikolics K, Parada LF | title = The neurotrophic factors brain-derived neurotrophic factor and neurotrophin-3 are ligands for the trkB tyrosine kinase receptor | journal = Cell | volume = 65 | issue = 5 | pages = 895–903 | date = May 1991 | pmid = 1645620 | doi = 10.1016/0092-8674(91)90396-G | s2cid = 37843818 }} * {{cite journal | vauthors = Squinto SP, Stitt TN, Aldrich TH, Davis S, Blanco SM, RadzieJewski C, Glass DJ, Masiakowski P, Furth ME, Valenzuela DM, Distefano PS, Yancopoulos GD | title = trkB encodes a functional receptor for brain-derived neurotrophic factor and neurotrophin-3 but not nerve growth factor | journal = Cell | volume = 65 | issue = 5 | pages = 885–893 | date = May 1991 | pmid = 1710174 | doi = 10.1016/0092-8674(91)90395-F | s2cid = 28853455 }} * {{cite journal | vauthors = Haniu M, Talvenheimo J, Le J, Katta V, Welcher A, Rohde MF | title = Extracellular domain of neurotrophin receptor trkB: disulfide structure, N-glycosylation sites, and ligand binding | journal = Archives of Biochemistry and Biophysics | volume = 322 | issue = 1 | pages = 256–264 | date = September 1995 | pmid = 7574684 | doi = 10.1006/abbi.1995.1460 }} * {{cite journal | vauthors = Ip NY, Stitt TN, Tapley P, Klein R, Glass DJ, Fandl J, Greene LA, Barbacid M, Yancopoulos GD | title = Similarities and differences in the way neurotrophins interact with the Trk receptors in neuronal and nonneuronal cells | journal = Neuron | volume = 10 | issue = 2 | pages = 137–149 | date = February 1993 | pmid = 7679912 | doi = 10.1016/0896-6273(93)90306-C | s2cid = 46072027 }} * {{cite journal | vauthors = Slaugenhaupt SA, Blumenfeld A, Liebert CB, Mull J, Lucente DE, Monahan M, Breakefield XO, Maayan C, Parada L, Axelrod FB | title = The human gene for neurotrophic tyrosine kinase receptor type 2 (NTRK2) is located on chromosome 9 but is not the familial dysautonomia gene | journal = Genomics | volume = 25 | issue = 3 | pages = 730–732 | date = February 1995 | pmid = 7759111 | doi = 10.1016/0888-7543(95)80019-I | doi-access = free }} * {{cite journal | vauthors = Shelton DL, Sutherland J, Gripp J, Camerato T, Armanini MP, Phillips HS, Carroll K, Spencer SD, Levinson AD | title = Human trks: molecular cloning, tissue distribution, and expression of extracellular domain immunoadhesins | journal = The Journal of Neuroscience | volume = 15 | issue = 1 Pt 2 | pages = 477–491 | date = January 1995 | pmid = 7823156 | pmc = 6578290 | doi = 10.1523/JNEUROSCI.15-01-00477.1995 | doi-access = free }} * {{cite journal | vauthors = Allen SJ, Dawbarn D, Eckford SD, Wilcock GK, Ashcroft M, Colebrook SM, Feeney R, MacGowan SH | title = Cloning of a non-catalytic form of human trkB and distribution of messenger RNA for trkB in human brain | journal = Neuroscience | volume = 60 | issue = 3 | pages = 825–834 | date = June 1994 | pmid = 7936202 | doi = 10.1016/0306-4522(94)90507-X | s2cid = 29288978 }} * {{cite journal | vauthors = Rydén M, Ibáñez CF | title = Binding of neurotrophin-3 to p75LNGFR, TrkA, and TrkB mediated by a single functional epitope distinct from that recognized by trkC | journal = The Journal of Biological Chemistry | volume = 271 | issue = 10 | pages = 5623–5627 | date = March 1996 | pmid = 8621424 | doi = 10.1074/jbc.271.10.5623 | doi-access = free }} * {{cite journal | vauthors = Yamamoto M, Sobue G, Yamamoto K, Terao S, Mitsuma T | title = Expression of mRNAs for neurotrophic factors (NGF, BDNF, NT-3, and GDNF) and their receptors (p75NGFR, trkA, trkB, and trkC) in the adult human peripheral nervous system and nonneural tissues | journal = Neurochemical Research | volume = 21 | issue = 8 | pages = 929–938 | date = August 1996 | pmid = 8895847 | doi = 10.1007/BF02532343 | s2cid = 20559271 }} * {{cite journal | vauthors = Valent A, Danglot G, Bernheim A | title = Mapping of the tyrosine kinase receptors trkA (NTRK1), trkB (NTRK2) and trkC(NTRK3) to human chromosomes 1q22, 9q22 and 15q25 by fluorescence in situ hybridization | journal = European Journal of Human Genetics | volume = 5 | issue = 2 | pages = 102–104 | year = 1997 | pmid = 9195161 | doi = 10.1159/000484742 }} * {{cite journal | vauthors = Haniu M, Montestruque S, Bures EJ, Talvenheimo J, Toso R, Lewis-Sandy S, Welcher AA, Rohde MF | title = 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 | journal = The Journal of Biological Chemistry | volume = 272 | issue = 40 | pages = 25296–25303 | date = October 1997 | pmid = 9312147 | doi = 10.1074/jbc.272.40.25296 | doi-access = free }} * {{cite journal | vauthors = Nakamura T, Muraoka S, Sanokawa R, Mori N | title = N-Shc and Sck, two neuronally expressed Shc adapter homologs. Their differential regional expression in the brain and roles in neurotrophin and Src signaling | journal = The Journal of Biological Chemistry | volume = 273 | issue = 12 | pages = 6960–6967 | date = March 1998 | pmid = 9507002 | doi = 10.1074/jbc.273.12.6960 | doi-access = free }} * {{cite journal | vauthors = Hackett SF, Friedman Z, Freund J, Schoenfeld C, Curtis R, DiStefano PS, Campochiaro PA | title = A splice variant of trkB and brain-derived neurotrophic factor are co-expressed in retinal pigmented epithelial cells and promote differentiated characteristics | journal = Brain Research | volume = 789 | issue = 2 | pages = 201–212 | date = April 1998 | pmid = 9573364 | doi = 10.1016/S0006-8993(97)01440-6 | s2cid = 1814445 | doi-access = free }} * {{cite journal | vauthors = Iwasaki Y, Gay B, Wada K, Koizumi S | title = Association of the Src family tyrosine kinase Fyn with TrkB | journal = Journal of Neurochemistry | volume = 71 | issue = 1 | pages = 106–111 | date = July 1998 | pmid = 9648856 | doi = 10.1046/j.1471-4159.1998.71010106.x | s2cid = 9012343 }} * {{cite journal | vauthors = Qian X, Riccio A, Zhang Y, Ginty DD | title = Identification and characterization of novel substrates of Trk receptors in developing neurons | journal = Neuron | volume = 21 | issue = 5 | pages = 1017–1029 | date = November 1998 | pmid = 9856458 | doi = 10.1016/S0896-6273(00)80620-0 | s2cid = 12354383 | doi-access = free }} * {{cite journal | vauthors = Bibel M, Hoppe E, Barde YA | title = Biochemical and functional interactions between the neurotrophin receptors trk and p75NTR | journal = The EMBO Journal | volume = 18 | issue = 3 | pages = 616–622 | date = February 1999 | pmid = 9927421 | pmc = 1171154 | doi = 10.1093/emboj/18.3.616 }} * {{cite journal | vauthors = Yamada M, Ohnishi H, Sano S, Araki T, Nakatani A, Ikeuchi T, Hatanaka H | title = Brain-derived neurotrophic factor stimulates interactions of Shp2 with phosphatidylinositol 3-kinase and Grb2 in cultured cerebral cortical neurons | journal = Journal of Neurochemistry | volume = 73 | issue = 1 | pages = 41–49 | date = July 1999 | pmid = 10386953 | doi = 10.1046/j.1471-4159.1999.0730041.x | s2cid = 25333848 }} * {{cite journal | vauthors = Ultsch MH, Wiesmann C, Simmons LC, Henrich J, Yang M, Reilly D, Bass SH, de Vos AM | title = Crystal structures of the neurotrophin-binding domain of TrkA, TrkB and TrkC | journal = Journal of Molecular Biology | volume = 290 | issue = 1 | pages = 149–159 | date = July 1999 | pmid = 10388563 | doi = 10.1006/jmbi.1999.2816 }} {{Refend}}

== External links == * [https://www.newscientist.com/channel/being-human/brain/mg19325864.500-memories-are-made-of-this-molecule.html Memories are made of this molecule] - New Scientist, 15 January 2007.

{{Growth factor receptors}} {{Tyrosine kinases}} {{Enzymes}} {{Growth factor receptor modulators}} {{Portal bar|Biology|border=no}} {{Use dmy dates|date=August 2019}}

{{DEFAULTSORT:Trkb}} [[Category:Tyrosine kinase receptors]] [[Category:Developmental neuroscience]]