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Article: Amitriptyline is a TrkA and TrkB Receptor Agonist that Promotes TrkA/TrkB Heterodimerization and Has Potent Neurotrophic Activity

TitleAmitriptyline is a TrkA and TrkB Receptor Agonist that Promotes TrkA/TrkB Heterodimerization and Has Potent Neurotrophic Activity
Authors
KeywordsMOLNEURO
CELLBIO
SIGNALING
Issue Date2009
Citation
Chemistry and Biology, 2009, v. 16, n. 6, p. 644-656 How to Cite?
AbstractNeurotrophins, the cognate ligands for the Trk receptors, are homodimers and induce Trk dimerization through a symmetric bivalent mechanism. We report here that amitriptyline, an antidepressant drug, directly binds TrkA and TrkB and triggers their dimerization and activation. Amitriptyline, but not any other tricyclic or selective serotonin reuptake inhibitor antidepressants, promotes TrkA autophosphorylation in primary neurons and induces neurite outgrowth in PC12 cells. Amitriptyline binds the extracellular domain of both TrkA and TrkB and promotes TrkA-TrkB receptor heterodimerization. Truncation of amitriptyline binding motif on TrkA abrogates the receptor dimerization by amitriptyline. Administration of amitriptyline to mice activates both receptors and significantly reduces kainic acid-triggered neuronal cell death. Inhibition of TrkA, but not TrkB, abolishes amitriptyline's neuroprotective effect without impairing its antidepressant activity. Thus, amitriptyline acts as a TrkA and TrkB agonist and possesses marked neurotrophic activity. © 2009 Elsevier Ltd. All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/225077
ISSN
2015 Impact Factor: 5.774
2015 SCImago Journal Rankings: 3.282

 

DC FieldValueLanguage
dc.contributor.authorJang, Sung Wuk-
dc.contributor.authorLiu, Xia-
dc.contributor.authorChan, Chi Bun-
dc.contributor.authorWeinshenker, David-
dc.contributor.authorHall, Randy A.-
dc.contributor.authorXiao, Ge-
dc.contributor.authorYe, Keqiang-
dc.date.accessioned2016-04-18T11:16:43Z-
dc.date.available2016-04-18T11:16:43Z-
dc.date.issued2009-
dc.identifier.citationChemistry and Biology, 2009, v. 16, n. 6, p. 644-656-
dc.identifier.issn1074-5521-
dc.identifier.urihttp://hdl.handle.net/10722/225077-
dc.description.abstractNeurotrophins, the cognate ligands for the Trk receptors, are homodimers and induce Trk dimerization through a symmetric bivalent mechanism. We report here that amitriptyline, an antidepressant drug, directly binds TrkA and TrkB and triggers their dimerization and activation. Amitriptyline, but not any other tricyclic or selective serotonin reuptake inhibitor antidepressants, promotes TrkA autophosphorylation in primary neurons and induces neurite outgrowth in PC12 cells. Amitriptyline binds the extracellular domain of both TrkA and TrkB and promotes TrkA-TrkB receptor heterodimerization. Truncation of amitriptyline binding motif on TrkA abrogates the receptor dimerization by amitriptyline. Administration of amitriptyline to mice activates both receptors and significantly reduces kainic acid-triggered neuronal cell death. Inhibition of TrkA, but not TrkB, abolishes amitriptyline's neuroprotective effect without impairing its antidepressant activity. Thus, amitriptyline acts as a TrkA and TrkB agonist and possesses marked neurotrophic activity. © 2009 Elsevier Ltd. All rights reserved.-
dc.languageeng-
dc.relation.ispartofChemistry and Biology-
dc.subjectMOLNEURO-
dc.subjectCELLBIO-
dc.subjectSIGNALING-
dc.titleAmitriptyline is a TrkA and TrkB Receptor Agonist that Promotes TrkA/TrkB Heterodimerization and Has Potent Neurotrophic Activity-
dc.typeArticle-
dc.description.natureLink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.chembiol.2009.05.010-
dc.identifier.pmid19549602-
dc.identifier.scopuseid_2-s2.0-67649522902-
dc.identifier.volume16-
dc.identifier.issue6-
dc.identifier.spage644-
dc.identifier.epage656-

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