title: Effect of synthetic cell-penetrating peptides on TrkA activity in PC12 cells.
abstract: As TrkA, a high-affinity receptor of nerve growth factor (NGF), is a potential target for relieving uncontrolled inflammatory pain, an effective inhibitor of TrkA has been required for pain management. To identify a specific inhibitor of TrkA activity, we designed cell-penetrating peptides combined with amino-acid sequences in the activation loop of TrkA to antagonize tyrosine kinase activity. To select a peptide inhibiting TrkA activity, we examined the effect of cell-penetrating peptides on tyrosine kinase activity of recombinant TrkA in vitro and studied their effects on NGF-stimulated neurite outgrowth and protein phosphorylation in PC12 cells. Thereafter we investigated the effect of the selected peptide on NGF-stimulated TrkA activity and the expression of transient receptor potential channel 1 in PC12 cells. The selected peptide inhibited TrkA activity, but did not inhibit tyrosine kinase activities of other receptor-type tyrosine kinases in vitro. It also suppressed NGF-stimulated responses in PC12 cells. The selected synthetic cell-penetrating peptide antagonizing TrkA function would be a candidate for inflammatory pain therapy.
authors.affiliation: Department of Anesthesiology and Reanimatology, Faculty of Medical Sciences, Fukui University, Eiheijicho, Yoshidagun, Fukui, Japan. hirosem@u-fukui.ac.jp
authors.forename: Munetaka
authors.initials: M
authors.lastname: Hirose
authors.forename: Mayumi
authors.initials: M
authors.lastname: Takatori
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kuroda
authors.forename: Mineo
authors.initials: M
authors.lastname: Abe
authors.forename: Eri
authors.initials: E
authors.lastname: Murata
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Isada
authors.forename: Koyo
authors.initials: K
authors.lastname: Ueda
authors.forename: Kenji
authors.initials: K
authors.lastname: Shigemi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Shibazaki
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Shimizu
authors.forename: Masashi
authors.initials: M
authors.lastname: Hirata
authors.forename: Keita
authors.initials: K
authors.lastname: Fukazawa
authors.forename: Masahiro
authors.initials: M
authors.lastname: Sakaguchi
authors.forename: Kyoko
authors.initials: K
authors.lastname: Kageyama
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Tanaka
mesh_terms: D000700:Analgesics / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002463:Cell Membrane Permeability; D004305:Dose-Response Relationship, Drug; D020932:Nerve Growth Factor / Q000378:metabolism; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology*; D016716:PC12 Cells; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D020917:Receptor, trkA / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D050052:TRPC Cation Channels / Q000187:drug effects / Q000378:metabolism
chemical_list: D000700:Analgesics; C551391:IPTRK3 peptide; D009842:Oligopeptides; D010455:Peptides; D047428:Protein Kinase Inhibitors; D011994:Recombinant Proteins; D050052:TRPC Cation Channels; C096351:transient receptor potential cation channel, subfamily C, member 1; D020932:Nerve Growth Factor; D020917:Receptor, trkA