A chemical-genetic approach to studying neurotrophin signaling

Xi Chen, Haihong Ye, Rejji Kuruvilla, Narendrakumar Ramanan, Katherine W. Scangos, Chao Zhang, Nicolas M. Johnson, Pamela M. England, Kevan M. Shokat, David D. Ginty

Research output: Contribution to journalArticle

Abstract

Trk tyrosine kinases are receptors for members of the neurotrophin family and are crucial for growth and survival of specific populations of neurons. Yet, the functions of neurotrophin-Trk signaling in postnatal development as well as maintenance and plasticity of the adult nervous system are less clear. We report here the generation of mice harboring Trk knockin alleles that allow for pharmacological control of Trk kinase activity. Nanomolar concentrations of either 1NMPP1 or 1NaPP1, derivatives of the general kinase inhibitor PP1, inhibit NGF and BDNF signaling in TrkAF592A and TrkBF616A neurons, respectively, while no such Trk inhibition is observed in wild-type neurons. Moreover, oral administration of 1NMPP1 leads to specific inhibition of TrkAF592A, TrkBF616A, and TrkCF167A signaling in vivo. Thus, Trk knockin mice provide valuable tools for selective, rapid, and reversible inhibition of neurotrophin signaling in vitro and in vivo.

Original languageEnglish (US)
Pages (from-to)13-21
Number of pages9
JournalNeuron
Volume46
Issue number1
DOIs
StatePublished - Apr 7 2005

ASJC Scopus subject areas

  • Neuroscience(all)

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    Chen, X., Ye, H., Kuruvilla, R., Ramanan, N., Scangos, K. W., Zhang, C., Johnson, N. M., England, P. M., Shokat, K. M., & Ginty, D. D. (2005). A chemical-genetic approach to studying neurotrophin signaling. Neuron, 46(1), 13-21. https://doi.org/10.1016/j.neuron.2005.03.009