A chemical-genetic approach to studying neurotrophin signaling

被引：198

作者：

Chen, X

Ye, HH

Kuruvilla, R

Ramanan, N

Scangos, KW

Zhang, C

Johnson, NM

England, PM

Shokat, KM

Ginty, DD ^{[1
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Dept Neurosci, Baltimore, MD 21205 USA

[2] Univ Calif San Francisco, Dept Mol & Cellular Pharmacol, San Francisco, CA 94143 USA

[3] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94143 USA

来源：

NEURON | 2005年 / 46卷 / 01期

关键词：

D O I：

10.1016/j.neuron.2005.03.009

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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 TrkA(F592A) and TrkB(F616A) neurons, respectively, while no such Trk inhibition is observed in wild-type neurons. Moreover, oral administration of 1NMPP1 leads to specific inhibition of TrkA(F592A), TrkB(F616A), and TrkC(F167A) signaling in vivo. Thus, Trk knockin mice provide valuable tools for selective, rapid, and reversible inhibition of neurotrophin signaling in vitro and in vivo.

引用

页码：13 / 21

页数：9

共 29 条

[1] Control of landmark events in meiosis by the CDK Cdc28 and the meiosis-specific kinase Ime2 [J].