A chemical-genetic approach to studying neurotrophin signaling
A chemical-genetic approach to studying neurotrophin signaling
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DOI：
10.1016/j.neuron.2005.03.009
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发表时间：
2005-04-07
期刊：
影响因子：
16.2
通讯作者：
Ginty, DD
中科院分区：
文献类型：
--
作者：
Chen, X;Ye, HH;Ginty, DD
Trk酪氨酸激酶是神经营养因子家族成员的受体，对特定神经元群体的生长和存活至关重要。然而，神经营养因子- trk信号在出生后发育以及成人神经系统的维持和可塑性中的作用尚不清楚。我们在这里报道了携带Trk敲入基因等位基因的小鼠，这些等位基因允许对Trk激酶活性进行药理学控制。一般激酶抑制剂PP1的衍生物1NMPP1或1NaPP1的纳摩尔浓度分别抑制TrkA（F592A）和TrkB（F616A）神经元中的NGF和BDNF信号传导，而在野生型神经元中没有观察到这种抑制作用。此外，口服1NMPP1可导致体内TrkA（F592A）、TrkB（F616A）和TrkC（F167A）信号通路的特异性抑制。因此，Trk敲入小鼠为体外和体内选择性、快速、可逆地抑制神经营养因子信号提供了有价值的工具。
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.