Activation of Trk neurotrophin receptors by glucocorticoids provides a neuroprotective effect
Activation of Trk neurotrophin receptors by glucocorticoids provides a neuroprotective effect
复制标题
DOI：
10.1073/pnas.0709102105
复制
发表时间：
2008-03-25
影响因子：
11.1
通讯作者：
Chao, Moses V.
中科院分区：
文献类型：
--
作者：
Jeanneteau, Freddy;Garabedian, Michael J.;Chao, Moses V.
糖皮质激素(GC)对神经系统既有保护作用，也有破坏作用。此外，GCs在应激或脑损伤后会产生神经元损伤；然而，肾上腺类固醇的神经保护作用也已有报道。解释这些积极行动的机制还没有被很好地理解。在此，我们报道了GCs在体内给药后，在脑内以及在培养的海马神经元和皮质神经元中可以选择性地激活Trk受体酪氨酸激酶。Trk受体通常被神经营养因子如NGF和脑源性神经营养因子激活，但GCs对Trk受体的激活并不依赖于神经营养因子的增加。其他酪氨酸激酶受体，如EGF和成纤维细胞生长因子受体，不被GCs激活。GCs增加Trk受体活性的能力导致了对失去营养支持的神经元的神经保护，并可能受到类固醇转换酶的调节。药理学和shRNA实验表明，GCs对Trk受体的激活依赖于GC受体的基因组作用。GCs促进Trk受体活性的能力代表了一种整合了GCs和神经营养因子作用的分子机制。
Glucocorticoids (GCs) display both protective and destructive effects in the nervous system. In excess, GCs produce neuronal damage after stress or brain injury; however, the neuroprotective effects of adrenal steroids also have been reported. The mechanisms that account for the positive actions are not well understood. Here we report that GCs can selectively activate Trk receptor tyrosine kinases after in vivo administration in the brain and in cultures of hippocampal and cortical neurons. Trk receptors are normally activated by neurotrophins, such as NGF and brain-derived neurotrophic factor, but the activation of Trk receptors by GCs does not depend on increased production of neurotrophins. Other tyrosine kinase receptors, such as EGF and FGF receptors, were not activated by GCs. The ability of GCs to increase Trk receptor activity resulted in the neuroprotection of neurons deprived of trophic support and could be modulated by steroid-converting enzymes. Pharmacological and shRNA experiments indicate that Trk receptor activation by GCs depends on a genomic action of the GC receptor. The ability of GCs to promote Trk receptor activity represents a molecular mechanism that integrates the actions of GCs and neurotrophins.