Narisawa-Saito M, Silva A J, Yamaguchi T, Hayashi T, Yamamoto T, Nawa H
Department of Molecular Neurobiology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan.
Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):2461-6. doi: 10.1073/pnas.96.5.2461.
Src-family protein tyrosine kinases (PTKs) transduce signals to regulate neuronal development and synaptic plasticity. However, the nature of their activators and molecular mechanisms underlying these neural processes are unknown. Here, we show that brain-derived neurotrophic factor (BDNF) and platelet-derived growth factor enhance expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor 1 and 2/3 proteins in rodent neocortical neurons via the Src-family PTK(s). The increase in AMPA receptor levels was blocked in cultured neocortical neurons by addition of a Src-family-selective PTK inhibitor. Accordingly, neocortical cultures from Fyn-knockout mice failed to respond to BDNF whereas those from wild-type mice responded. Moreover, the neocortex of young Fyn mutants exhibited a significant in vivo reduction in these AMPA receptor proteins but not in their mRNA levels. In vitro kinase assay revealed that BDNF can indeed activate the Fyn kinase: It enhanced tyrosine phosphorylation of Fyn as well as that of enolase supplemented exogenously. All of these results suggest that the Src-family kinase Fyn, activated by the growth factors, plays a crucial role in modulating AMPA receptor expression during brain development.
Src家族蛋白酪氨酸激酶（PTK）转导信号以调节神经元发育和突触可塑性。然而，其激活剂的性质以及这些神经过程背后的分子机制尚不清楚。在这里，我们表明脑源性神经营养因子（BDNF）和血小板衍生生长因子通过Src家族PTK增强啮齿动物新皮质神经元中α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）型谷氨酸受体1和2/3蛋白的表达。通过添加Src家族选择性PTK抑制剂，培养的新皮质神经元中AMPA受体水平的增加被阻断。因此，来自Fyn基因敲除小鼠的新皮质培养物对BDNF无反应，而来自野生型小鼠的培养物有反应。此外，年轻Fyn突变体的新皮质在体内这些AMPA受体蛋白显著减少，但其mRNA水平未减少。体外激酶测定表明BDNF确实可以激活Fyn激酶：它增强了Fyn以及外源添加的烯醇化酶的酪氨酸磷酸化。所有这些结果表明，由生长因子激活的Src家族激酶Fyn在大脑发育过程中调节AMPA受体表达方面起着关键作用。
