Mao Li-Min, Wang John Q
Department of Biomedical Sciences, School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA.
Department of Biomedical Sciences, School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA; Department of Anesthesiology, School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA.
Neuroscience. 2020 May 1;433:11-20. doi: 10.1016/j.neuroscience.2020.02.048. Epub 2020 Mar 5.
The Src family kinase (SFK) is a subfamily of non-receptor tyrosine kinases. The SFK member Fyn is enriched at synaptic sites in the limbic reward circuit and plays a pivotal role in the regulation of glutamate receptors. In this study, we investigated changes in phosphorylation and function of the two key SFK members (Fyn and Src) and SFK interactions with a metabotropic glutamate (mGlu) receptor in the limbic striatum of adult rats in response to chronic passive stress, i.e., prolonged social isolation which is a pre-validated animal paradigm modeling depression in adulthood. In rats that showed typical anhedonic/depression-like behavior after chronic social isolation, phosphorylation of SFKs at a conserved and activation-associated autophosphorylation site (Y416) was not altered in the two subdivisions of the striatum, the nucleus accumbens and caudate putamen. The total level of phosphorylation and kinase activity of individual Fyn and Src immunopurified from the striatum also remained stable after social isolation. Noticeably, Fyn and Src were found to interact with a G-coupled mGlu5 receptor in striatal neurons. The interaction of Fyn with mGlu5 receptors was selectively elevated in socially isolated rats. Moreover, social isolation induced an increase in surface expression of striatal mGlu5 receptors, which was reduced by an SFK inhibitor. These results indicate that Fyn interacts with mGlu5 receptors in striatal neurons. Adulthood social isolation in rats enhances the Fyn-mGlu5 interaction, which appears to be critical for the upregulation of surface mGlu5 receptor expression in striatal neurons.
Src家族激酶（SFK）是一类非受体酪氨酸激酶亚家族。SFK成员Fyn在边缘奖赏回路的突触部位富集，在谷氨酸受体的调节中起关键作用。在本研究中，我们研究了成年大鼠边缘纹状体中两个关键SFK成员（Fyn和Src）的磷酸化和功能变化，以及SFK与代谢型谷氨酸（mGlu）受体的相互作用，以应对慢性被动应激，即长期社会隔离，这是一种预先验证的成年期抑郁症动物模型。在慢性社会隔离后表现出典型快感缺失/抑郁样行为的大鼠中，纹状体的两个亚区伏隔核和尾壳核中，SFKs在一个保守的、与激活相关的自磷酸化位点（Y416）的磷酸化没有改变。从纹状体免疫纯化的单个Fyn和Src的总磷酸化水平和激酶活性在社会隔离后也保持稳定。值得注意的是，发现Fyn和Src与纹状体神经元中的G偶联mGlu5受体相互作用。在社会隔离的大鼠中，Fyn与mGlu5受体的相互作用选择性升高。此外，社会隔离诱导纹状体mGlu5受体的表面表达增加，而SFK抑制剂可使其降低。这些结果表明Fyn在纹状体神经元中与mGlu5受体相互作用。成年大鼠的社会隔离增强了Fyn-mGlu5的相互作用，这似乎对纹状体神经元中表面mGlu5受体表达的上调至关重要。
