Nonphosphorylatable Src Ser75 Mutation Increases Ethanol Preference and Consumption in Mice
Nonphosphorylatable Src Ser75 Mutation Increases Ethanol Preference and Consumption in Mice
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DOI：
10.1523/eneuro.0418-18.2019
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发表时间：
2019-03-01
期刊：
影响因子：
3.4
通讯作者：
Kato, Goro
中科院分区：
文献类型：
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作者：
Kato, Goro
SRC在中枢神经系统神经元中高度表达，不仅对发育中的增殖和分化有贡献，而且对大脑的高级功能也有贡献，例如那些导致饮酒的功能。SRC基因敲除小鼠没有表现出中枢神经系统异常，这可能是由于其他Src家族激酶(SFK)的补偿，但存在寿命缩短和骨化病相关缺陷，阻碍了对Src在成年小鼠行为中作用的研究。然而，Src的独特结构域不同于其他SFK的结构域，在Ser75位被细胞周期蛋白依赖性激酶1(CDK1)和CDK5磷酸化，从而影响其在神经元中的有丝分裂后功能。因此，研究了含有非磷酸化(Ser75Ala)或拟磷化(Ser75Asp)Src突变体的小鼠的酒精消耗。携带Ser75Ala Src突变的小鼠，而不是Ser75Asp突变的小鼠，比野生型小鼠更喜欢和消费含有5%和10%乙醇的溶液。然而，血浆乙醇浓度和对乙醇镇静作用的敏感性在不同组之间没有差异。在携带Ser75Ala Src突变体的小鼠中，纹状体中Rho相关激酶(ROCK)的活性显著低于野生型小鼠，Akt Ser473的磷酸化水平显著高于野生型小鼠。这些结果表明，Src以一种依赖于Ser75磷酸化的方式调节自愿饮酒。
Src is highly expressed in CNS neurons and contributes not only to developmental proliferation and differentiation but also to high-order brain functions, such as those contributing to alcohol consumption. Src knock-out mice exhibit no CNS abnormalities, presumably due to compensation by other Src family kinases (SFKs), but have a shortened lifespan and osteopetrosis-associated defects, impeding investigations of the role of Src on behavior in adult mice. However, the Unique domain of Src differs from those in other SFKs and is phosphorylated by cyclin-dependent kinase 1 (Cdk1) and Cdk5 at Ser75, which influences its postmitotic function in neurons. Therefore, ethanol consumption in mice harboring nonphosphorylatable (Ser75Ala) or phosphomimetic (Ser75Asp) Src mutants was investigated. Mice harboring the Ser75Ala Src mutant, but not the Ser75Asp mutant, had a higher preference for and consumption of solutions containing 5% and 10% ethanol than wild-type mice. However, plasma ethanol concentrations and sensitivities to the sedative effects of ethanol were not different among the groups. In mice harboring the Ser75Ala Src mutant, the activity of Rho-associated kinase (ROCK) in the striatum was significantly lower and Akt Ser473 phosphorylation was significantly higher than in wild-type mice. These results suggest that Src regulates voluntary ethanol drinking in a manner that depends on Ser75 phosphorylation.