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Proteasome phosphorylation regulates cocaine-induced sensitization
Molecular and Cellular Neuroscience ( IF 2.6 ) Pub Date : 2017-12-05 , DOI: 10.1016/j.mcn.2017.12.001
Frankie R. Gonzales , Kristin K. Howell , Lara E. Dozier , Stephan G. Anagnostaras , Gentry N. Patrick

Repeated exposure to cocaine produces structural and functional modifications at synapses from neurons in several brain regions including the nucleus accumbens. These changes are thought to underlie cocaine-induced sensitization. The ubiquitin proteasome system plays a crucial role in the remodeling of synapses and has recently been implicated in addiction-related behavior. The ATPase Rpt6 subunit of the 26S proteasome is phosphorylated by Ca2 +/calmodulin-dependent protein kinases II alpha at ser120 which is thought to regulate proteasome activity and distribution in neurons. Here, we demonstrate that Rpt6 phosphorylation is involved in cocaine-induced locomotor sensitization. Cocaine concomitantly increases proteasome activity and Rpt6 S120 phosphorylation in cultured neurons and in various brain regions of wild type mice including the nucleus accumbens and prefrontal cortex. In contrast, cocaine does not increase proteasome activity in Rpt6 phospho-mimetic (ser120Asp) mice. Strikingly, we found a complete absence of cocaine-induced locomotor sensitization in the Rpt6 ser120Asp mice. Together, these findings suggest a critical role for Rpt6 phosphorylation and proteasome function in the regulation cocaine-induced behavioral plasticity.



中文翻译:

蛋白酶体的磷酸化调节可卡因诱导的致敏作用

反复接触可卡因会在包括伏伏核在内的多个大脑区域的神经元突触处产生结构和功能修饰。这些变化被认为是可卡因引起的过敏的基础。泛素蛋白酶体系统在突触的重塑中起关键作用,并且最近与成瘾相关的行为有关。26S蛋白酶体的ATPase Rpt6亚基被Ca 2 +磷酸化/钙调蛋白依赖性蛋白激酶II alpha在ser120处,被认为可调节蛋白酶体的活性和在神经元中的分布。在这里,我们证明Rpt6磷酸化参与可卡因诱导的运动敏化。可卡因在培养的神经元和野生型小鼠的各个大脑区域(包括伏隔核和前额皮层)的神经元和各个脑区中,伴随地增加了蛋白酶体的活性和Rpt6 S120的磷酸化。相反,可卡因在Rpt6磷酸模拟(ser120Asp)小鼠中不增加蛋白酶体活性。令人惊讶的是,我们发现Rpt6 ser120Asp小鼠中完全没有可卡因诱导的运动致敏作用。在一起,这些发现表明Rpt6磷酸化和蛋白酶体功能在可卡因诱导的行为可塑性调节中的关键作用。

更新日期:2017-12-05
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