Arrestin-2 and arrestin-3 differentially modulate locomotor responses and sensitization to amphetamine.
Arrestin-2 and arrestin-3 differentially modulate locomotor responses and sensitization to amphetamine.
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DOI：
10.1016/j.neuropharm.2017.04.021
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发表时间：
2017-07-15
影响因子：
4.7
通讯作者：
Gurevich EV
中科院分区：
文献类型：
--
作者：
Zurkovsky L;Sedaghat K;Ahmed MR;Gurevich VV;Gurevich EV
抑制蛋白在通过G蛋白偶联受体关闭信号传导中起着重要作用。近年来，已经发现抑制蛋白在受体脱敏中的信号传导作用与其功能无关。两种普遍表达的抑制蛋白亚型，抑制蛋白-2和抑制蛋白-3，在脱敏过程中表现相似，并共享许多信号传导功能，使它们能够相互替代。然而，也已经描述了对每个同种型特异的信号传导作用。据报道，缺乏arrestin-3（ARR 3 KO）的小鼠对苯丙胺（AMPH）的运动刺激作用表现出迟钝的急性反应。已经表明，具有抑制蛋白-2缺失的小鼠显示出相似的表型。在这里，我们证明了在7天的治疗期间和7天停药后的AMPH激发期间，雄性ARR 3 KO小鼠的AMPH诱导的运动减少。这些数据与AMPH的运动敏感性受损一致，并表明arrestin-3介导的信号传导在致敏过程中的作用。相反，雄性ARR 2KO小鼠表现出对AMPH的早期反应性增强，并且缺乏进一步的致敏作用，这表明受损的受体脱敏作用。将具有一个arrestin-3等位基因而无arrestin-2的小鼠与ARR 2KO同窝小鼠进行比较，发现前者的活性降低，这与arrestin-3介导的信号传导对AMPH应答的贡献一致。令人惊讶的是，与ARR 3 KO系相比，具有一个arrestin-2等位基因的ARR 3 KO小鼠显示出对AMPH的运动反应显著降低，并且新颖性诱导的运动较低。这些数据表明，一个等位基因的arrestin-2是不能支持正常的运动行为，由于信号和/或发育缺陷。
Arrestins play a prominent role in shutting down signaling via G protein-coupled receptors. In recent years, a signaling role for arrestins independent of their function in receptor desensitization has been discovered. Two ubiquitously expressed arrestin isoforms, arrestin-2 and arrestin-3, perform similarly in the desensitization process and share many signaling functions, enabling them to substitute for one another. However, signaling roles specific to each isoform have also been described. Mice lacking arrestin-3 (ARR3KO) were reported to show blunted acute responsiveness to the locomotor stimulatory effect of amphetamine (AMPH). It has been suggested that mice with deletion of arrestin-2 display a similar phenotype. Here we demonstrate that the AMPH-induced locomotion of male ARR3KO mice is reduced over the 7-day treatment period and during AMPH challenge after a 7-day withdrawal. The data are consistent with impaired locomotor sensitization to AMPH and suggest a role for arrestin-3-mediated signaling in the sensitization process. In contrast, male ARR2KO mice showed enhanced early responsiveness to AMPH and the lack of further sensitization, suggesting a role for impaired receptor desensitization. The comparison of mice possessing one allele of arrestin-3 and no arrestin-2 with ARR2KO littermates revealed reduced activity of the former line, consistent with a contribution of arrestin-3-mediated signaling to AMPH responses. Surprisingly, ARR3KO mice with one arrestin-2 allele showed significantly reduced locomotor responses to AMPH combined with lower novelty-induced locomotion, as compared to the ARR3KO line. These data suggest that one allele of arrestin-2 is unable to support normal locomotor behavior due to signaling and/or developmental defects.
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