来自美国加州大学的Robert O. Messing实验室研究发现,PKM-ζ的缺失对LTP或记忆形成没有影响。而且尽管没有这种激酶,但PKM-ζ的药理性抑制因子仍然会破坏这些突变小鼠的记忆。这些数据向PKM-ζ在LTP维持中的作用提出了质疑,并且重新开启了寻找调控长期弹性的关键分子的工作。

-2013年1月17日《自然》

中文翻译


【题目】Prkcz缺失小鼠表现出正常的学习和记忆

【译文】蛋白激酶M-ζ (PKM-ζ)是非典型蛋白激酶C的一种构成性活化形式,它特异性地在脑部表达,并与长期记忆的维持相关。支持PKM-ζ在记忆维持中作用的大多数研究利用PKM-ζ药理学抑制剂,如豆蔻酰化的ζ抑制肽(ZIP)或白屈菜红碱。本研究利用一种遗传方法并靶向Prkcz基因的第9外显子以产生缺乏蛋白激酶C-ζ (PKC-ζ)和PKM-ζ的小鼠 (Prkcz−/−小鼠)。笼子环境中以及在运动功能和感觉基本测试中Prkcz−/−小鼠表现正常行为,但焦虑样行为减少。值得注意的是,与野生型同胞小鼠相比,Prkcz−/−小鼠在信号恐惧条件反射、新事物识别、目标定位识别、可卡因条件性位置偏好实验测试中并没有表现出学习和记忆,或运动学习的缺陷。Prkcz−/−小鼠中,将ZIP注射入伏隔核中会减少可卡因条件性的位置偏好性。体外条件下,ZIP和随机ZIP可以抑制PKM-ζ, PKC-ι 和PKC-ζ,并具有类似的抑制常数值(Ki)。白屈菜红碱是PKM-ζ的一种较弱抑制剂(Ki = 76 μM)。我们的发现表明小鼠中PKM-ζ缺陷并不会损伤学习和记忆,而ZIP在PKM-ζ不存在的时候仍然可以消除奖赏记忆。

英文原稿


[Title]: Prkcz null mice show normal learning and memory

[Authors]:Anna M. Lee,1 Benjamin R. Kanter,1 Dan Wang,1 Jana P. Lim,1 Mimi E. Zou,1 Chichen Qiu,1 Thomas McMahon,1 Jahan Dadgar,1 Sarah C. Fischbach-Weiss1 & Robert O. Messing1

[Abstract]Protein kinase M-ζ (PKM-ζ) is a constitutively active form of atypical protein kinase C that is exclusively expressed in the brain and implicated in the maintenance of long-term memory. Most studies that support a role for PKM-ζ in memory maintenance have used pharmacological PKM-ζ inhibitors such as the myristoylated zeta inhibitory peptide (ZIP) or chelerythrine. Here we use a genetic approach and target exon 9 of the Prkcz gene to generate mice that lack both protein kinase C-ζ (PKC-ζ) and PKM-ζ (Prkcz−/− mice). Prkcz−/− mice showed normal behaviour in a cage environment and in baseline tests of motor function and sensory perception, but displayed reduced anxiety-like behaviour. Notably, Prkcz−/− mice did not show deficits in learning or memory in tests of cued fear conditioning, novel object recognition, object location recognition, conditioned place preference for cocaine, or motor learning, when compared with wild-type littermates. ZIP injection into the nucleus accumbens reduced expression of cocaine-conditioned place preference in Prkcz−/− mice. In vitro, ZIP and scrambled ZIP inhibited PKM-ζ, PKC-ι and PKC-ζ with similar inhibition constant (Ki) values. Chelerythrine was a weak inhibitor of PKM-ζ (Ki = 76 μM). Our findings show that absence of PKM-ζ does not impair learning and memory in mice, and that ZIP can erase reward memory even when PKM-ζ is not present.

原文地址

http://www.nature.com/nature/journal/v493/n7432/full/nature11803.html

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