小柯机器人

美国科罗拉多大学安舒茨医学院K. Ulrich Bayer团队近期取得重要工作进展，他们研究发现，LTP的诱导依赖CaMKII的结构功能而不是酶活性。相关研究成果2023年8月30日在线发表于《自然》杂志上。

据介绍，学习和记忆被认为需要海马长时程增强（LTP），三十多年来无可争议的分子神经科学的少数核心教条之一是，LTP诱导需要Ca2⁺/钙调蛋白依赖性蛋白激酶II（CaMKII）的酶活性。

然而，实验证据远非结论性的。所有先前抑制酶促CaMKII活性和LTP的干预措施也会干扰CaMKII的结构作用，特别是与NMDA型谷氨酸受体亚基GluN2B的结合。因此，研究人员在这里表征并利用一组互补的新的光/药物遗传学工具来区分酶促和结构CaMKII功能。一些独立的证据表明，LTP的诱导是通过CaMKII的结构功能，而不是通过其酶活性。激酶活性的唯一贡献是通过T286自身磷酸化来自动调节这种结构作用，这解释了为什么几十年来这种区别一直难以捉摸。即使在酶促CaMKII活性被阻断的情况下，以绕过T286作用的方式直接启动结构功能也足以引发强大的LTP。

附：英文原文

Title: LTP induction by structural rather than enzymatic functions of CaMKII

Author: Tullis, Jonathan E., Larsen, Matthew E., Rumian, Nicole L., Freund, Ronald K., Boxer, Emma E., Brown, Carolyn Nicole, Coultrap, Steven J., Schulman, Howard, Aoto, Jason, DellAcqua, Mark L., Bayer, K. Ulrich

Issue&Volume: 2023-08-30

Abstract: Learning and memory are thought to require hippocampal long-term potentiation (LTP), and one of the few central dogmas of molecular neuroscience that has stood undisputed for more than three decades is that LTP induction requires enzymatic activity of the Ca2+/calmodulin-dependent protein kinase II (CaMKII)1,2,3. However, as we delineate here, the experimental evidence is surprisingly far from conclusive. All previous interventions inhibiting enzymatic CaMKII activity and LTP4,5,6,7,8 also interfere with structural CaMKII roles, in particular binding to the NMDA-type glutamate receptor subunit GluN2B9,10,11,12,13,14. Thus, we here characterized and utilized complementary sets of new opto-/pharmaco-genetic tools to distinguish between enzymatic and structural CaMKII functions. Several independent lines of evidence demonstrated LTP induction by a structural function of CaMKII rather than by its enzymatic activity. The sole contribution of kinase activity was autoregulation of this structural role via T286 autophosphorylation, which explains why this distinction has been elusive for decades. Directly initiating the structural function in a manner that circumvented this T286 role was sufficient to elicit robust LTP, even when enzymatic CaMKII activity was blocked.

DOI: 10.1038/s41586-023-06465-y

Source: https://www.nature.com/articles/s41586-023-06465-y

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html