Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Mol Cell. 2019 Jul 11;75(1):13-25.e5. doi: 10.1016/j.molcel.2019.05.004. Epub 2019 May 28.
Arc is a synaptic protein essential for memory consolidation. Recent studies indicate that Arc originates in evolution from a Ty3-Gypsy retrotransposon GAG domain. The N-lobe of Arc GAG domain acquired a hydrophobic binding pocket in higher vertebrates that is essential for Arc's canonical function to weaken excitatory synapses. Here, we report that Arc GAG also acquired phosphorylation sites that can acutely regulate its synaptic function. CaMKII phosphorylates the N-lobe of the Arc GAG domain and disrupts an interaction surface essential for high-order oligomerization. In Purkinje neurons, CaMKII phosphorylation acutely reverses Arc's synaptic action. Mutant Arc that cannot be phosphorylated by CaMKII enhances metabotropic receptor-dependent depression in the hippocampus but does not alter baseline synaptic transmission or long-term potentiation. Behavioral studies indicate that hippocampus- and amygdala-dependent learning requires Arc GAG domain phosphorylation. These studies provide an atomic model for dynamic and local control of Arc function underlying synaptic plasticity and memory.
Arc 是一种对记忆巩固至关重要的突触蛋白。最近的研究表明，Arc 起源于 Ty3-Gypsy 反转录转座子 GAG 结构域的进化。Arc GAG 结构域的 N lobe 在高等脊椎动物中获得了一个疏水结合口袋，这对于 Arc 的经典功能（即削弱兴奋性突触）至关重要。在这里，我们报告说，Arc GAG 还获得了可急性调节其突触功能的磷酸化位点。CaMKII 磷酸化 Arc GAG 结构域的 N lobe，并破坏了高阶寡聚所必需的相互作用表面。在浦肯野神经元中，CaMKII 磷酸化可急性逆转 Arc 的突触作用。不能被 CaMKII 磷酸化的突变 Arc 增强了海马体中代谢型受体依赖性抑制，但不会改变基线突触传递或长时程增强。行为研究表明，海马体和杏仁核依赖性学习需要 Arc GAG 结构域磷酸化。这些研究为突触可塑性和记忆的 Arc 功能的动态和局部控制提供了原子模型。
