Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong, China.
Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Hong Kong, China.
Nat Commun. 2016 Oct 31;7:13282. doi: 10.1038/ncomms13282.
Dendritic spine stabilization depends on afferent synaptic input and requires changes in actin cytoskeleton dynamics and protein synthesis. However, the underlying molecular mechanism remains unclear. Here we report the identification of 'calmodulin kinase-like vesicle-associated' (CaMKv), a pseudokinase of the CaMK family with unknown function, as a synaptic protein crucial for dendritic spine maintenance. CaMKv mRNA localizes at dendrites, and its protein synthesis is regulated by neuronal activity. CaMKv function is inhibited upon phosphorylation by cyclin-dependent kinase 5 (Cdk5) at Thr345. Furthermore, CaMKv knockdown in mouse hippocampal CA1 pyramidal neurons impairs synaptic transmission and plasticity in vivo, resulting in hyperactivity and spatial memory impairment. These findings collectively indicate that the precise regulation of CaMKv through activity-dependent synthesis and post-translational phosphorylation is critical for dendritic spine maintenance, revealing an unusual signalling pathway in the regulation of synaptic transmission and brain function that involves a pseudokinase.
树突棘稳定取决于传入的突触输入，并需要肌动蛋白细胞骨架动力学和蛋白质合成的变化。然而，其潜在的分子机制尚不清楚。在这里，我们报告了“钙调蛋白激酶样囊泡相关”（CaMKv）的鉴定，CaMKv 是 CaMK 家族的一种具有未知功能的拟激酶，是一种对于树突棘维持至关重要的突触蛋白。CaMKv mRNA 定位于树突上，其蛋白质合成受神经元活动调节。CaMKv 的功能通过 cyclin-dependent kinase 5（Cdk5）在 Thr345 上的磷酸化而受到抑制。此外，在小鼠海马 CA1 锥体神经元中敲低 CaMKv 会损害体内的突触传递和可塑性，导致过度活跃和空间记忆障碍。这些发现共同表明，通过活性依赖性合成和翻译后磷酸化对 CaMKv 的精确调节对于树突棘的维持至关重要，揭示了一种涉及拟激酶的调节突触传递和大脑功能的异常信号通路。
