Wang Shiyi, Stanika Ruslan I, Wang Xiaohan, Hagen Jussara, Kennedy Mary B, Obermair Gerald J, Colbran Roger J, Lee Amy
Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa 52242.
Division of Physiology, Medical University Innsbruck, 6020 Innsbruck, Austria.
J Neurosci. 2017 May 3;37(18):4679-4691. doi: 10.1523/JNEUROSCI.2583-16.2017. Epub 2017 Mar 31.
Voltage-gated Ca1.2 and Ca1.3 (L-type) Ca channels regulate neuronal excitability, synaptic plasticity, and learning and memory. Densin-180 (densin) is an excitatory synaptic protein that promotes Ca-dependent facilitation of voltage-gated Ca1.3 Ca channels in transfected cells. Mice lacking densin (densin KO) exhibit defects in synaptic plasticity, spatial memory, and increased anxiety-related behaviors-phenotypes that more closely match those in mice lacking Ca1.2 than Ca1.3. Therefore, we investigated the functional impact of densin on Ca1.2. We report that densin is an essential regulator of Ca1.2 in neurons, but has distinct modulatory effects compared with its regulation of Ca1.3. Densin binds to the N-terminal domain of Ca1.2, but not that of Ca1.3, and increases Ca1.2 currents in transfected cells and in neurons. In transfected cells, densin accelerates the forward trafficking of Ca1.2 channels without affecting their endocytosis. Consistent with a role for densin in increasing the number of postsynaptic Ca1.2 channels, overexpression of densin increases the clustering of Ca1.2 in dendrites of hippocampal neurons in culture. Compared with wild-type mice, the cell surface levels of Ca1.2 in the brain, as well as Ca1.2 current density and signaling to the nucleus, are reduced in neurons from densin KO mice. We conclude that densin is an essential regulator of neuronal Ca1 channels and ensures efficient Ca1.2 Ca signaling at excitatory synapses. The number and localization of voltage-gated Ca Ca channels are crucial determinants of neuronal excitability and synaptic transmission. We report that the protein densin-180 is highly enriched at excitatory synapses in the brain and enhances the cell surface trafficking and postsynaptic localization of Ca1.2 L-type Ca channels in neurons. This interaction promotes coupling of Ca1.2 channels to activity-dependent gene transcription. Our results reveal a mechanism that may contribute to the roles of Ca1.2 in regulating cognition and mood.
电压门控Ca1.2和Ca1.3（L型）钙通道调节神经元兴奋性、突触可塑性以及学习和记忆。致密素-180（致密素）是一种兴奋性突触蛋白，在转染细胞中可促进电压门控Ca1.3钙通道的钙依赖性易化。缺乏致密素的小鼠（致密素基因敲除小鼠）表现出突触可塑性、空间记忆方面的缺陷以及焦虑相关行为增加，这些表型与缺乏Ca1.2而非Ca1.3的小鼠更为相似。因此，我们研究了致密素对Ca1.2的功能影响。我们发现致密素是神经元中Ca1.2的重要调节因子，但与其对Ca1.3的调节相比具有不同的调节作用。致密素与Ca1.2的N端结构域结合，但不与Ca1.3的N端结构域结合，并增加转染细胞和神经元中的Ca1.2电流。在转染细胞中，致密素加速Ca1.2通道的正向运输，而不影响其胞吞作用。与致密素在增加突触后Ca1.2通道数量方面的作用一致，致密素的过表达增加了培养的海马神经元树突中Ca1.2的聚集。与野生型小鼠相比，致密素基因敲除小鼠神经元中大脑中Ca1.2的细胞表面水平以及Ca1.2电流密度和向细胞核的信号传导均降低。我们得出结论，致密素是神经元钙通道的重要调节因子，并确保在兴奋性突触处有高效的Ca1.2钙信号传导。电压门控钙通道的数量和定位是神经元兴奋性和突触传递的关键决定因素。我们发现蛋白致密素-180在大脑兴奋性突触中高度富集，并增强神经元中Ca1.2 L型钙通道的细胞表面运输和突触后定位。这种相互作用促进了Ca1.2通道与活性依赖基因转录的偶联。我们的结果揭示了一种可能有助于Ca1.2在调节认知和情绪中发挥作用的机制。
