ABSTRACT

Voltage-gated calcium channels (VGCCs) represent key regulators of the calcium influx through the plasma membrane of excitable cells, like neurons. Activated by the depolarization of the membrane, the opening of VGCCs induces very transient and local changes in the intracellular calcium concentration, known as calcium nanodomains, that in turn trigger calcium-dependent signaling cascades and the release of chemical neurotransmitters. Based on their central importance as concierges of excitation-secretion coupling and therefore neuronal communication, VGCCs have been studied in multiple aspects of neuronal function and malfunction. However, studies on molecular interaction partners and recent progress in omics technologies have extended the actual concept of these molecules. With this review, we want to illustrate some new perspectives of VGCCs reaching beyond their function as calcium-permeable pores in the plasma membrane. Therefore, we will discuss the relevance of VGCCs as voltage sensors in functional complexes with ryanodine receptors, channel-independent actions of auxiliary VGCC subunits, and provide an insight into how VGCCs even directly participate in gene regulation. Furthermore, we will illustrate how structural changes in the intracellular C-terminus of VGCCs generated by alternative splicing events might not only affect the biophysical channel characteristics but rather determine their molecular environment and downstream signaling pathways.

 抽象的

电压门控钙通道 (VGCC) 是钙离子通过可兴奋细胞（如神经元）质膜流入的关键调节因子。在膜去极化的激活下，VGCC 的开放会引起细胞内钙浓度（称为钙纳米域）的非常短暂和局部的变化，进而触发钙依赖性信号级联反应和化学神经递质的释放。基于 VGCC 作为兴奋-分泌耦合和神经元通讯的看门人的核心重要性，人们在神经元功能和故障的多个方面对 VGCC 进行了研究。然而，对分子相互作用伙伴的研究和组学技术的最新进展扩展了这些分子的实际概念。通过这篇综述，我们想说明 VGCC 的一些新观点，其范围超出了其作为质膜中钙渗透孔的功能。因此，我们将讨论 VGCC 作为兰尼碱受体功能复合物中电压传感器的相关性、辅助 VGCC 亚基的通道独立作用，并深入了解 VGCC 如何直接参与基因调控。此外，我们将说明可变剪接事件产生的 VGCC 细胞内 C 末端的结构变化不仅会影响生物物理通道特征，还会决定其分子环境和下游信号通路。