Pinheiro Paulo S, Houy Sébastien, Sørensen Jakob B
Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
J Neurochem. 2016 Dec;139(6):943-958. doi: 10.1111/jnc.13865. Epub 2016 Nov 9.
The molecular mechanisms for calcium-triggered membrane fusion have long been sought for, and detailed models now exist that account for at least some of the functions of the many proteins involved in the process. Key players in the fusion reaction are a group of proteins that, upon binding to calcium, trigger the merger of cargo-filled vesicles with the plasma membrane. Low-affinity, fast-kinetics calcium sensors of the synaptotagmin family - especially synaptotagmin-1 and synaptotagmin-2 - are the main calcium sensors for fast exocytosis triggering in many cell types. Their functions extend beyond fusion triggering itself, having been implicated in the calcium-dependent vesicle recruitment during activity, docking of vesicles to the plasma membrane and priming, and even in post-fusion steps, such as fusion pore expansion and endocytosis. Furthermore, synaptotagmin diversity imparts distinct properties to the release process itself. Other calcium-sensing proteins such as Munc13s and protein kinase C play important, but more indirect roles in calcium-triggered exocytosis. Because of their higher affinity, but intrinsic slower kinetics, they operate on longer temporal and spatial scales to organize assembly of the release machinery. Finally, the high-affinity synaptotagmin-7 and Doc2 (Double C2-domain) proteins are able to trigger membrane fusion in vitro, but cellular measurements in different systems show that they may participate in either fusion or vesicle priming. Here, we summarize the properties and possible interplay of (some of) the major C2-domain containing calcium sensors in calcium-triggered exocytosis. This article is part of a mini review series: "Synaptic Function and Dysfunction in Brain Diseases".
长期以来，人们一直在探寻钙触发膜融合的分子机制，现在已经有了详细的模型，这些模型至少解释了该过程中许多相关蛋白质的部分功能。融合反应中的关键角色是一组蛋白质，它们在与钙结合后，会触发充满货物的囊泡与质膜的融合。突触结合蛋白家族的低亲和力、快速动力学钙传感器——尤其是突触结合蛋白-1和突触结合蛋白-2——是许多细胞类型中快速胞吐触发的主要钙传感器。它们的功能不仅限于触发融合本身，还参与了活动期间钙依赖性囊泡募集、囊泡与质膜的对接和引发，甚至还参与了融合后步骤，如融合孔扩张和内吞作用。此外，突触结合蛋白的多样性赋予了释放过程本身独特的特性。其他钙传感蛋白，如Munc13s和蛋白激酶C，在钙触发的胞吐作用中发挥着重要但更间接的作用。由于它们具有较高的亲和力，但内在动力学较慢，它们在更长的时间和空间尺度上发挥作用，以组织释放机制的组装。最后，高亲和力的突触结合蛋白-7和Doc2（双C2结构域）蛋白能够在体外触发膜融合，但在不同系统中的细胞测量表明，它们可能参与融合或囊泡引发。在这里，我们总结了（部分）主要含C2结构域的钙传感器在钙触发胞吐作用中的特性以及可能的相互作用。本文是“脑疾病中的突触功能与功能障碍”小型综述系列的一部分。
