Bornschein Grit, Schmidt Hartmut
Carl-Ludwig Institute for Physiology, Medical Faculty, University of Leipzig, Leipzig, Germany.
Front Mol Neurosci. 2019 Jan 15;11:494. doi: 10.3389/fnmol.2018.00494. eCollection 2018.
Ca concentrations drop rapidly over a distance of a few tens of nanometers from an open voltage-gated Ca channel (Ca), thereby, generating a spatially steep and temporally short-lived Ca gradient that triggers exocytosis of a neurotransmitter filled synaptic vesicle. These non-steady state conditions make the Ca-binding kinetics of the Ca sensors for release and their spatial coupling to the Cas important parameters of synaptic efficacy. In the mammalian central nervous system, the main release sensors linking action potential mediated Ca influx to synchronous release are Synaptotagmin (Syt) 1 and 2. We review here quantitative work focusing on the Ca kinetics of Syt2-mediated release. At present similar quantitative detail is lacking for Syt1-mediated release. In addition to triggering release, Ca remaining bound to Syt after the first of two successive high-frequency activations was found to be capable of facilitating release during the second activation. More recently, the Ca sensor Syt7 was identified as additional facilitation sensor. We further review how several recent functional studies provided quantitative insights into the spatial topographical relationships between Syts and Cas and identified mechanisms regulating the sensor-to-channel coupling distances at presynaptic active zones. Most synapses analyzed in matured cortical structures were found to operate at tight, nanodomain coupling. For fast signaling synapses a developmental switch from loose, microdomain to tight, nanodomain coupling was found. The protein Septin5 has been known for some time as a developmentally down-regulated "inhibitor" of tight coupling, while Munc13-3 was found only recently to function as a developmentally up-regulated mediator of tight coupling. On the other hand, a highly plastic synapse was found to operate at loose coupling in the matured hippocampus. Together these findings suggest that the coupling topography and its regulation is a specificity of the type of synapse. However, to definitely draw such conclusion our knowledge of functional active zone topographies of different types of synapses in different areas of the mammalian brain is too incomplete.
在距离开放的电压门控钙通道（Ca）几十纳米的范围内，钙浓度会迅速下降，从而产生一个空间上陡峭且时间上短暂的钙梯度，该梯度触发充满神经递质的突触小泡的胞吐作用。这些非稳态条件使得用于释放的钙传感器的钙结合动力学及其与钙通道的空间偶联成为突触效能的重要参数。在哺乳动物中枢神经系统中，将动作电位介导的钙内流与同步释放联系起来的主要释放传感器是突触结合蛋白（Syt）1和2。我们在此回顾聚焦于Syt2介导释放的钙动力学的定量研究工作。目前，Syt1介导释放缺乏类似的定量细节。除了触发释放外，在连续两次高频激活中的第一次激活后，发现仍与Syt结合的钙能够在第二次激活期间促进释放。最近，钙传感器Syt7被确定为另一种促进传感器。我们还将进一步回顾最近的几项功能研究如何对Syt和钙通道之间的空间拓扑关系提供了定量见解，并确定了调节突触前活跃区传感器与通道偶联距离的机制。在成熟的皮质结构中分析的大多数突触被发现以紧密的纳米域偶联方式运作。对于快速信号突触，发现存在从松散的微域偶联到紧密的纳米域偶联的发育转变。蛋白质Septin5长期以来被认为是紧密偶联的发育下调的“抑制剂”，而Munc13 - 3直到最近才被发现是紧密偶联的发育上调的介导因子。另一方面，在成熟的海马体中发现一个高度可塑性的突触以松散偶联方式运作。这些发现共同表明偶联拓扑及其调节是突触类型的一种特异性。然而，要明确得出这样的结论，我们对哺乳动物大脑不同区域不同类型突触的功能性活跃区拓扑的了解还不够完整。
