Quantifying the synaptic Ca2+-binding kinetics of Synaptotagmin-1, the Ca2+ sensor for transmitter release in the forebrain

量化 Synaptotagmin-1（前脑中递质释放的 Ca2 传感器）的突触 Ca2 结合动力学

• 批准号: 351151455
• 负责人: Professor Dr. Hartmut Schmidt
• 金额: --
• 依托单位: Carl-Ludwig-Institut für Physiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/351151455?language=en
• 关键词: Quantifying; synaptic; Ca2+; binding; kinetics

Central nervous system neurons communicate via Ca2+-triggered release of neurotransmitters from presynaptic terminals. Upon depolarization of a terminal voltage-gated Ca2+ channels open and the inflowing Ca2+ builds a steep, short lasting concentration gradient around the mouth of the open channel that rapidly diminishes with increasing distance from the channel. Ca2+ binds to specialized Ca2+ sensor proteins (Synaptotagmins, Syt), thereby, triggering the fusion of neurotransmitter filled vesicles with the plasma membrane of the presynaptic active zone and the subsequent release of the transmitter. Due to the steepness and short duration of the Ca2+ gradient a chemical equilibrium is never established in this process. This makes the intracellular Ca2+-binding kinetics of the release sensor (as opposed by its affinity at equilibrium) central in the control of speed, reliability and modulation capability of release. Thus, in order to derive a quantitative understanding of synaptic information transfer but also of its modulation via synaptic plasticity it is required to know the intracellular Ca2+-binding kinetics of the release sensor. Two Syt isoforms, Syt1 and Syt2, are the main Ca2+ sensors triggering fast transmitter release in the brain; however, only Ca2+-binding to Syt2, the dominant isoform in the hindbrain has been studied in detail in synapses. Syt1, the dominating sensor in the forebrain, is thought to behave differently but detailed quantitative data of its synaptic Ca2+-binding kinetics are missing. Resolving this major uncertainty for understanding synaptic information flow and its regulation in forebrain regions like the neocortex is topic of the present proposal.

中枢神经系统神经元通过突触前末梢的Ca2+触发的神经递质释放进行通信。在末端电压门控Ca2+通道去极化时打开，流入的Ca2+在开放通道的口部周围建立陡峭的、持续时间短的浓度梯度，该浓度梯度随着与通道距离的增加而迅速减小。Ca2+结合到专门的Ca2+传感器蛋白（突触结合蛋白，Syt），从而触发神经递质填充的囊泡与突触前活性区的质膜的融合以及随后的递质释放。由于Ca2+梯度的陡度和持续时间短，在该过程中从未建立化学平衡。这使得释放传感器的细胞内Ca2+结合动力学（与其平衡时的亲和力相反）在释放的速度、可靠性和调节能力的控制中处于中心地位。因此，为了获得突触信息传递的定量理解，但也通过突触可塑性的调制，它需要知道的释放传感器的细胞内Ca2+结合动力学。两个Syt亚型，Syt 1和Syt 2，是主要的Ca2+传感器触发快速发射器释放在大脑中，然而，只有Ca2+结合Syt 2，在后脑中占主导地位的亚型已在突触中详细研究。Syt1是前脑中的主要传感器，被认为表现不同，但其突触Ca2+结合动力学的详细定量数据缺失。解决这个主要的不确定性，以了解突触信息流及其在前脑区域如新皮层的调节是本提案的主题。