美国哈佛医学院Pascal S. Kaeser研究组发现，海马突触处的Ca²⁺通道簇集和囊泡启动是由不同的活性区蛋白质机器介导的。这一研究成果发表在2024年8月19日出版的国际学术期刊《自然—神经科学》上。

传统模型认为支架蛋白直接将囊泡与Ca_V2通道连接在一起；然而，在小鼠海马突触中，研究人员发现Ca_V2簇集和囊泡启动是由独立的蛋白质机器执行的。Ca_V2纳米簇集的位置与启动蛋白Munc13的纳米簇集之间存在可变距离。活性区组织蛋白RIM锚定了这两种蛋白质，但独特的相互作用基序独立执行这些功能。

在转染的细胞中，Liprin-α和RIM形成与Ca_V2组织复合物分开的共组装体。在突触处，敲除Liprin-α1–Liprin-α4会损害囊泡启动，但不影响Ca_V2簇集。细胞黏附蛋白PTPσ招募Liprin-α、RIM和Munc13形成启动复合体，但不会与Ca_V2共同簇集。研究人员认为，活性区由不同的蛋白质机器组成，分别负责Ca_V2的组织和囊泡的启动，而Liprin-α和PTPσ专门支持启动位点的组装。

研究人员表示，动作电位以时空精度触发突触前活性区的神经递质释放，这依赖于介导突触囊泡启动和Ca_V2Ca²⁺通道簇集的蛋白质机器。

附：英文原文

Title: Distinct active zone protein machineries mediate Ca2+ channel clustering and vesicle priming at hippocampal synapses

Author: Emperador-Melero, Javier, Andersen, Jonathan W., Metzbower, Sarah R., Levy, Aaron D., Dharmasri, Poorna A., de Nola, Giovanni, Blanpied, Thomas A., Kaeser, Pascal S.

Issue&Volume: 2024-08-19

Abstract: Action potentials trigger neurotransmitter release at the presynaptic active zone with spatiotemporal precision. This is supported by protein machinery that mediates synaptic vesicle priming and clustering of CaV2 Ca2+ channels nearby. One model posits that scaffolding proteins directly tether vesicles to CaV2s; however, here we find that at mouse hippocampal synapses, CaV2 clustering and vesicle priming are executed by separate machineries. CaV2 nanoclusters are positioned at variable distances from those of the priming protein Munc13. The active zone organizer RIM anchors both proteins but distinct interaction motifs independently execute these functions. In transfected cells, Liprin-α and RIM form co-assemblies that are separate from CaV2-organizing complexes. At synapses, Liprin-α1–Liprin-α4 knockout impairs vesicle priming but not CaV2 clustering. The cell adhesion protein PTPσ recruits Liprin-α, RIM and Munc13 into priming complexes without co-clustering CaV2s. We conclude that active zones consist of distinct machineries to organize CaV2s and prime vesicles, and Liprin-α and PTPσ specifically support priming site assembly.

DOI: 10.1038/s41593-024-01720-5

Source: https://www.nature.com/articles/s41593-024-01720-5