Abstract：
Exocytosis and endocytosis are tightly coupled. In addition to initiating exocytosis, Ca2+ plays critical roles in exocytosis–endocytosis coupling in neurons and nonneuronal cells. Both positive and negative roles of Ca2+ in endocytosis have been reported; however, Ca2+ inhibition in endocytosis remains debatable with unknown mechanisms. Here, we show that synaptotagmin-1 (Syt1), the primary Ca2+ sensor initiating exocytosis, plays bidirectional and opposite roles in exocytosis–endocytosis coupling by promoting slow, small-sized clathrin-mediated endocytosis but inhibiting fast, large-sized bulk endocytosis. Ca2+-binding ability is required for Syt1 to regulate both types of endocytic pathways, the disruption of which leads to inefficient vesicle recycling under mild stimulation and excessive membrane retrieval following intense stimulation. Ca2+-dependent membrane tubulation may explain the opposite endocytic roles of Syt1 and provides a general membrane-remodeling working model for endocytosis determination. Thus, Syt1 is a primary bidirectional Ca2+ sensor facilitating clathrin-mediated endocytosis but clamping bulk endocytosis, probably by manipulating membrane curvature to ensure both efficient and precise coupling of endocytosis to exocytosis.
摘要：
胞吐作用和内吞作用是紧密耦合的。除了启动胞吐作用,Ca2+在神经元和非神经元细胞的胞吐-胞吞偶联中起关键作用。已经报道了Ca2+在内吞作用中的积极和消极作用；然而，胞吞中的Ca2抑制仍然存在未知机制的争议。这里,我们表明突触蛋白-1(Syt1)，启动胞吐作用的主要Ca2+传感器，在胞吐-内吞偶联中发挥双向和相反的作用，小尺寸的网格蛋白介导的内吞作用，但抑制快速，大体积内吞作用。Ca2+结合能力是Syt1调节两种内吞途径所必需的，其破坏导致轻度刺激下的囊泡回收效率低下，而强烈刺激后的膜回收过多。Ca2依赖性膜管可以解释Syt1的相反内吞作用，并为内吞作用测定提供一般的膜重塑工作模型。因此，Syt1是一个主要的双向Ca2+传感器，促进网格蛋白介导的内吞作用，但钳制大量内吞作用，可能通过操纵膜曲率来确保胞吞作用与胞吐作用的有效和精确耦合。
