Tang Jiong, Maximov Anton, Shin Ok-Ho, Dai Han, Rizo Josep, Südhof Thomas C
The Center for Basic Neuroscience, UT Southwestern Medical Center, Dallas, TX 75390, USA.
Cell. 2006 Sep 22;126(6):1175-87. doi: 10.1016/j.cell.2006.08.030.
Ca(2+) binding to synaptotagmin 1 triggers fast exocytosis of synaptic vesicles that have been primed for release by SNARE-complex assembly. Besides synaptotagmin 1, fast Ca(2+)-triggered exocytosis requires complexins. Synaptotagmin 1 and complexins both bind to assembled SNARE complexes, but it is unclear how their functions are coupled. Here we propose that complexin binding activates SNARE complexes into a metastable state and that Ca(2+) binding to synaptotagmin 1 triggers fast exocytosis by displacing complexin from metastable SNARE complexes. Specifically, we demonstrate that, biochemically, synaptotagmin 1 competes with complexin for SNARE-complex binding, thereby dislodging complexin from SNARE complexes in a Ca(2+)-dependent manner. Physiologically, increasing the local concentration of complexin selectively impairs fast Ca(2+)-triggered exocytosis but retains other forms of SNARE-dependent fusion. The hypothesis that Ca(2+)-induced displacement of complexins from SNARE complexes triggers fast exocytosis accounts for the loss-of-function and gain-of-function phenotypes of complexins and provides a molecular explanation for the high speed and synchronicity of fast Ca(2+)-triggered neurotransmitter release.
钙离子与突触结合蛋白1结合会触发突触小泡的快速胞吐作用，这些突触小泡已通过SNARE复合体组装而准备好释放。除了突触结合蛋白1外，快速的钙离子触发的胞吐作用还需要复合体蛋白。突触结合蛋白1和复合体蛋白都与组装好的SNARE复合体结合，但它们的功能如何耦合尚不清楚。在这里，我们提出复合体蛋白的结合将SNARE复合体激活到亚稳态，并且钙离子与突触结合蛋白1的结合通过将复合体蛋白从亚稳态SNARE复合体中置换出来而触发快速胞吐作用。具体而言，我们证明，在生化方面，突触结合蛋白1与复合体蛋白竞争SNARE复合体结合，从而以钙离子依赖的方式将复合体蛋白从SNARE复合体中逐出。在生理上，增加复合体蛋白的局部浓度会选择性地损害快速的钙离子触发的胞吐作用，但保留其他形式的SNARE依赖性融合。钙离子诱导复合体蛋白从SNARE复合体中置换出来触发快速胞吐作用的假说解释了复合体蛋白的功能丧失和功能获得表型，并为快速的钙离子触发的神经递质释放的高速性和同步性提供了分子解释。
