期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：23
页码：7297-7302
DOI：10.1073/pnas.1501627112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceBrain function depends on neurotransmission, and alterations in this process are linked to neurological disorders. Neurotransmitter release requires the rapid recycling of synaptic vesicles (SVs) by endocytosis. How synapses maintain the molecular composition of SVs during recycling is poorly understood. We demonstrate that overlapping functions of two completely distinct proteins, the vesicle protein SV2A/B and the adaptor stonin 2, mediate endocytic sorting of the vesicular calcium sensor synaptotagmin 1. As SV2A is the target of the commonly used antiepileptic drug levetiracetam and is linked to late onset Alzheimer's disease, our findings bear implications for the treatment of neurological and neurodegenerative disorders. Neurotransmission involves the calcium-regulated exocytic fusion of synaptic vesicles (SVs) and the subsequent retrieval of SV membranes followed by reformation of properly sized and shaped SVs. An unresolved question is whether each SV protein is sorted by its own dedicated adaptor or whether sorting is facilitated by association between different SV proteins. We demonstrate that endocytic sorting of the calcium sensor synaptotagmin 1 (Syt1) is mediated by the overlapping activities of the Syt1-associated SV glycoprotein SV2A/B and the endocytic Syt1-adaptor stonin 2 (Stn2). Deletion or knockdown of either SV2A/B or Stn2 results in partial Syt1 loss and missorting of Syt1 to the neuronal surface, whereas deletion of both SV2A/B and Stn2 dramatically exacerbates this phenotype. Selective missorting and degradation of Syt1 in the absence of SV2A/B and Stn2 impairs the efficacy of neurotransmission at hippocampal synapses. These results indicate that endocytic sorting of Syt1 to SVs is mediated by the overlapping activities of SV2A/B and Stn2 and favor a model according to which SV protein sorting is guarded by both cargo-specific mechanisms as well as association between SV proteins.
