Abstract
The recycling of synaptic vesicles requires the recovery of vesicle proteins and membrane. Members of the stonin protein family (Drosophila Stoned B, mammalian stonin 2) have been shown to link the synaptic vesicle protein synaptotagmin to the endocytic machinery. Here we characterize the unc-41 gene, which encodes the stonin ortholog in the nematode Caenorhabditis elegans. Transgenic expression of Drosophila stonedB rescues unc-41 mutant phenotypes, demonstrating that UNC-41 is a bona fide member of the stonin family. In unc-41 mutants, synaptotagmin is present in axons, but is mislocalized and diffuse. In contrast, UNC-41 is localized normally in synaptotagmin mutants, demonstrating a unidirectional relationship for localization. The phenotype of snt-1 unc-41 double mutants is stronger than snt-1 mutants, suggesting that UNC-41 may have additional, synaptotagmin-independent functions. We also show that unc-41 mutants have defects in synaptic vesicle membrane endocytosis, including a ∼50% reduction of vesicles in both acetylcholine and GABA motor neurons. These endocytic defects are similar to those observed in apm-2 mutants, which lack the µ2 subunit of the AP2 adaptor complex. However, no further reduction in synaptic vesicles was observed in unc-41 apm-2 double mutants, suggesting that UNC-41 acts in the same endocytic pathway as µ2 adaptin.
Highlights
The release of neurotransmitters at synapses occurs through the regulated fusion of synaptic vesicles with the plasma membrane
We show that the absence of UNC-41/stonin in C. elegans leads to defects in synaptotagmin localization and synaptic vesicle endocytosis
Unc-41 mutants resemble synaptotagmin-deficient mutants [27], suggesting that the unc-41 gene products play a role in synaptic vesicle fusion or recycling
Summary
The release of neurotransmitters at synapses occurs through the regulated fusion of synaptic vesicles with the plasma membrane. The recovery of synaptic vesicle membrane and proteins through endocytosis is dependent on a large complex of proteins associated with clathrin [1]. The AP2 complex recruits synaptic vesicle proteins to endocytic sites [2]. Other synaptic vesicle proteins require specific adaptors to recruit them to endocytic sites. The adaptors CALM and AP180, for example, are required to recruit the v-SNARE synaptobrevin into recycling synaptic vesicles [4,5,6,7,8]. Stonins are likely to be the adaptors that recruit the calcium sensor synaptotagmin to endocytosing synaptic vesicles [10]
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