Exocytosis and Endocytosis of Synaptic Vesicles and Functional Roles of Vesicle Pools: Lessons from the Drosophila Neuromuscular Junction

ArticleinThe Neuroscientist 11(2):138-47 · May 2005with18 Reads
DOI: 10.1177/1073858404271679 · Source: PubMed
To maintain synaptic transmission during intense neuronal activities, the synaptic vesicle (SV) pool at release sites is effectively replenished by recruitment of SVs from the reserve pool and/or by endocytosis. The authors have studied dynamics of SVs using a fluorescence dye, FM1-43, which is incorporated into SVs during endocytosis and released by exocytosis. Drosophila is one of the most suitable preparations for genetic and pharmacological analyses, and this provides a useful model system. The authors found at the neuromuscular junctions of Drosophila that exocytosis and endocytosis of SVs are triggered by Ca(2+) influx through distinct routes and that selective inhibition of exocytosis or endocytosis resulted in depression of synaptic transmission with a distinct time course. They identified two SV pools in a single presynaptic bouton. The exo/endo cycling pool (ECP) is loaded with FM1-43 during low-frequency stimulation and locates close to release sites in the periphery of boutons, whereas the reserve pool (RP) is loaded and unloaded only during high-frequency stimulation and resides primarily in the center of boutons. The size of ECP closely correlates with the quantal content of evoked release, suggesting that SVs in the ECP are primarily involved in synaptic transmission. SVs in the RP are recruited to synaptic transmission by a process involving the cAMP/PKA cascade during high-frequency stimulation. Cytochalasin D blocked this recruitment process, suggesting involvement of filamentous actin. Endocytosed SVs replenish the ECP during stimulation and the RP after tetanic stimulation. Replenishment of the ECP depends on Ca(2+) influx from external solutions, and that of the RP is initiated by Ca(2+) release from internal stores. Thus, SV dynamics is closely involved in modulation of synaptic efficacy and influences synaptic plasticity.
    • "The effects of actin disruption on synaptic vesicle recycling have been somewhat contradictory. However, there is evidence that actin is important in scaffolding of synaptic vesicles [67,68,69], their mobilization from synaptic vesicle pools707172737475, endocytosis after spontaneous release [76], ultrafast endocytosis milliseconds after exocytosis [3], and bulk endocytosis77787980. In addition, Nck could act as a scaffold to recruit other SH3 domaincontaining proteins. "
    [Show abstract] [Hide abstract] ABSTRACT: Exocytotic release of glutamate depends upon loading of the neurotransmitter into synaptic vesicles by vesicular glutamate transporters, VGLUTs. The major isoforms, VGLUT1 and 2, exhibit a complementary pattern of expression in synapses of the adult rodent brain that correlates with the probability of release and potential for plasticity. Indeed, expression of different VGLUT protein isoforms confers different properties of release probability. Expression of VGLUT1 or 2 protein also determines the kinetics of synaptic vesicle recycling. To identify molecular determinants that may be related to reported differences in VGLUT trafficking and glutamate release properties, we investigated some of the intrinsic differences between the two isoforms. VGLUT1 and 2 exhibit a high degree of sequence homology, but differ in their N- and C-termini. While the C-termini of VGLUT1 and 2 share a dileucine-like trafficking motif and a proline-, glutamate-, serine-, and threonine-rich PEST domain, only VGLUT1 contains two polyproline domains and a phosphorylation consensus sequence in a region of acidic amino acids. The interaction of a VGLUT1 polyproline domain with the endocytic protein endophilin recruits VGLUT1 to a fast recycling pathway. To identify trans-acting cellular proteins that interact with the distinct motifs found in the C-terminus of VGLUT1, we performed a series of in vitro biochemical screening assays using the region encompassing the polyproline motifs, phosphorylation consensus sites, and PEST domain. We identify interactors that belong to several classes of proteins that modulate cellular function, including actin cytoskeletal adaptors, ubiquitin ligases, and tyrosine kinases. The nature of these interactions suggests novel avenues to investigate the modulation of synaptic vesicle protein recycling.
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    • "It is well established that calcium influx through voltage-dependent calcium channels (VDCCs) serves as the trigger for evoked synaptic vesicle exocytosis and neurotransmitter release (Katz and Miledi 1967; Augustine 2001; Jahn and Fasshauer 2012; Sudhof 2012 ). In general , calcium positively regulates the initiation, speed, and amount of vesicle endocytosis in a range of central and peripheral synapses in vertebrates and invertebrates (von Gersdorff and Matthews 1994; Gad et al. 1998; Ales et al. 1999; Neves et al. 2001; Sankaranarayanan and Ryan 2001; Kuromi and Kidokoro 2005; Wu et al. 2005 Wu et al. , 2009 Balaji et al. 2008; Yamashita 2012; Yao et al. 2012b). For a long time, it was assumed that the calcium influx needed for synaptic vesicle endocytosis is through VDCCs on the presynaptic plasma membrane. "
    [Show abstract] [Hide abstract] ABSTRACT: The release and uptake of neurotransmitters by synaptic vesicles is a tightly controlled process that occurs in response to diverse stimuli at morphologically disparate synapses. To meet these architectural and functional synaptic demands, it follows that there should be diversity in the mechanisms that control their secretion and retrieval and possibly in the composition of synaptic vesicles within the same terminal. Here we pay particular attention to areas where such diversity is generated, such as the variance in exocytosis/endocytosis coupling, SNAREs defining functionally diverse synaptic vesicle populations and the adaptor-dependent sorting machineries capable of generating vesicle diversity. We argue that there are various synaptic vesicle recycling pathways at any given synapse and discuss several lines of evidence that support the role of the endosome in synaptic vesicle recycling.
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    • "An additional feature is that R t P vesicles are recruited by intracellular signaling pathways. For example , at the Drosophila NMJ, the vesicles most reluctant to release can be recruited to the RRP using a protein kinase A pathway involving filamentous actin (Kuromi and Kidokoro 2005). In hippocampal terminals, R t P mobilization can be achieved by inhibition of cyclin-dependent kinase 5 (CDK5) (Kim and Ryan 2010). "
    [Show abstract] [Hide abstract] ABSTRACT: Synaptic vesicles release neurotransmitter at chemical synapses, thus initiating the flow of information in neural networks. To achieve this, vesicles undergo a dynamic cycle of fusion and retrieval to maintain the structural and functional integrity of the presynaptic terminals in which they reside. Moreover, compelling evidence indicates these vesicles differ in their availability for release and mobilization in response to stimuli, prompting classification into at least three different functional pools. Ongoing studies of the molecular and cellular bases for this heterogeneity attempt to link structure to physiology and clarify how regulation of vesicle pools influences synaptic strength and presynaptic plasticity. We discuss prevailing perspectives on vesicle pools, the role they play in shaping synaptic transmission, and the open questions that challenge current understanding.
    Article · Jun 2012
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