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Review
. 2009 Jan 12;158(1):189-203.
doi: 10.1016/j.neuroscience.2008.03.029. Epub 2008 Mar 22.

Synaptic vesicle protein trafficking at the glutamate synapse

M S Santos  1 , H Li, S M Voglmaier
Affiliations
Review

Synaptic vesicle protein trafficking at the glutamate synapse

M S Santos et al. Neuroscience. .

Abstract

Expression of the integral and associated proteins of synaptic vesicles is subject to regulation over time, by region, and in response to activity. The process by which changes in protein levels and isoforms result in different properties of neurotransmitter release involves protein trafficking to the synaptic vesicle. How newly synthesized proteins are incorporated into synaptic vesicles at the presynaptic bouton is poorly understood. During synaptogenesis, synaptic vesicle proteins sort through the secretory pathway and are transported down the axon in precursor vesicles that undergo maturation to form synaptic vesicles. Changes in protein content of synaptic vesicles could involve the formation of new vesicles that either mix with the previous complement of vesicles or replace them, presumably by their degradation or inactivation. Alternatively, new proteins could individually incorporate into existing synaptic vesicles, changing their functional properties. Glutamatergic vesicles likely express many of the same integral membrane proteins and share certain common mechanisms of biogenesis, recycling, and degradation with other synaptic vesicles. However, glutamatergic vesicles are defined by their ability to package glutamate for release, a property conferred by the expression of a vesicular glutamate transporter (VGLUT). VGLUTs are subject to regional, developmental, and activity-dependent changes in expression. In addition, VGLUT isoforms differ in their trafficking, which may target them to different pathways during biogenesis or after recycling, which may in turn sort them to different vesicle pools. Emerging data indicate that differences in the association of VGLUTs and other synaptic vesicle proteins with endocytic adaptors may influence their trafficking. These observations indicate that independent regulation of synaptic vesicle protein trafficking has the potential to influence synaptic vesicle protein composition, the maintenance of synaptic vesicle pools, and the release of glutamate in response to changing physiological requirements.

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Figures

Figure 1
Figure 1. VGLUT trafficking in neurons
A schematic model for VGLUT sorting in neurons, based on current models of secretory vesicle trafficking, is depicted. During biogenesis, all three isoforms of VGLUTs may be delivered to the axon by trafficking to constitutive secretory vesicles (CSVs) at the level of the TGN. Constitutive exocytosis of CSVs could deliver VGLUTs to the cell surface in axons, where they could be incorporated into synaptic vesicles (SVs). In contrast, VGLUT3 is also observed in somatodendritic vesicles, suggesting that it may also sort to regulated secretory vesicles (RSVs), similarly to VMAT2. RSVs bud directly from the TGN as part of the regulated secretory pathway, with a full complement of the proteins that confer competence for regulated neurotransmitter release. RSVs could transport VGLUT3 to appropriate sites of release, either in dendrites or axons. In this case, VGLUT3-containing RSVs would fuse with the plasma membrane (PM) only upon stimulation, such as increased cytoplasmic Ca2+.
Figure 2
Figure 2. Axonal transport of synaptic vesicle membrane proteins
A schematic model of the microtubule-based transport of synaptic vesicle membrane proteins within an axon is depicted. Specific kinesin family motor proteins (KIFs) deliver distinct cargoes from the soma toward the axon terminal. Active zone proteins, such as Piccolo and Bassoon, are transported on dense core vesicles (blue dense core circles). Synaptic vesicle membrane proteins are transported by distinct membrane carriers (synaptic vesicle precursors, black and green ovals). Recent evidence suggests that both dense core vesicles and synaptic vesicle precursors may cluster into transport packets that contain VAMP2, SV2, amphiphysin, and synapsins. Transport vesicles may undergo dynamic membrane exchange and remodeling by recycling of membrane vesicles along the axon (blue circles).
Figure 3
Figure 3. Model of synaptic vesicle protein recycling
Synaptic vesicles comprise three functional pools. The readily releasable pool (RRP) is released with mild stimulation. With more intense stimulation, vesicles are also recruited from the recycling pool and then the reserve pool, where vesicles are tethered by cytoskeletal elements. Three proposed mechanisms for the recycling of synaptic vesicle components are depicted. A fast kiss and run mechanism involves the reversible opening of a fusion pore without full collapse into the plasma membrane. In contrast, after full fusion, synaptic vesicle proteins recognized by the clathrin adaptor protein AP2 are recycled by clathrin-mediated endocytosis (CME). Strong stimulation activates bulk membrane retrieval into large membrane compartments from which synaptic vesicles are generated. Since strong stimulation activates both bulk endocytosis and the AP3 pathway, they might be related processes. AP3 may recognize protein cargoes in plasma membrane invaginations or endosomal membranes and function in their incorporation into synaptic vesicles.
Figure 4
Figure 4
Alignment of sequences from the VGLUTs with similar targeting sequences from other synaptic vesicle proteins (bold). The dileucine-like sequences are underlined. “r”: rat; “m”: mouse; “STG”: synaptotagmin.
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