VAMP4 directs synaptic vesicles to a pool that selectively maintains asynchronous neurotransmission

Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Nature Neuroscience (Impact Factor: 16.1). 03/2012; 15(5):738-45. DOI: 10.1038/nn.3067
Source: PubMed


Synaptic vesicles in the brain harbor several soluble N-ethylmaleimide-sensitive-factor attachment protein receptor (SNARE) proteins. With the exception of synaptobrevin2, or VAMP2 (syb2), which is directly involved in vesicle fusion, the role of these SNAREs in neurotransmission is unclear. Here we show that in mice syb2 drives rapid Ca(2+)-dependent synchronous neurotransmission, whereas the structurally homologous SNARE protein VAMP4 selectively maintains bulk Ca(2+)-dependent asynchronous release. At inhibitory nerve terminals, up- or downregulation of VAMP4 causes a correlated change in asynchronous release. Biochemically, VAMP4 forms a stable complex with SNAREs syntaxin-1 and SNAP-25 that does not interact with complexins or synaptotagmin-1, proteins essential for synchronous neurotransmission. Optical imaging of individual synapses indicates that trafficking of VAMP4 and syb2 show minimal overlap. Taken together, these findings suggest that VAMP4 and syb2 diverge functionally, traffic independently and support distinct forms of neurotransmission. These results provide molecular insight into how synapses diversify their release properties by taking advantage of distinct synaptic vesicle-associated SNAREs.

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    • "This task is inherently more complex as SVs are homogenous in size and display a defined protein and lipid composition that can only be maintained by high fidelity adaptor-mediated sorting processes that serve to ''proofread'' SV composition. This task may be further complicated by the existence of functionally distinct pools of vesicles that may display compositional heterogeneity (Hua et al., 2011b; Raingo et al., 2012; Ramirez et al., 2012). However, CME as well as endosomal pathways of vesicle budding employed to reform functional SVs operate on a timescale of tens of seconds and, thus, provide a potential kinetic bottleneck when used for compensatory membrane retrieval at synapses undergoing high rates of firing. "
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    ABSTRACT: The function of the nervous system depends on the exocytotic release of neurotransmitter from synaptic vesicles (SVs). To sustain neurotransmission, SV membranes need to be retrieved, and SVs have to be reformed locally within presynaptic nerve terminals. In spite of more than 40 years of research, the mechanisms underlying presynaptic membrane retrieval and SV recycling remain controversial. Here, we review the current state of knowledge in the field, focusing on the molecular mechanism involved in presynaptic membrane retrieval and SV reformation. We discuss the challenges associated with studying these pathways and present perspectives for future research.
    Neuron 02/2015; 85(3):484-496. DOI:10.1016/j.neuron.2014.12.016 · 15.05 Impact Factor
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    • "Multiple homologues of syb exist on SVs 7,68. These non-canonical sybs control the fusion of functionally distinct SVs that mediate either spontaneous or asynchronous neurotransmitter release 69–71. For example both sybVII and Vps10p-tail-interactor-1a (Vti1a) are proposed to define the resting pool of SVs 69,70. "
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    ABSTRACT: Synaptobrevin II (sybII) is a key fusogenic molecule on synaptic vesicles (SVs) therefore the active maintenance of both its conformation and location in sufficient numbers on this organelle is critical in both mediating and sustaining neurotransmitter release. Recently three proteins have been identified having key roles in the presentation, trafficking and retrieval of sybII during the fusion and endocytosis of SVs. The nerve terminal protein α-synuclein catalyses sybII entry into SNARE complexes, whereas the monomeric adaptor protein AP180 is required for sybII retrieval during SV endocytosis. Overarching these events is the tetraspan SV protein synaptophysin, which is a major sybII interaction partner on the SV. This review will evaluate recent studies to propose working models for the control of sybII traffic by synaptophysin and other sybtraps (sybII trafficking partners) and suggest how dysfunction in sybII traffic may contribute to human disease.
    Traffic 11/2013; 15(3). DOI:10.1111/tra.12140 · 4.35 Impact Factor
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    • "Surprisingly, however, the effect of Reelin persisted in neurons deficient in syb2, which is the most abundant vesicular SNARE protein in the central nervous system (Schoch et al., 2001; Takamori et al., 2006). A functional survey of alternative SV-associated SNAREs VAMP4, vti1a, and VAMP7 (Hua et al., 2011; Raingo et al., 2012; Ramirez et al., 2012; Takamori et al., 2006) revealed that Reelin-mediated Figure 7. VAMP7 Knockdown Is Necessary and Sufficient to Abolish the Effect of Reelin (A and B) Immunoblot and quantification of blots for the knockdown (KD) of VAMP7 (N = 4) (KD3 15.2% ± 5.9% of control [p < 0.01] KD4 is 9.3% ± 6.3% [p < 0.01]) in hippocampal neurons. (C) Example traces of AMPAR mEPSCs from, vit1a-KD, VAMP4-KD and two different constructs of VAMP7-KD. "
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    ABSTRACT: Reelin is a glycoprotein that is critical for proper layering of neocortex during development as well as dynamic regulation of glutamatergic postsynaptic signaling in mature synapses. Here, we show that Reelin also acts presynaptically, resulting in robust rapid enhancement of spontaneous neurotransmitter release without affecting properties of evoked neurotransmission. This effect of Reelin requires a modest but significant increase in presynaptic Ca(2+) initiated via ApoER2 signaling. The specificity of Reelin action on spontaneous neurotransmitter release is encoded at the level of vesicular SNARE machinery as it requires VAMP7 and SNAP-25 but not synaptobrevin2, VAMP4, or vti1a. These results uncover a presynaptic regulatory pathway that utilizes the heterogeneity of synaptic vesicle-associated SNAREs and selectively augments action potential-independent neurotransmission.
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