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

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    • "Recent investigations of vti1a and VAMP4 in neurons have implicated these 'endosomal' SNAREs in regulated exocytosis reactions: VAMP4 is involved in asynchronous neurotransmitter release (Raingo et al, 2012), whereas vti1a was suggested to play a role in the action-potential-independent—spontaneous—fusion of synaptic vesicles (Ramirez et al, 2012). This is controversial, since vti1a- carrying vesicles also fused during prolonged stimulation trains (Hoopmann et al, 2010; Ramirez et al, 2012), and other studies have shown that spontaneous release is modulated by mutation of the neuronal SNAREs (Deak et al, 2006; Weber et al, 2010). "
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