Journal Article

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

Khvotchev, Mikhail, Liu, Pei, Davletov, Bazbek, Toth, Katalin, Darios, Frederic, Li, Ying C, Lemieux, Philippe, Kavalali, Ege T, Adachi, Megumi, Raingo, Jesica, Ramirez, Denise M O

2012

Overview

The authors show that the SNARE protein VAMP4 acts to maintain calcium-dependent asynchronous synaptic vesicle release. These findings suggest that VAMP4 is functionally distinct from synaptobrevin2, which primarily drives fast, synchronous release. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 6-Cyano-7-nitroquinoxaline-2,3-dione - pharmacology / 631/208/200 / 631/378/548/2588 / 631/378/548/2590 / Ammonium Chloride - pharmacology / Analysis of Variance / Animal Genetics and Genomics / Animals / Animals, Newborn / Behavioral Sciences / Biological Techniques / Biomedical and Life Sciences / Biomedicine / Calcium - metabolism / Cells, Cultured / Cholecystokinin - metabolism / Egtazic Acid - analogs & derivatives / Egtazic Acid - pharmacology / Electric Stimulation / Excitatory Amino Acid Antagonists - pharmacology / Gene Knockdown Techniques / Genetic aspects / Hippocampus - cytology / Humans / Immunocytochemistry / Inhibitory Postsynaptic Potentials - drug effects / Inhibitory Postsynaptic Potentials - genetics / Localization / Mice / Mice, Knockout / Microscopy, Immunoelectron / Mutation - physiology / Neural transmission / Neurobiology / Neurons - cytology / Neurons - drug effects / Neurons - ultrastructure / Neurosciences / Patch-Clamp Techniques / Physiological aspects / Physiology / Protein Binding - drug effects / Protein Binding - genetics / Protein Transport - drug effects / Protein Transport - genetics / Proteins / R-SNARE Proteins - genetics / R-SNARE Proteins - metabolism / Rats / Rats, Sprague-Dawley / RNA Interference - physiology / SNARE Proteins - metabolism / Synapses - genetics / Synapses - metabolism / Synapses - ultrastructure / Synaptic Transmission - genetics / Synaptic Transmission - physiology / Synaptic Vesicles - drug effects / Synaptic Vesicles - physiology / Synaptic Vesicles - ultrastructure / Synaptosomal-Associated Protein 25 - deficiency / Syntaxin 1 - metabolism / Transfection / Valine - analogs & derivatives / Valine - pharmacology / Vesicle-Associated Membrane Protein 2 - deficiency