title: VAMP4 directs synaptic vesicles to a pool that selectively maintains asynchronous neurotransmission.
abstract: 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.
authors.affiliation: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Jesica
authors.initials: J
authors.lastname: Raingo
authors.forename: Mikhail
authors.initials: M
authors.lastname: Khvotchev
authors.forename: Pei
authors.initials: P
authors.lastname: Liu
authors.forename: Frederic
authors.initials: F
authors.lastname: Darios
authors.forename: Ying C
authors.initials: YC
authors.lastname: Li
authors.forename: Denise M O
authors.initials: DM
authors.lastname: Ramirez
authors.forename: Megumi
authors.initials: M
authors.lastname: Adachi
authors.forename: Philippe
authors.initials: P
authors.lastname: Lemieux
authors.forename: Katalin
authors.initials: K
authors.lastname: Toth
authors.forename: Bazbek
authors.initials: B
authors.lastname: Davletov
authors.forename: Ege T
authors.initials: ET
authors.lastname: Kavalali
mesh_terms: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000643:Ammonium Chloride / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002766:Cholecystokinin / Q000378:metabolism; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004558:Electric Stimulation; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D016253:Microscopy, Immunoelectron; D009154:Mutation / Q000502:physiology; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000648:ultrastructure; D018408:Patch-Clamp Techniques; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D050683:R-SNARE Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D050600:SNARE Proteins / Q000378:metabolism; D013569:Synapses / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000235:genetics / Q000502:physiology*; D013572:Synaptic Vesicles / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D050825:Synaptosomal-Associated Protein 25 / Q000172:deficiency; D050827:Syntaxin 1 / Q000378:metabolism; D014162:Transfection; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D050988:Vesicle-Associated Membrane Protein 2 / Q000172:deficiency
chemical_list: D018691:Excitatory Amino Acid Antagonists; D050683:R-SNARE Proteins; D050600:SNARE Proteins; C494209:Snap25 protein, mouse; D050825:Synaptosomal-Associated Protein 25; D050827:Syntaxin 1; C476456:VAMP4 protein, human; D050988:Vesicle-Associated Membrane Protein 2; C494808:vesicle-associated membrane protein 2, mouse; D000643:Ammonium Chloride; D004533:Egtazic Acid; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; C056639:2-amino-5-phosphopentanoic acid; D002766:Cholecystokinin; C046770:EGTA acetoxymethyl ester; D014633:Valine; D002118:Calcium