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

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

doi:10.1038/nn.3067

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

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

Research output: Contribution to journal › Article › peer-review

122 Scopus citations

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.

Original language	English (US)
Pages (from-to)	738-745
Number of pages	8
Journal	Nature neuroscience
Volume	15
Issue number	5
DOIs	https://doi.org/10.1038/nn.3067
State	Published - May 2012

ASJC Scopus subject areas

General Neuroscience

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10.1038/nn.3067

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@article{32146ab0be8f4b39a4106f2fa8c2dbec,

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.",

author = "Jesica Raingo and Mikhail Khvotchev and Pei Liu and Frederic Darios and Li, {Ying C.} and Ramirez, {Denise M O} and Megumi Adachi and Philippe Lemieux and Katalin Toth and Bazbek Davletov and Kavalali, {Ege T.}",

note = "Funding Information: We thank J. Leitz for technical assistance and H. Kramer, L. Monteggia, E. Nelson and E. Nosyreva for advice and discussions. We also thank T.C. S{\"u}dhof (Stanford University) for the gift of synaptobrevin2 knockout mice and M.C. Wilson (University of New Mexico) for the gift of SNAP-25 knockout mice. This work was supported by grants from the US National Institute of Mental Health to E.T.K. (MH066198). E.T.K. is an established investigator of the American Heart Association.",

year = "2012",

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doi = "10.1038/nn.3067",

language = "English (US)",

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T1 - VAMP4 directs synaptic vesicles to a pool that selectively maintains asynchronous neurotransmission

AU - Raingo, Jesica

AU - Khvotchev, Mikhail

AU - Liu, Pei

AU - Darios, Frederic

AU - Li, Ying C.

AU - Ramirez, Denise M O

AU - Adachi, Megumi

AU - Lemieux, Philippe

AU - Toth, Katalin

AU - Davletov, Bazbek

AU - Kavalali, Ege T.

N1 - Funding Information: We thank J. Leitz for technical assistance and H. Kramer, L. Monteggia, E. Nelson and E. Nosyreva for advice and discussions. We also thank T.C. Südhof (Stanford University) for the gift of synaptobrevin2 knockout mice and M.C. Wilson (University of New Mexico) for the gift of SNAP-25 knockout mice. This work was supported by grants from the US National Institute of Mental Health to E.T.K. (MH066198). E.T.K. is an established investigator of the American Heart Association.

PY - 2012/5

Y1 - 2012/5

N2 - 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.

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

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