Cited by 210Cellular transport and secretionNeuroscience and Neuropharmacology ResearchExtracellular vesicles in disease

Mechanism of neurotransmitter release coming into focus

Open access
Rizo, Josep·2018·Protein Science

Abstract

Research for three decades and major recent advances have provided crucial insights into how neurotransmitters are released by Ca 2+ ‐triggered synaptic vesicle exocytosis, leading to reconstitution of basic steps that underlie Ca 2+ ‐dependent membrane fusion and yielding a model that assigns defined functions for central components of the release machinery. The soluble N ‐ethyl maleimide sensitive factor attachment protein receptors (SNAREs) syntaxin‐1, SNAP‐25, and synaptobrevin‐2 form a tight SNARE complex that brings the vesicle and plasma membranes together and is key for membrane fusion. N ‐ethyl maleimide sensitive factor (NSF) and soluble NSF attachment proteins (SNAPs) disassemble the SNARE complex to recycle the SNAREs for another round of fusion. Munc18‐1 and Munc13‐1 orchestrate SNARE complex formation in an NSF‐SNAP‐resistant manner by a mechanism whereby Munc18‐1 binds to synaptobrevin and to a self‐inhibited “closed” conformation of syntaxin‐1, thus forming a template to assemble the SNARE complex, and Munc13‐1 facilitates assembly by bridging the vesicle and plasma membranes and catalyzing opening of syntaxin‐1. Synaptotagmin‐1 functions as the major Ca 2+ sensor that triggers release by binding to membrane phospholipids and to the SNAREs, in a tight interplay with complexins that accelerates membrane fusion. Many of these proteins act as both inhibitors and activators of exocytosis, which is critical for the exquisite regulation of neurotransmitter release. It is still unclear how the actions of these various proteins and multiple other components that control release are integrated and, in particular, how they induce membrane fusion, but it can be expected that these fundamental questions can be answered in the near future, building on the extensive knowledge already available.

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Crossref · 10.1002/pro.3445

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  • Neurotransmitter release is mediated by the SNARE complex, comprising syntaxin-1, SNAP25, and synaptobrevin, and triggered by the calcium sensor synaptotagmin-1.

    “Neurotransmitter release is mediated by the SNARE complex, comprising syntaxin-1, SNAP25, and synaptobrevin, and triggered by the calcium sensor synaptotagmin-1.”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [22]

  • Neurotransmitter release is a multi-step process, not just a single fusion event, because Munc18-1 and Munc13-1 orchestrate SNARE complex formation and vesicle priming.

    “The observation that Munc18-1 and Munc13-1 orchestrate SNARE complex formation and vesicle priming reveals that neurotransmitter release is a multi-step process, not just a single fusion event [22].”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [22]

  • The SNARE complex is formed by synaptobrevin (VAMP2), syntaxin-1, and SNAP25, which assemble into a stable four-helix bundle that pulls vesicle and plasma membranes into close proximity, driving membrane fusion.

    “This complex is formed by the interaction of three key proteins: synaptobrevin (also known as VAMP2), a v-SNARE located on the synaptic vesicle membrane, and syntaxin-1 and SNAP25, which are t-SNAREs anchored to the presynaptic plasma membrane [22]. These SNARE proteins assemble into a stable four-helix bundle, a structure that physically pulls the vesicle and plasma membranes into close proximity”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [22]

  • Munc13-1 facilitates SNARE complex assembly by bridging the synaptic vesicle and plasma membranes.

    “Munc13-1 further facilitates this assembly process by bridging the synaptic vesicle and plasma membranes.”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [22]

  • Following fusion, the SNARE complex is disassembled by NSF and SNAPs, allowing SNARE proteins to be recycled.

    “Following fusion, the SNARE complex is disassembled by the N-ethylmalemaleimide sensitive factor (NSF) and soluble NSF attachment proteins (SNAPs), allowing the SNARE proteins to be recycled for subsequent rounds of neurotransmitter release [22].”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [22]

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Research works printed but not linked: 3

  1. [160]160. Kummel D, Krishnakumar SS, Radoff DT, Li F, Giraudo CG, Pincet F, Rothman JE, Reinisch KM (2011) Complexin cross‐links prefusion SNAREs into a zigzag array. Nat Struct Mol Biol 18:927–933. [DOI] [PMC free article] [PubMed] [Google Scholar]
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Authors
Rizo, J.
Affiliations
The University of Texas Southwestern Medical Center (US)
Corresponding author
Rizo, Josep
Venue
Protein Science
Publisher
Wiley
Published
2018-07-10
Volume
27
Issue
8
Pages
1364-1391
ISSN
  • 0961-8368 (ISSN-L)
  • 1469-896X
OpenAlex
W2941374900
Cited by
210
References
242
Citations by year
2026: 19 · 2025: 16 · 2024: 18 · 2023: 24 · 2022: 37 · 2021: 36 · 2020: 34 · 2019: 23 · 2018: 3
FWCI
2.70
Type
journal article
Language
en
Open access
Locations
  • Protein Science (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Welch Foundation (I‐1304)
  • NIH (R35‐NS097333)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
Keywords
neurotransmitter release, synaptic vesicle exocytosis, SNARE complex, syntaxin-1, SNAP-25, synaptobrevin 2, NSF, Munc18-1, Munc13-1, synaptotagmin-1, complexin, calcium sensor, exocytosis regulation
MeSH terms
Animals, Humans, Membrane Fusion, Synaptic Transmission, Neurotransmitter Agents, SNARE Proteins, Mice

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