Munc13-1 is essential for fusion competence of glutamatergic synaptic vesicles
Abstract
Neurotransmitter release at synapses between nerve cells is mediated by calcium-triggered exocytotic fusion of synaptic vesicles. Before fusion, vesicles dock at the presynaptic release site where they mature to a fusion-competent state. Here we identify Munc13-1, a brain-specific presynaptic phorbol ester receptor, as an essential protein for synaptic vesicle maturation. We show that glutamatergic hippocampal neurons from mice lacking Munc13-1 form ultrastructurally normal synapses whose synaptic-vesicle cycle is arrested at the maturation step. Transmitter release from mutant synapses cannot be triggered by action potentials, calcium-ionophores or hypertonic sucrose solution. In contrast, release evoked by alpha-latrotoxin is indistinguishable from wild-type controls, indicating that the toxin can bypass Munc13-1-mediated vesicle maturation. A small subpopulation of synapses of any given glutamatergic neuron as well as all synapses of GABA (gamma-aminobutyric acid)-containing neurons are unaffected by Munc13-1 loss, demonstrating the existence of multiple and transmitter-specific synaptic vesicle maturation processes in synapses.
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Forskolin slightly reduces the distance between CaV2.1 Ca2+ channels and Munc13-1.
“Furthermore, we discovered that forskolin slightly reduced the distance between CaV2.1 (P/Q-type) Ca2+ channels and Munc13-1, an essential vesicle priming protein and putative marker of primed vesicles [14,40–45].”
From Presynaptic cAMP-PKA-mediated potentiation induces reconfiguration of synaptic vesicle pools and channel-vesicle coupling at hippocampal mossy fiber boutons (2024) · cites this paper as [41]
Munc13 proteins are active zone proteins essential for synaptic vesicle priming.
“Characterization of the mammalian homologs of UNC-13—named Munc13s—revealed that Munc13 proteins are active zone proteins essential for synaptic vesicle priming (Brose et al., 1995; Augustin et al., 1999).”
From The Presynaptic Active Zone (2012) · cites this paper as Augustin et al., 1999
In Munc13-1 KO mice synaptic vesicle docking appears to be normal as analyzed by EM of chemically fixed synapses but impaired as analyzed by cryo-EM of unfixed samples.
“For example, in Munc13-1 KO mice synaptic vesicle docking appears to be normal as analyzed by EM of chemically fixed synapses (Augustin et al., 1999) but impaired as analyzed by cryo-EM of unfixed samples (Siksou et al., 2009).”
From The Presynaptic Active Zone (2012) · cites this paper as Augustin et al., 1999
Mutations in synapsins, Munc13, and RIMs alter short-term plasticity in a manner independent of the first two sets of mechanisms.
“Mutations in several proteins associated with the release machinery alter short-term plasticity in a manner independent of the first two sets of mechanisms, for example mutations in synapsins (Rosahl et al., 1995), Munc13 (Augustin et al., 1999), and RIMs (Schoch et al., 2002).”
From The Presynaptic Active Zone (2012) · cites this paper as Augustin et al., 1999
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References 17 · Cited by 787
- Authors
- Augustin, I., Rosenmund, C., Südhof, T. C., & Brose, N.
- Affiliations
- Max Planck Society (DE)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Brose, Nils
- Venue
- Nature
- Published
- 1999-07
- Volume
- 400
- Issue
- 6743
- Pages
- 457-461
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1618714882
- Cited by
- 787
- References
- 17
- Citations by year
- 2026: 21 · 2025: 28 · 2024: 22 · 2023: 36 · 2022: 45 · 2021: 37 · 2020: 26 · 2019: 27 · 2018: 22 · 2017: 42 · 2016: 14 · 2015: 23 · 2014: 26 · 2013: 34 · 2012: 34
- FWCI
- 8.39
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- GRO (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- 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
- Munc13-1, exocytosis, glutamatergic synapses, neurotransmitter release, presynaptic release sites, phorbol ester receptor, alpha-latrotoxin, hippocampal neurons, GABAergic synapses, calcium-triggered fusion, synaptic ultrastructure
- MeSH terms
- Action Potentials, Animals, Cells, Cultured, gamma-Aminobutyric Acid, Hippocampus, Membrane Fusion, Nerve Tissue Proteins, Synaptic Transmission, Neurons, Spider Venoms, Synapses, Synaptic Vesicles, Receptors, N-Methyl-D-Aspartate, Dizocilpine Maleate, Sequence Deletion, Excitatory Amino Acid Antagonists, Glutamic Acid, Intracellular Signaling Peptides and Proteins, Mice
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