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Cited by 3Cellular transport and secretionNeuroscience and Neuropharmacology ResearchExtracellular vesicles in disease

RIM and MUNC13 membrane–binding domains are essential for neuropeptide secretion

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Murphy, Fiona H., Abramian, Adlin, Klaassen, Remco V., Koopmans, Frank, Persoon, Claudia M., Smit, August B., Toonen, Ruud F., Verhage, Matthijs·2025·Journal of Cell Biology
DOI 10.1083/jcb.202409196PMC PMC12077229
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Abstract

Neurons release neurotransmitters from synaptic vesicles (SVs) and neuropeptides from dense-core vesicles (DCVs). The presynaptic proteins RIM and MUNC13 play key roles in both pathways. It remains unclear how DCVs are targeted to release sites and whether RIM and MUNC13 are involved in this process. Here, we show that three membrane-binding domains in RIM and MUNC13 regulate DCV exocytosis differently from SV exocytosis. Using neuropeptide secretion assays with single-vesicle resolution and peptidomics analysis of endogenous neuropeptide release in MUNC13/RIM null neurons, we demonstrate that MUNC13 is essential for DCV exocytosis. The RIM N terminus prevents MUNC13 degradation via the proteasome, and inhibiting proteasomal degradation partially rescues DCV exocytosis in RIM’s absence. Unlike SV exocytosis, the PIP2-binding RIM C2B domain and MUNC13 C1-C2B polybasic face are redundant for DCV exocytosis, while the lipid-binding MUNC13 C2C domain is crucial. These results show that RIM and MUNC13 synergistically regulate DCV exocytosis through membrane interactions and reveal new mechanistic differences between SV and DCV exocytosis.

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  • Munc13 is essential for both fast and modulatory release; its membrane-binding C2C domain is specifically crucial for neuropeptide secretion from large dense-core vesicles (DCVs), unlike the redundant C2B domain in small synaptic vesicle (SV) exocytosis.

    “Munc13 is essential for both fast and modulatory release; however, its membrane-binding C2C domain is specifically crucial for neuropeptide secretion from large dense-core vesicles (DCVs), unlike the redundant C2B domain in small synaptic vesicle (SV) exocytosis [4,21].”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [21]

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Authors
Murphy, F. H., Abramian, A., Klaassen, R. V., Koopmans, F., Persoon, C. M., Smit, A. B., Toonen, R. F., & Verhage, M.
Affiliations
  • Amsterdam University Medical Centers (NL)
  • Vrije Universiteit Amsterdam (NL)
Corresponding author
Verhage, Matthijs
ORCID
Venue
Journal of Cell Biology
Publisher
Rockefeller University Press
Published
2025-05-12
Volume
224
Issue
7
ISSN
  • 0021-9525 (ISSN-L)
  • 1540-8140
DOI
10.1083/jcb.202409196
PMC
PMC12077229
OpenAlex
W4410304474
Cited by
3
References
54
Citations by year
2026: 3
FWCI
1.50
Type
journal article
Language
en
Open access
Licence
Locations
  • The Journal of Cell Biology (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • VU Research Portal (publishedVersion, other-oa)
  • Pure Amsterdam UMC (submittedVersion, other-oa)
Funders
  • European Research Council (322966)
  • Amsterdam UMC Location VUmc
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
RIM, Munc13, neuropeptide release, dense core vesicles, synaptic vesicles, exocytosis, membrane-binding domain, C2B domain, PIP2 binding, proteasomal degradation, presynaptic proteins, peptidomics
MeSH terms
Protein Domains, Animals, Exocytosis, Nerve Tissue Proteins, Neurons, Neuropeptides, Protein Binding, Synaptic Vesicles, Mice, Knockout, GTP-Binding Proteins, Secretory Vesicles, Mice

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