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PreprintCited by 6RNA regulation and diseaseCellular transport and secretionNeuroscience and Neuropharmacology Research

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Stochastic RNA editing of the Complexin C-terminus within single neurons regulates neurotransmitter release

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Brija, Elizabeth A., Guan, Zhuo, Jetti, Suresh K., Littleton, J. Troy·2023·Cell Reports
DOI 10.1101/2023.05.30.542887PMC PMC10591831

Preprint — published as 10.1016/j.celrep.2023.113152 · Paper page

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Abstract

Neurotransmitter release requires assembly of the SNARE complex fusion machinery, with multiple SNARE-binding proteins regulating this process to control when and where synaptic vesicle fusion occurs. Complexin (Cpx) controls spontaneous and evoked neurotransmitter release by modulating SNARE complex zippering. Although the central SNARE-binding helix is essential, post-translational modifications to Cpx’s C-terminal membrane-binding amphipathic helix modulate its activity. Here we demonstrate that RNA editing of the Cpx C-terminus regulates its ability to clamp SNARE-mediated fusion and alters presynaptic output. RNA editing of Cpx within single neurons is stochastic, generating up to eight edit variants that fine-tune neurotransmitter release by changing the subcellular localization and clamping properties of the protein. Similar editing rules for other synaptic genes were observed, indicating stochastic editing at single adenosines and across multiple mRNAs can generate unique synaptic proteomes within the same population of neurons to fine-tune presynaptic output.

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Metadata

Authors
Brija, E. A., Guan, Z., Jetti, S. K., & Littleton, J. T.
Affiliations
Massachusetts Institute of Technology (US)
Corresponding author
Littleton, J. Troy
ORCID
Venue
Cell Reports
Publisher
openRxiv
Published
2023-05-30
Volume
42
Issue
9
Pages
113152-113152
ISSN
2211-1247 (ISSN-L)
DOI
10.1101/2023.05.30.542887
PMC
PMC10591831
OpenAlex
W4386818208
Cited by
6
References
1
Citations by year
2026: 1 · 2025: 5
FWCI
0.53
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Cell Reports (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Science Foundation (1122374)
  • Indiana University
  • JPB Foundation
  • National Institutes of Health (NIH P40OD018537, 1122374, NS40296, P40OD018537)
  • National Institute of Mental Health (R01MH104536)
  • National Institute of Neurological Disorders and Stroke (NS40296, R01NS040296)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
RNA editing, complexin, SNARE complex, synaptic vesicle fusion, neurotransmitter release, presynaptic proteins, single neurons, synaptic proteome, subcellular localization

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