α-Neurexins couple Ca2+ channels to synaptic vesicle exocytosis
Abstract
Synapses are specialized intercellular junctions in which cell adhesion molecules connect the presynaptic machinery for neurotransmitter release to the postsynaptic machinery for receptor signalling. Neurotransmitter release requires the presynaptic co-assembly of Ca2+ channels with the secretory apparatus, but little is known about how synaptic components are organized. Alpha-neurexins, a family of >1,000 presynaptic cell-surface proteins encoded by three genes, link the pre- and postsynaptic compartments of synapses by binding extracellularly to postsynaptic cell adhesion molecules and intracellularly to presynaptic PDZ domain proteins. Using triple-knockout mice, we show that alpha-neurexins are not required for synapse formation, but are essential for Ca2+-triggered neurotransmitter release. Neurotransmitter release is impaired because synaptic Ca2+ channel function is markedly reduced, although the number of cell-surface Ca2+ channels appears normal. These data suggest that alpha-neurexins organize presynaptic terminals by functionally coupling Ca2+ channels to the presynaptic machinery.
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Mice lacking neurexin-1α have defects in synaptic calcium channel function and neurotransmitter release.
“Mice lacking neurexin-1α have defects in synaptic calcium channel function and neurotransmitter release (Missler et al., 2003).”
From CNVs: Harbingers of a Rare Variant Revolution in Psychiatric Genetics (2012) · cites this paper as Missler et al., 2003
Triple and double Nrxn KO mice show fewer inhibitory synapses in the brainstem and neocortex, respectively, compared to wild-type controls.
“Triple and double KO mice show fewer inhibitory synapses in the brainstem and neocortex, respectively, compared to the wild-type (WT) controls [242].”
From Autism spectrum disorder: neuropathology and animal models (2017) · cites this paper as [242]
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Xie, M., Wang, T., Feng, J., Ma, D., Feng, L., & Hao, Y. (2025) · Current Neuropharmacology · doi:10.2174/1570159x23666250225091729 · Cited by 7 · see citing works
Principles of synaptogenesis: Insights from Caenorhabditis elegans
Frankel, E. B., & Kurshan, P. T. (2025) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2025.103056 · Cited by 7 · see citing works
- Authors
- Missler, M., Zhang, W., Rohlmann, A., Kattenstroth, G., Hammer, R. E., Gottmann, K., & Südhof, T. C.
- Affiliations
- University of Göttingen (DE)
- Ruhr University Bochum (DE)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Missler, Markus
- Südhof, Thomas C.
- Venue
- Nature
- Published
- 2003-06
- Volume
- 423
- Issue
- 6943
- Pages
- 939-948
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1546762987
- Cited by
- 699
- References
- 52
- Citations by year
- 2026: 20 · 2025: 26 · 2024: 31 · 2023: 36 · 2022: 45 · 2021: 20 · 2020: 26 · 2019: 36 · 2018: 27 · 2017: 27 · 2016: 27 · 2015: 30 · 2014: 39 · 2013: 34 · 2012: 27
- FWCI
- 8.20
- 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)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Keywords
- calcium channels, synaptic vesicle exocytosis, neurotransmitter release, presynaptic terminals, synaptogenesis, PDZ domain proteins, adhesion molecules, triple knockout mice
- MeSH terms
- Animals, Brain Stem, Calcium, Cell Adhesion, Cells, Cultured, Evoked Potentials, Exocytosis, Glycoproteins, Mice, Inbred C57BL, Mice, Transgenic, Nerve Tissue Proteins, Synaptic Transmission, Neuropeptides, Recombinant Fusion Proteins, Synapses, Synaptic Vesicles, Calcium Channels, Cell Adhesion Molecules, Neuronal, Mice, Knockout, Neurotransmitter Agents, Neocortex, Calcium Signaling, Mice, In Vitro Techniques
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