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RIM genes differentially contribute to organizing presynaptic release sites
Open accessAbstract
Tight coupling of Ca(2+) channels to the presynaptic active zone is critical for fast synchronous neurotransmitter release. RIMs are multidomain proteins that tether Ca(2+) channels to active zones, dock and prime synaptic vesicles for release, and mediate presynaptic plasticity. Here, we use conditional knockout mice targeting all RIM isoforms expressed by the Rims1 and Rims2 genes to examine the contributions and mechanism of action of different RIMs in neurotransmitter release. We show that acute single deletions of each Rims gene decreased release and impaired vesicle priming but did not alter the extracellular Ca(2+)-responsiveness of release (which for Rims gene mutants is a measure of presynaptic Ca(2+) influx). Moreover, single deletions did not affect the synchronization of release (which depends on the close proximity of Ca(2+) channels to release sites). In contrast, deletion of both Rims genes severely impaired the Ca(2+) responsiveness and synchronization of release. RIM proteins may act on Ca(2+) channels in two modes: They tether Ca(2+) channels to active zones, and they directly modulate Ca(2+)-channel inactivation. The first mechanism is essential for localizing presynaptic Ca(2+) influx to nerve terminals, but the role of the second mechanism remains unknown. Strikingly, we find that although the RIM2 C(2)B domain by itself significantly decreased Ca(2+)-channel inactivation in transfected HEK293 cells, it did not rescue any aspect of the RIM knockout phenotype in cultured neurons. Thus, RIMs primarily act in release as physical Ca(2+)-channel tethers and not as Ca(2+)-channel modulators. Different RIM proteins compensate for each other in recruiting Ca(2+) channels to active zones, but contribute independently and incrementally to vesicle priming.
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“RIM1/2 recruits Munc13-1s to AZs [72,73] and interacts with other AZ components to enable exocytosis [73–76].”
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 [74]
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“This might result from direct, fixed-length interaction between the PZD domain of RIM1/2 and the CaV2.1 C-terminus [73,74], which is difficult to modulate.”
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 [74]
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Citations
Cites
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Self-citationRIM1α forms a protein scaffold for regulating neurotransmitter release at the active zone
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RIM-Binding Protein, a Central Part of the Active Zone, Is Essential for Neurotransmitter Release
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Metadata
- Authors
- Kaeser, P. S., Deng, L., Fan, M., & Südhof, T. C.
- Affiliations
- Howard Hughes Medical Institute (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-07-02
- Volume
- 109
- Issue
- 29
- Pages
- 11830-11835
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3406861
- OpenAlex
- W2029142270
- Cited by
- 115
- References
- 39
- Citations by year
- 2026: 6 · 2025: 2 · 2024: 6 · 2023: 11 · 2022: 11 · 2021: 4 · 2020: 10 · 2019: 10 · 2018: 9 · 2017: 10 · 2016: 8 · 2015: 4 · 2014: 10 · 2013: 10 · 2012: 4
- FWCI
- 3.69
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- U.S. Public Health Service (P0MH086403)
- National Institute on Drug Abuse (DA029044, K01DA029044)
- National Institute of Neurological Disorders and Stroke (R01NS077906)
- 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
- active zone, synaptic vesicle priming, neurotransmitter release, calcium channel inactivation, presynaptic calcium influx, conditional knockout mice, C2B domain
- MeSH terms
- Animals, Calcium, Evoked Potentials, Hippocampus, Humans, Lipids, Calcium Channels, Presynaptic Terminals, Mice, Knockout, Patch-Clamp Techniques, GTP-Binding Proteins, rab3 GTP-Binding Proteins, Mice, HEK293 Cells
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