RIM proteins tether Ca2+ channels to presynaptic active zones via a direct PDZ-domain interaction
Open accessAbstract
At a synapse, fast synchronous neurotransmitter release requires localization of Ca(2+) channels to presynaptic active zones. How Ca(2+) channels are recruited to active zones, however, remains unknown. Using unbiased yeast two-hybrid screens, we here identify a direct interaction of the central PDZ domain of the active-zone protein RIM with the C termini of presynaptic N- and P/Q-type Ca(2+) channels but not L-type Ca(2+) channels. To test the physiological significance of this interaction, we generated conditional knockout mice lacking all multidomain RIM isoforms. Deletion of RIM proteins ablated most neurotransmitter release by simultaneously impairing the priming of synaptic vesicles and by decreasing the presynaptic localization of Ca(2+) channels. Strikingly, rescue of the decreased Ca(2+)-channel localization required the RIM PDZ domain, whereas rescue of vesicle priming required the RIM N terminus. We propose that RIMs tether N- and P/Q-type Ca(2+) channels to presynaptic active zones via a direct PDZ-domain-mediated interaction, thereby enabling fast, synchronous triggering of neurotransmitter release at a synapse.
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In chemically fixed RIM mutant synapses, vesicles are at least partially undocked.
“However, in chemically fixed RIM mutant synapses, vesicles are at least partially undocked (Kaeser et al., 2011).”
From The Presynaptic Active Zone (2012) · cites this paper as Kaeser et al., 2011
The Results section (‘Conditional KO mice for presynaptic RIM isoforms’; page unavailable) reports nearly two-fold fewer docked vesicles per active zone in RIM-deficient neurons, supporting partial undocking. Our copy does not specify that the synapses examined by electron microscopy were chemically fixed. (LLM, conf=0.82)
Experimental — accuracy not yet measuredCa2+ channels are recruited to active zones by a tripartite complex composed of RIMs, RIM-BPs, and the C-terminal tails of the channels.
“Together, these data suggest that Ca2+ channels are recruited to active zones by a tripartite complex composed of RIMs, RIM-BPs, and the C-terminal tails of the channels (Figure 3).”
From The Presynaptic Active Zone (2012) · cites this paper as Kaeser et al., 2011
Binding of the RIM PDZ-domain to Ca2+ channels is essential for recruiting Ca2+ channels to active zones.
“In contrast, the binding of the RIM PDZ-domain to Ca2+ channels is essential for recruiting Ca2+ channels to active zones (Kaeser et al., 2011; Han et al., 2011).”
From The Presynaptic Active Zone (2012) · cites this paper as Kaeser et al., 2011
The central PDZ-domain of RIMs binds N- and P/Q-type but not L-type Ca2+ channels.
“The central PDZ-domain of RIMs binds at least two proteins: ELKS (Ohtsuka et al., 2002; Wang et al., 2002) and N- and P/Q-type but not L-type Ca2+ channels (Kaeser et al., 2011).”
From The Presynaptic Active Zone (2012) · cites this paper as Kaeser et al., 2011
Ca2+ channels are recruited to active zones by binding simultaneously to both RIM and RIM-BPs.
“This problem was resolved when the RIM PDZ-domains were found to bind to N- and P/Q-type but not L-type Ca2+ channels (Kaeser et al., 2011), indicating that Ca2+ channels are recruited to active zones by binding simultaneously to both RIM and RIM-BPs (Figure 3).”
From The Presynaptic Active Zone (2012) · cites this paper as Kaeser et al., 2011
RIM-BPs bind to RIMs and to N-, P/Q-, and L-type Ca2+ channels.
“However, the latter identification may be erroneous since subsequent studies showed that RIM-BPs are highly expressed only in brain and not peripherally and tightly bind to RIM (Wang et al., 2000) and to N-, P/Q-, and L-type Ca2+ channels (Hibino et al., 2002; Kaeser et al., 2011).”
From The Presynaptic Active Zone (2012) · cites this paper as Kaeser et al., 2011
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- Authors
- Kaeser, P. S., Deng, L., Wang, Y., Dulubova, I., Liu, X., Rizo, J., & Südhof, T. C.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Südhof, Thomas C.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2011-01
- Volume
- 144
- Issue
- 2
- Pages
- 282-295
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3063406
- OpenAlex
- W2041733763
- Cited by
- 607
- References
- 3
- Citations by year
- 2026: 19 · 2025: 23 · 2024: 35 · 2023: 42 · 2022: 46 · 2021: 42 · 2020: 42 · 2019: 46 · 2018: 46 · 2017: 43 · 2016: 28 · 2015: 44 · 2014: 36 · 2013: 45 · 2012: 39
- FWCI
- 19.75
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 928 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- National Institutes of Health
- U.S. Public Health Service (NINDS 33564)
- National Institute on Drug Abuse (DA029044, K01DA029044)
- National Institute of Neurological Disorders and Stroke (NS 37200, R01NS037200)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- PDZ domain, active zone, L-type Ca2+ channels, synaptic vesicle priming, synaptic transmission
- MeSH terms
- Animals, Calcium, Nerve Tissue Proteins, Calcium Channels, Protein Structure, Tertiary, Presynaptic Terminals, Mice, Knockout, Neurotransmitter Agents, ATP-Binding Cassette Transporters, GTP-Binding Proteins, Protein Isoforms, Two-Hybrid System Techniques, Mice
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