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Proc Natl Acad Sci U S A. 2016 Oct 11;113(41):11615-11620. Epub 2016 Sep 26.

RIM-binding protein 2 regulates release probability by fine-tuning calcium channel localization at murine hippocampal synapses.

Author information

1
Institute of Neurophysiology, Charité Universitätsmedizin, 10117 Berlin, Germany; NeuroCure Cluster of Excellence, Charité Universitätsmedizin, 10117 Berlin, Germany; Institute of Biology, Department of Biology, Chemistry, Pharmacy, Freie Universität Berlin, 14195 Berlin, Germany.
2
NeuroCure Cluster of Excellence, Charité Universitätsmedizin, 10117 Berlin, Germany; Institute of Biology, Department of Biology, Chemistry, Pharmacy, Freie Universität Berlin, 14195 Berlin, Germany; Department of Molecular Pharmacology and Cell Biology, Leibniz Institut für Molekulare Pharmakologie (FMP), 13125 Berlin, Germany.
3
NeuroCure Cluster of Excellence, Charité Universitätsmedizin, 10117 Berlin, Germany; Institute of Biology, Department of Biology, Chemistry, Pharmacy, Freie Universität Berlin, 14195 Berlin, Germany.
4
NeuroCure Cluster of Excellence, Charité Universitätsmedizin, 10117 Berlin, Germany; Institute of Biochemistry, Charité Universitätsmedizin, 10117 Berlin, Germany; Neuroscience Research Center (NWFZ), Charité Universitätsmedizin, 10117 Berlin, Germany.
5
Institute of Neurophysiology, Charité Universitätsmedizin, 10117 Berlin, Germany; NeuroCure Cluster of Excellence, Charité Universitätsmedizin, 10117 Berlin, Germany.
6
NeuroCure Cluster of Excellence, Charité Universitätsmedizin, 10117 Berlin, Germany; Neuroscience Research Center (NWFZ), Charité Universitätsmedizin, 10117 Berlin, Germany.
7
Molecular and Theoretical Neuroscience, Leibniz-Institut für Molekulare Pharmakologie, 10117 Berlin, Germany.
8
NeuroCure Cluster of Excellence, Charité Universitätsmedizin, 10117 Berlin, Germany; Neuroscience Research Center (NWFZ), Charité Universitätsmedizin, 10117 Berlin, Germany; DZNE- German Center for Neurodegenerative Diseases, Charité Universitätsmedizin, 10117 Berlin, Germany.
9
NeuroCure Cluster of Excellence, Charité Universitätsmedizin, 10117 Berlin, Germany; Institute of Biochemistry, Charité Universitätsmedizin, 10117 Berlin, Germany.
10
NeuroCure Cluster of Excellence, Charité Universitätsmedizin, 10117 Berlin, Germany; Department of Molecular Pharmacology and Cell Biology, Leibniz Institut für Molekulare Pharmakologie (FMP), 13125 Berlin, Germany; Institute of Chemistry and Biochemistry, Department of Biology, Chemistry, Pharmacy, Freie Universität Berlin, 14195 Berlin, Germany.
11
NeuroCure Cluster of Excellence, Charité Universitätsmedizin, 10117 Berlin, Germany; Neuroscience Research Center (NWFZ), Charité Universitätsmedizin, 10117 Berlin, Germany; DZNE- German Center for Neurodegenerative Diseases, Charité Universitätsmedizin, 10117 Berlin, Germany; christian.rosenmund@charite.de dietmar.schmitz@charite.de stephan.sigrist@fu-berlin.de.
12
NeuroCure Cluster of Excellence, Charité Universitätsmedizin, 10117 Berlin, Germany; Institute of Biology, Department of Biology, Chemistry, Pharmacy, Freie Universität Berlin, 14195 Berlin, Germany; christian.rosenmund@charite.de dietmar.schmitz@charite.de stephan.sigrist@fu-berlin.de.
13
Institute of Neurophysiology, Charité Universitätsmedizin, 10117 Berlin, Germany; NeuroCure Cluster of Excellence, Charité Universitätsmedizin, 10117 Berlin, Germany; christian.rosenmund@charite.de dietmar.schmitz@charite.de stephan.sigrist@fu-berlin.de.

Abstract

The tight spatial coupling of synaptic vesicles and voltage-gated Ca2+ channels (CaVs) ensures efficient action potential-triggered neurotransmitter release from presynaptic active zones (AZs). Rab-interacting molecule-binding proteins (RIM-BPs) interact with Ca2+ channels and via RIM with other components of the release machinery. Although human RIM-BPs have been implicated in autism spectrum disorders, little is known about the role of mammalian RIM-BPs in synaptic transmission. We investigated RIM-BP2-deficient murine hippocampal neurons in cultures and slices. Short-term facilitation is significantly enhanced in both model systems. Detailed analysis in culture revealed a reduction in initial release probability, which presumably underlies the increased short-term facilitation. Superresolution microscopy revealed an impairment in CaV2.1 clustering at AZs, which likely alters Ca2+ nanodomains at release sites and thereby affects release probability. Additional deletion of RIM-BP1 does not exacerbate the phenotype, indicating that RIM-BP2 is the dominating RIM-BP isoform at these synapses.

KEYWORDS:

RIM-BP2; active zone structure; calcium channel coupling; release probability; short-term plasticity

PMID:
27671655
PMCID:
PMC5068320
DOI:
10.1073/pnas.1605256113
[Indexed for MEDLINE]
Free PMC Article

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