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Research Article

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

M. Katharina Grauel, View ORCID ProfileMarta Maglione, Suneel Reddy-Alla, Claudia G. Willmes, Marisa M. Brockmann, Thorsten Trimbuch, Tanja Rosenmund, Maria Pangalos, Gülçin Vardar, Alexander Stumpf, Alexander M. Walter, Benjamin R. Rost, Britta J. Eickholt, Volker Haucke, Dietmar Schmitz, Stephan J. Sigrist, and Christian Rosenmund
  1. aInstitute of Neurophysiology, Charité Universitätsmedizin, 10117 Berlin, Germany;
  2. bNeuroCure Cluster of Excellence, Charité Universitätsmedizin, 10117 Berlin, Germany;
  3. cInstitute of Biology, Department of Biology, Chemistry, Pharmacy, Freie Universität Berlin, 14195 Berlin, Germany;
  4. dDepartment of Molecular Pharmacology and Cell Biology, Leibniz Institut für Molekulare Pharmakologie (FMP), 13125 Berlin, Germany;
  5. eInstitute of Biochemistry, Charité Universitätsmedizin, 10117 Berlin, Germany;
  6. fNeuroscience Research Center (NWFZ), Charité Universitätsmedizin, 10117 Berlin, Germany;
  7. gMolecular and Theoretical Neuroscience, Leibniz-Institut für Molekulare Pharmakologie, 10117 Berlin, Germany;
  8. hDZNE- German Center for Neurodegenerative Diseases, Charité Universitätsmedizin, 10117 Berlin, Germany;
  9. iInstitute of Chemistry and Biochemistry, Department of Biology, Chemistry, Pharmacy, Freie Universität Berlin, 14195 Berlin, Germany

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PNAS October 11, 2016 113 (41) 11615-11620; first published September 26, 2016; https://doi.org/10.1073/pnas.1605256113
M. Katharina Grauel
aInstitute of Neurophysiology, Charité Universitätsmedizin, 10117 Berlin, Germany;
bNeuroCure Cluster of Excellence, Charité Universitätsmedizin, 10117 Berlin, Germany;
cInstitute of Biology, Department of Biology, Chemistry, Pharmacy, Freie Universität Berlin, 14195 Berlin, Germany;
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Marta Maglione
bNeuroCure Cluster of Excellence, Charité Universitätsmedizin, 10117 Berlin, Germany;
cInstitute of Biology, Department of Biology, Chemistry, Pharmacy, Freie Universität Berlin, 14195 Berlin, Germany;
dDepartment of Molecular Pharmacology and Cell Biology, Leibniz Institut für Molekulare Pharmakologie (FMP), 13125 Berlin, Germany;
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  • ORCID record for Marta Maglione
Suneel Reddy-Alla
bNeuroCure Cluster of Excellence, Charité Universitätsmedizin, 10117 Berlin, Germany;
cInstitute of Biology, Department of Biology, Chemistry, Pharmacy, Freie Universität Berlin, 14195 Berlin, Germany;
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Claudia G. Willmes
bNeuroCure Cluster of Excellence, Charité Universitätsmedizin, 10117 Berlin, Germany;
eInstitute of Biochemistry, Charité Universitätsmedizin, 10117 Berlin, Germany;
fNeuroscience Research Center (NWFZ), Charité Universitätsmedizin, 10117 Berlin, Germany;
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Marisa M. Brockmann
aInstitute of Neurophysiology, Charité Universitätsmedizin, 10117 Berlin, Germany;
bNeuroCure Cluster of Excellence, Charité Universitätsmedizin, 10117 Berlin, Germany;
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Thorsten Trimbuch
aInstitute of Neurophysiology, Charité Universitätsmedizin, 10117 Berlin, Germany;
bNeuroCure Cluster of Excellence, Charité Universitätsmedizin, 10117 Berlin, Germany;
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Tanja Rosenmund
aInstitute of Neurophysiology, Charité Universitätsmedizin, 10117 Berlin, Germany;
bNeuroCure Cluster of Excellence, Charité Universitätsmedizin, 10117 Berlin, Germany;
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Maria Pangalos
bNeuroCure Cluster of Excellence, Charité Universitätsmedizin, 10117 Berlin, Germany;
fNeuroscience Research Center (NWFZ), Charité Universitätsmedizin, 10117 Berlin, Germany;
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Gülçin Vardar
aInstitute of Neurophysiology, Charité Universitätsmedizin, 10117 Berlin, Germany;
bNeuroCure Cluster of Excellence, Charité Universitätsmedizin, 10117 Berlin, Germany;
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Alexander Stumpf
bNeuroCure Cluster of Excellence, Charité Universitätsmedizin, 10117 Berlin, Germany;
fNeuroscience Research Center (NWFZ), Charité Universitätsmedizin, 10117 Berlin, Germany;
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Alexander M. Walter
gMolecular and Theoretical Neuroscience, Leibniz-Institut für Molekulare Pharmakologie, 10117 Berlin, Germany;
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Benjamin R. Rost
bNeuroCure Cluster of Excellence, Charité Universitätsmedizin, 10117 Berlin, Germany;
fNeuroscience Research Center (NWFZ), Charité Universitätsmedizin, 10117 Berlin, Germany;
hDZNE- German Center for Neurodegenerative Diseases, Charité Universitätsmedizin, 10117 Berlin, Germany;
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Britta J. Eickholt
bNeuroCure Cluster of Excellence, Charité Universitätsmedizin, 10117 Berlin, Germany;
eInstitute of Biochemistry, Charité Universitätsmedizin, 10117 Berlin, Germany;
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Volker Haucke
bNeuroCure Cluster of Excellence, Charité Universitätsmedizin, 10117 Berlin, Germany;
dDepartment of Molecular Pharmacology and Cell Biology, Leibniz Institut für Molekulare Pharmakologie (FMP), 13125 Berlin, Germany;
iInstitute of Chemistry and Biochemistry, Department of Biology, Chemistry, Pharmacy, Freie Universität Berlin, 14195 Berlin, Germany
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Dietmar Schmitz
bNeuroCure Cluster of Excellence, Charité Universitätsmedizin, 10117 Berlin, Germany;
fNeuroscience Research Center (NWFZ), Charité Universitätsmedizin, 10117 Berlin, Germany;
hDZNE- German Center for Neurodegenerative Diseases, Charité Universitätsmedizin, 10117 Berlin, Germany;
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  • For correspondence: christian.rosenmund@charite.de dietmar.schmitz@charite.de stephan.sigrist@fu-berlin.de
Stephan J. Sigrist
bNeuroCure Cluster of Excellence, Charité Universitätsmedizin, 10117 Berlin, Germany;
cInstitute of Biology, Department of Biology, Chemistry, Pharmacy, Freie Universität Berlin, 14195 Berlin, Germany;
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  • For correspondence: christian.rosenmund@charite.de dietmar.schmitz@charite.de stephan.sigrist@fu-berlin.de
Christian Rosenmund
aInstitute of Neurophysiology, Charité Universitätsmedizin, 10117 Berlin, Germany;
bNeuroCure Cluster of Excellence, Charité Universitätsmedizin, 10117 Berlin, Germany;
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  • For correspondence: christian.rosenmund@charite.de dietmar.schmitz@charite.de stephan.sigrist@fu-berlin.de
  1. Edited by Thomas C. Südhof, Stanford University School of Medicine, Stanford, CA, and approved August 15, 2016 (received for review March 31, 2016)

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Significance

Highly regulated and precise positioning of Ca2+ channels at the active zone (AZ) controls Ca2+ nanodomains at release sites. Their exact localization affects vesicular release probability (PVR) and is important for proper synaptic transmission during repetitive stimulation. We provide a detailed analysis of synaptic transmission combined with superresolution imaging of the AZ organization in mouse hippocampal synapses lacking Rab-interacting molecule-binding protein 2 (RIM-BP2). By dual- and triple-channel time-gated stimulated emission depletion (gSTED) microscopy, we directly show that RIM-BP2 fine-tunes voltage-gated Ca2+ channel 2.1 (CaV2.1) localization at the AZ. We reveal that RIM-BP2 likely regulates the Ca2+ nanodomain by positioning CaV2.1 channels close to synaptic vesicle release sites. Loss of RIM-BP2 reduces PVR and alters short-term plasticity.

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.

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

Footnotes

  • ↵1M.K.G., M.M., and S.R.-A. contributed equally to this work.

  • ↵2To whom correspondence may be addressed. Email: christian.rosenmund{at}charite.de, dietmar.schmitz{at}charite.de, or stephan.sigrist{at}fu-berlin.de.
  • Author contributions: M.K.G., M.M., S.R.-A., B.J.E., V.H., D.S., S.J.S., and C.R. designed research; M.K.G., M.M., S.R.-A., C.G.W., M.M.B., T.T., T.R., M.P., G.V., A.S., and B.R.R. performed research; A.M.W. contributed new reagents/analytic tools; M.K.G., M.M., S.R.-A., C.G.W., M.M.B., T.T., T.R., M.P., and B.R.R. analyzed data; A.M.W. provided data discussion; and M.K.G., M.M., S.R.-A., V.H., D.S., S.J.S., and C.R. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1605256113/-/DCSupplemental.

Freely available online through the PNAS open access option.

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RIM-BP2 sets release probability at mouse synapses
M. Katharina Grauel, Marta Maglione, Suneel Reddy-Alla, Claudia G. Willmes, Marisa M. Brockmann, Thorsten Trimbuch, Tanja Rosenmund, Maria Pangalos, Gülçin Vardar, Alexander Stumpf, Alexander M. Walter, Benjamin R. Rost, Britta J. Eickholt, Volker Haucke, Dietmar Schmitz, Stephan J. Sigrist, Christian Rosenmund
Proceedings of the National Academy of Sciences Oct 2016, 113 (41) 11615-11620; DOI: 10.1073/pnas.1605256113

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RIM-BP2 sets release probability at mouse synapses
M. Katharina Grauel, Marta Maglione, Suneel Reddy-Alla, Claudia G. Willmes, Marisa M. Brockmann, Thorsten Trimbuch, Tanja Rosenmund, Maria Pangalos, Gülçin Vardar, Alexander Stumpf, Alexander M. Walter, Benjamin R. Rost, Britta J. Eickholt, Volker Haucke, Dietmar Schmitz, Stephan J. Sigrist, Christian Rosenmund
Proceedings of the National Academy of Sciences Oct 2016, 113 (41) 11615-11620; DOI: 10.1073/pnas.1605256113
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