RIM-binding protein 2 regulates release probability by fine-tuning calcium channel localization at murine hippocampal synapses.
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.
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.
M Katharina
MK
Grauel
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.
Marta
0000-0001-9052-9271
M
Maglione
NeuroCure Cluster of Excellence, Charité Universitätsmedizin, 10117 Berlin, Germany; Institute of Biology, Department of Biology, Chemistry, Pharmacy, Freie Universität Berlin, 14195 Berlin, Germany.
Suneel
S
Reddy-Alla
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.
Claudia G
CG
Willmes
Institute of Neurophysiology, Charité Universitätsmedizin, 10117 Berlin, Germany; NeuroCure Cluster of Excellence, Charité Universitätsmedizin, 10117 Berlin, Germany.
Marisa M
MM
Brockmann
Institute of Neurophysiology, Charité Universitätsmedizin, 10117 Berlin, Germany; NeuroCure Cluster of Excellence, Charité Universitätsmedizin, 10117 Berlin, Germany.
Thorsten
T
Trimbuch
Institute of Neurophysiology, Charité Universitätsmedizin, 10117 Berlin, Germany; NeuroCure Cluster of Excellence, Charité Universitätsmedizin, 10117 Berlin, Germany.
Tanja
T
Rosenmund
NeuroCure Cluster of Excellence, Charité Universitätsmedizin, 10117 Berlin, Germany; Neuroscience Research Center (NWFZ), Charité Universitätsmedizin, 10117 Berlin, Germany.
Maria
M
Pangalos
Institute of Neurophysiology, Charité Universitätsmedizin, 10117 Berlin, Germany; NeuroCure Cluster of Excellence, Charité Universitätsmedizin, 10117 Berlin, Germany.
Gülçin
G
Vardar
NeuroCure Cluster of Excellence, Charité Universitätsmedizin, 10117 Berlin, Germany; Neuroscience Research Center (NWFZ), Charité Universitätsmedizin, 10117 Berlin, Germany.
Alexander
A
Stumpf
Molecular and Theoretical Neuroscience, Leibniz-Institut für Molekulare Pharmakologie, 10117 Berlin, Germany.
Alexander M
AM
Walter
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.
Benjamin R
BR
Rost
NeuroCure Cluster of Excellence, Charité Universitätsmedizin, 10117 Berlin, Germany; Institute of Biochemistry, Charité Universitätsmedizin, 10117 Berlin, Germany.
Britta J
BJ
Eickholt
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.
Volker
V
Haucke
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.
Dietmar
D
Schmitz
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.
Stephan J
SJ
Sigrist
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.
Christian
C
Rosenmund
D000200:Action Potentials; D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism*; D002478:Cells, Cultured; D055724:Electrophysiological Phenomena; D005260:Female; D017353:Gene Deletion; D015870:Gene Expression; D018390:Gene Targeting; D056426:Genetic Loci; D006624:Hippocampus / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D010641:Phenotype; D021381:Protein Transport; D013569:Synapses / Q000378:metabolism*; D009435:Synaptic Transmission / Q000235:genetics; D013572:Synaptic Vesicles / Q000378:metabolism
D015220:Calcium Channels; D002118:Calcium
RIM-BP2; active zone structure; calcium channel coupling; release probability; short-term plasticity
J Neurosci. 1997 Aug 1;17(15):5858-67
9221783
Neuron. 2016 May 18;90(4):795-809
27133464
Biophys J. 1997 Jul;73(1):220-9
9199786
Neuron. 2015 Mar 4;85(5):1056-69
25704950
Nat Commun. 2013;4:2392
23999086
Mol Autism. 2011 Jan 19;2(1):1
21247446
J Neurosci. 2013 Oct 16;33(42):16698-714
24133272
J Neurosci. 2012 Nov 21;32(47):16586-96
23175814
Nature. 2013 Jul 18;499(7458):295-300
23868258
Nat Struct Mol Biol. 2010 May;17(5):568-75
20400951
Neuron. 2015 Sep 23;87(6):1234-47
26402606
Neuron. 2002 Apr 25;34(3):411-23
11988172
PLoS Genet. 2009 Jun;5(6):e1000536
19557195
Nature. 2002 Jan 17;415(6869):321-6
11797009
Neuron. 2007 Oct 25;56(2):399-413
17964254
Neuron. 2014 Apr 2;82(1):181-94
24698275
Cell Rep. 2014 Jun 12;7(5):1417-25
24882013
Proc Natl Acad Sci U S A. 2012 Sep 4;109(36):14657-62
22908295
Nat Commun. 2014 Apr 11;5:3650
24722188
Science. 1993 Oct 29;262(5134):754-7
7901909
J Neurosci. 2014 Aug 27;34(35):11781-91
25164673
Neuron. 2011 Jan 27;69(2):317-31
21262469
J Neurosci. 2007 Jan 31;27(5):1200-10
17267576
Neuron. 1996 Jun;16(6):1197-207
8663996
Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):9037-42
12070347
Nat Neurosci. 2012 Jun 10;15(7):988-97
22683683
Neuron. 2010 Dec 9;68(5):843-56
21144999
Nature. 2014 Nov 13;515(7526):228-33
25296249
J Neurosci. 2012 Nov 21;32(47):16574-85
23175813
J Biol Chem. 2000 Jun 30;275(26):20033-44
10748113
Nature. 2002 Jan 17;415(6869):327-30
11797010
Science. 2011 Dec 16;334(6062):1565-9
22174254
J Neurosci. 2006 Jan 25;26(4):1239-46
16436611
J Biol Chem. 2003 Feb 21;278(8):6291-300
12473661
PLoS Biol. 2006 Jul;4(7):e207
16774451
Nature. 2010 Jul 15;466(7304):368-72
20531469
Nat Rev Neurosci. 2011 Dec 20;13(1):7-21
22183436
Cell. 2011 Jan 21;144(2):282-95
21241895