RIM determines Ca²+ channel density and vesicle docking at the presynaptic active zone.
At presynaptic active zones, neurotransmitter release is initiated by the opening of voltage-gated Ca²+ channels close to docked vesicles. The mechanisms that enrich Ca²+ channels at active zones are, however, largely unknown, possibly because of the limited presynaptic accessibility of most synapses. Here, we have established a Cre-lox based conditional knockout approach at a presynaptically accessible central nervous system synapse, the calyx of Held, to directly study the functions of RIM proteins. Removal of all RIM1/2 isoforms strongly reduced the presynaptic Ca²+ channel density, revealing a role of RIM proteins in Ca²+ channel targeting. Removal of RIMs also reduced the readily releasable pool, paralleled by a similar reduction of the number of docked vesicles, and the Ca²+ channel-vesicle coupling was decreased. Thus, RIM proteins co-ordinately regulate key functions for fast transmitter release, enabling a high presynaptic Ca²+ channel density and vesicle docking at the active zone.
Laboratory of Synaptic Mechanisms, Brain Mind Institute, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
Yunyun
Y
Han
Pascal S
PS
Kaeser
Thomas C
TC
Südhof
Ralf
R
Schneggenburger
D000818:Animals; D001933:Brain Stem / Q000033:anatomy & histology; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018377:Neurotransmitter Agents / Q000378:metabolism; D017729:Presynaptic Terminals / Q000378:metabolism* / Q000648:ultrastructure; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology*; D013572:Synaptic Vesicles / Q000378:metabolism* / Q000648:ultrastructure; D020692:rab3 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
D015220:Calcium Channels; D018377:Neurotransmitter Agents; D020033:Protein Isoforms; C491490:Rims1 protein, mouse; D019204:GTP-Binding Proteins; C475524:Rim2 protein, mouse; D020692:rab3 GTP-Binding Proteins; D002118:Calcium
Neuron. 2008 Feb 28;57(4):536-45
18304483
J Physiol. 2005 Oct 1;568(Pt 1):199-209
16037093
EMBO J. 2005 Aug 17;24(16):2839-50
16052212
Eur J Immunol. 2007 Jan;37(1):43-53
17171761
Neuropharmacology. 1995 Nov;34(11):1443-51
8606792
Nature. 1997 Aug 7;388(6642):593-8
9252191
J Neurosci. 2007 Mar 21;27(12):3198-210
17376981
J Biol Chem. 2003 Apr 25;278(17):15373-80
12578829
Neuron. 2001 Apr;30(1):183-96
11343654
J Neurosci. 1997 Aug 1;17(15):5858-67
9221783
J Neurosci. 2002 Dec 15;22(24):10567-79
12486149
J Biol Chem. 2001 Aug 31;276(35):32756-62
11438518
Eur J Neurosci. 2009 Jul;30(1):49-56
19558619
Nat Neurosci. 2001 Oct;4(10):997-1005
11559854
Nature. 1996 Nov 14;384(6605):170-2
8906792
Cell. 2003 Feb 21;112(4):519-33
12600315
Traffic. 2008 Sep;9(9):1414-24
18445120
J Neurosci. 2009 Sep 9;29(36):11123-33
19741118
Neurosci Lett. 2008 Oct 24;444(2):137-42
18721860
J Neurosci. 1999 Jan 15;19(2):726-36
9880593
Neuron. 2002 Dec 19;36(6):1127-43
12495627
J Neurosci. 2008 Dec 10;28(50):13435-47
19074017
Cell Tissue Res. 2006 Nov;326(2):379-91
16865347
Neuron. 2006 Apr 20;50(2):205-18
16630833
Pflugers Arch. 2006 Dec;453(3):261-8
17016737
Nature. 1996 Oct 3;383(6599):431-4
8837774
J Neurosci. 2004 Nov 17;24(46):10379-83
15548652
Genesis. 2000 Feb;26(2):123-6
10686605
J Biol Chem. 2000 Jun 30;275(26):20033-44
10748113
Neuron. 1998 Mar;20(3):389-99
9539117
Neuron. 2002 Apr 25;34(3):411-23
11988172
J Physiol. 2009 Jun 15;587(Pt 12):3009-23
19403608
Genomics. 2003 Feb;81(2):126-37
12620390
Nature. 2002 Jan 17;415(6869):327-30
11797010
J Neurosci. 2004 Jul 21;24(29):6629-37
15269275
Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):15245-50
10611370
Neuron. 2001 Dec 20;32(6):1119-31
11754842
J Neurosci. 2005 Apr 20;25(16):4131-40
15843616
Science. 2006 May 19;312(5776):1051-4
16614170
Neuroscience. 2007 Aug 10;148(1):1-6
17640821
Annu Rev Neurosci. 2004;27:509-47
15217342
Cell Tissue Res. 2006 Nov;326(2):311-37
16896951
Nature. 1999 Jul 29;400(6743):457-61
10440375
J Physiol. 2001 Aug 1;534(Pt 3):861-71
11483715
Nature. 2002 Jan 17;415(6869):321-6
11797009
Mol Biol Cell. 2001 Oct;12(10):3095-102
11598194
J Neurosci. 2003 Apr 1;23(7):2538-48
12684438
Pflugers Arch. 2004 Jul;448(4):347-62
14997396
Neuron. 2007 Feb 15;53(4):563-75
17296557
Brain Res Bull. 2003 Jun 15;60(5-6):457-74
12787867
J Neurosci. 2001 Jan 15;21(2):444-61
11160425
Neuron. 2004 Jun 24;42(6):889-96
15207234
Nat Neurosci. 2007 Jun;10(6):691-701
17496890
EMBO J. 2006 Dec 13;25(24):5852-63
17124501
Neuron. 1999 Jun;23(2):399-409
10399944
Nature. 2000 Aug 24;406(6798):889-93
10972290
PLoS Biol. 2010 Mar 09;8(3):e1000325
20231872
Nat Rev Mol Cell Biol. 2001 Feb;2(2):98-106
11252968
J Neurosci. 2000 Jan 1;20(1):59-65
10627581