Active zone scaffolds differentially accumulate Unc13 isoforms to tune Ca(2+) channel-vesicle coupling
Research output: Contribution to journal › Journal article › Research › peer-review
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Active zone scaffolds differentially accumulate Unc13 isoforms to tune Ca(2+) channel-vesicle coupling. / Böhme, Mathias A; Beis, Christina; Reddy-Alla, Suneel; Reynolds, Eric; Mampell, Malou M; Grasskamp, Andreas T; Lützkendorf, Janine; Bergeron, Dominique Dufour; Driller, Jan H; Babikir, Husam; Göttfert, Fabian; Robinson, Iain M; O'Kane, Cahir J; Hell, Stefan W; Wahl, Markus C; Stelzl, Ulrich; Loll, Bernhard; Walter, Alexander M; Sigrist, Stephan J.
In: Nature Neuroscience, Vol. 19, No. 10, 2016, p. 1311-1320.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Active zone scaffolds differentially accumulate Unc13 isoforms to tune Ca(2+) channel-vesicle coupling
AU - Böhme, Mathias A
AU - Beis, Christina
AU - Reddy-Alla, Suneel
AU - Reynolds, Eric
AU - Mampell, Malou M
AU - Grasskamp, Andreas T
AU - Lützkendorf, Janine
AU - Bergeron, Dominique Dufour
AU - Driller, Jan H
AU - Babikir, Husam
AU - Göttfert, Fabian
AU - Robinson, Iain M
AU - O'Kane, Cahir J
AU - Hell, Stefan W
AU - Wahl, Markus C
AU - Stelzl, Ulrich
AU - Loll, Bernhard
AU - Walter, Alexander M
AU - Sigrist, Stephan J
PY - 2016
Y1 - 2016
N2 - Brain function relies on fast and precisely timed synaptic vesicle (SV) release at active zones (AZs). Efficacy of SV release depends on distance from SV to Ca(2+) channel, but molecular mechanisms controlling this are unknown. Here we found that distances can be defined by targeting two unc-13 (Unc13) isoforms to presynaptic AZ subdomains. Super-resolution and intravital imaging of developing Drosophila melanogaster glutamatergic synapses revealed that the Unc13B isoform was recruited to nascent AZs by the scaffolding proteins Syd-1 and Liprin-α, and Unc13A was positioned by Bruchpilot and Rim-binding protein complexes at maturing AZs. Unc13B localized 120 nm away from Ca(2+) channels, whereas Unc13A localized only 70 nm away and was responsible for docking SVs at this distance. Unc13A(null) mutants suffered from inefficient, delayed and EGTA-supersensitive release. Mathematical modeling suggested that synapses normally operate via two independent release pathways differentially positioned by either isoform. We identified isoform-specific Unc13-AZ scaffold interactions regulating SV-Ca(2+)-channel topology whose developmental tightening optimizes synaptic transmission.
AB - Brain function relies on fast and precisely timed synaptic vesicle (SV) release at active zones (AZs). Efficacy of SV release depends on distance from SV to Ca(2+) channel, but molecular mechanisms controlling this are unknown. Here we found that distances can be defined by targeting two unc-13 (Unc13) isoforms to presynaptic AZ subdomains. Super-resolution and intravital imaging of developing Drosophila melanogaster glutamatergic synapses revealed that the Unc13B isoform was recruited to nascent AZs by the scaffolding proteins Syd-1 and Liprin-α, and Unc13A was positioned by Bruchpilot and Rim-binding protein complexes at maturing AZs. Unc13B localized 120 nm away from Ca(2+) channels, whereas Unc13A localized only 70 nm away and was responsible for docking SVs at this distance. Unc13A(null) mutants suffered from inefficient, delayed and EGTA-supersensitive release. Mathematical modeling suggested that synapses normally operate via two independent release pathways differentially positioned by either isoform. We identified isoform-specific Unc13-AZ scaffold interactions regulating SV-Ca(2+)-channel topology whose developmental tightening optimizes synaptic transmission.
KW - Animals
KW - Calcium Channels/metabolism
KW - Carrier Proteins/genetics
KW - Drosophila Proteins/metabolism
KW - Drosophila melanogaster/genetics
KW - Female
KW - GTPase-Activating Proteins/metabolism
KW - Intracellular Signaling Peptides and Proteins
KW - Male
KW - Models, Neurological
KW - Mutation
KW - Phosphoproteins/metabolism
KW - Presynaptic Terminals/metabolism
KW - Protein Isoforms
KW - Synaptic Vesicles/metabolism
KW - rab3 GTP-Binding Proteins/metabolism
U2 - 10.1038/nn.4364
DO - 10.1038/nn.4364
M3 - Journal article
C2 - 27526206
VL - 19
SP - 1311
EP - 1320
JO - Nature Neuroscience
JF - Nature Neuroscience
SN - 1097-6256
IS - 10
ER -
ID: 334035442