期刊
CELL REPORTS
卷 22, 期 8, 页码 1965-1973出版社
CELL PRESS
DOI: 10.1016/j.celrep.2018.02.010
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资金
- BIOSS-2
- German Research Foundation (DFG) [SCHM1838/1, FOR 2143]
Spatial relationships between Ca(v )channels and release sensors at active zones (AZs) are a major determinant of synaptic fidelity. They are regulated developmentally, but the underlying molecular mechanisms are largely unclear. Here, we show that Munc13-3 regulates the density of Ca(v)2.1 and Ca(v)2.2 channels, alters the localization of Ca(v)2.1, and is required for the development of tight, nanodomain coupling at parallel-fiber AZs. We combined EGTA application and Ca2+-channel pharmacology in electrophysiological and two-photon Ca2+ imaging experiments with quantitative freeze-fracture immunoelectron microscopy and mathematical modeling. We found that a normally occurring developmental shift from release being dominated by Ca2+ influx through Ca(v)2.1 and Ca-v 2.2 channels with domain overlap and loose coupling (microdomains) to a nanodomain Ca(v)2.1 to sensor coupling is impaired in Munc13-3-deficient synapses. Thus, at AZs lacking Munc13-3, release remained triggered by Ca(v)2.1 and Ca(v)2.2 microdomains, suggesting a critical role of Munc13-3 in the formation of release sites with calcium channel nanodomains.
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