| First Author | Kusch V | Year | 2018 |
| Journal | Cell Rep | Volume | 22 |
| Issue | 8 | Pages | 1965-1973 |
| PubMed ID | 29466725 | Mgi Jnum | J:271740 |
| Mgi Id | MGI:6280057 | Doi | 10.1016/j.celrep.2018.02.010 |
| Citation | Kusch V, et al. (2018) Munc13-3 Is Required for the Developmental Localization of Ca(2+) Channels to Active Zones and the Nanopositioning of Cav2.1 Near Release Sensors. Cell Rep 22(8):1965-1973 |
| abstractText | Spatial relationships between Cav 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 Cav2.1 and Cav2.2 channels, alters the localization of Cav2.1, and is required for the development of tight, nanodomain coupling at parallel-fiber AZs. We combined EGTA application and Ca(2+)-channel pharmacology in electrophysiological and two-photon Ca(2+) imaging experiments with quantitative freeze-fracture immunoelectron microscopy and mathematical modeling. We found that a normally occurring developmental shift from release being dominated by Ca(2+) influx through Cav2.1 and Cav2.2 channels with domain overlap and loose coupling (microdomains) to a nanodomain Cav2.1 to sensor coupling is impaired in Munc13-3-deficient synapses. Thus, at AZs lacking Munc13-3, release remained triggered by Cav2.1 and Cav2.2 microdomains, suggesting a critical role of Munc13-3 in the formation of release sites with calcium channel nanodomains. |
