TY  - JOUR
A1  - Kusch, Valentin
A1  - Bornschein, Grit
A1  - Loreth, Desiree
A1  - Bank, Julia
A1  - Jordan, Johannes
A1  - Baur, David
A1  - Watanabe, Masahiko
A1  - Kulik, Akos
A1  - Heckmann, Manfred
A1  - Eilers, Jens
A1  - Schmidt, Hartmut
T1  - Munc13-3 Is Required for the Developmental Localization of Ca2+ Channels to Active Zones and the Nanopositioning of Cav2.1 Near Release Sensors
JF  - Cell Reports
N2  - 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 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 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.
KW  - coupling
KW  - nanodomain
KW  - synapse
KW  - active zone
KW  - development
KW  - Ca2+ channels
KW  - Munc13-3
KW  - cerebellar cortex
KW  - transmitter release
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233468
VL  - 22
ER  -