Munc13-3 Is Required for the Developmental Localization of Ca2+ Channels to Active Zones and the Nanopositioning of Cav2.1 Near Release Sensors
Please always quote using this URN: urn:nbn:de:bvb:20-opus-233468
- 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+ imagingSpatial 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.…
Author: | Valentin Kusch, Grit Bornschein, Desiree Loreth, Julia Bank, Johannes Jordan, David Baur, Masahiko Watanabe, Akos Kulik, Manfred Heckmann, Jens Eilers, Hartmut Schmidt |
---|---|
URN: | urn:nbn:de:bvb:20-opus-233468 |
Document Type: | Journal article |
Faculties: | Medizinische Fakultät / Physiologisches Institut |
Language: | English |
Parent Title (English): | Cell Reports |
Year of Completion: | 2018 |
Volume: | 22 |
Pagenumber: | 1965-1973 |
Source: | Cell Reports (2018) 22:1965-1973. https://doi.org/10.1016/j.celrep.2018.02.010 |
DOI: | https://doi.org/10.1016/j.celrep.2018.02.010 |
Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
Tag: | Ca2+ channels; Munc13-3; active zone; cerebellar cortex; coupling; development; nanodomain; synapse; transmitter release |
Release Date: | 2024/08/08 |
Licence (German): | CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International |