Munc13-1 is a Ca

Autor: Noa, Lipstein, Shuwen, Chang, Kun-Han, Lin, Francisco José, López-Murcia, Erwin, Neher, Holger, Taschenberger, Nils, Brose
Rok vydání: 2021
Předmět:
Zdroj: Neuron
ISSN: 1097-4199
Popis: Summary During ongoing presynaptic action potential (AP) firing, transmitter release is limited by the availability of release-ready synaptic vesicles (SVs). The rate of SV recruitment (SVR) to release sites is strongly upregulated at high AP frequencies to balance SV consumption. We show that Munc13-1—an essential SV priming protein—regulates SVR via a Ca2+-phospholipid-dependent mechanism. Using knockin mouse lines with point mutations in the Ca2+-phospholipid-binding C2B domain of Munc13-1, we demonstrate that abolishing Ca2+-phospholipid binding increases synaptic depression, slows recovery of synaptic strength after SV pool depletion, and reduces temporal fidelity of synaptic transmission, while increased Ca2+-phospholipid binding has the opposite effects. Thus, Ca2+-phospholipid binding to the Munc13-1-C2B domain accelerates SVR, reduces short-term synaptic depression, and increases the endurance and temporal fidelity of neurotransmission, demonstrating that Munc13-1 is a core vesicle priming hub that adjusts SV re-supply to demand.
Graphical abstract
Highlights • The Munc13-1 C2B domain controls synaptic vesicle replenishment rates • Blocking Ca2+-phospholipid-C2B signaling attenuates vesicle replenishment • Enhancing Ca2+-phospholipid-C2B signaling accelerates vesicle replenishment • This process determines short-term plasticity and fidelity of synaptic transmission
Using novel knockin mouse models, Lipstein et al. show that Ca2+-phospholipid binding activates the presynaptic protein Munc13-1 to fine-tune the rate of synaptic vesicle replenishment according to synaptic activity. This process determines short-term synaptic plasticity and the temporal fidelity of synaptic transmission in the auditory brainstem and the hippocampus.
Databáze: OpenAIRE
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