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Munc13-1 is a Ca²⁺-phospholipid-dependent vesicle priming hub that shapes synaptic short-term plasticity and enables sustained neurotransmission.

ABSTRACT: 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.

SUBMITTER: Lipstein N

PROVIDER: S-EPMC8691950 | biostudies-literature |

REPOSITORIES: biostudies-literature

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