Munc13 C(2)B-Domain – an Activity-Dependent Ca(2+)-Regulator of Synaptic Exocytosis

Munc13 is a multidomain protein of presynaptic active zones that mediates the priming and plasticity of synaptic vesicle exocytosis, but the mechanisms involved remain unclear. Here, we use biophysical, biochemical, and electrophysiological approaches to demonstrate that the central C(2)B-domain of Munc13 functions as a Ca(2+)-regulator of short-term synaptic plasticity. The crystal structure of the C(2)B-domain revealed an unusual Ca(2+)-binding site with an amphipathic α-helix. This configuration confers onto the C(2)B-domain unique Ca(2+)-dependent phospholipid-binding properties favoring phosphatidylinositolphosphates. A mutation that inactivated Ca(2+)-dependent phospholipid binding to the C(2)B-domain did not alter neurotransmitter release evoked by isolated action potentials, but depressed release evoked by action potential trains. In contrast, a mutation that increased Ca(2+)-dependent phosphatidylinositolbisphosphate binding to the C(2)B-domain enhanced release evoked by isolated action potentials and by action potential trains. Our data suggest that during repeated action potentials, Ca(2+)- and phosphatidylinositolphosphate-binding to the Munc13 C(2)B-domain potentiate synaptic vesicle exocytosis, thereby offsetting synaptic depression induced by vesicle depletion.