Munc13 C2B domain is an activity-dependent Ca2+ regulator of synaptic exocytosis

Munc13 is a multidomain protein present in 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 show that the central C2B domain of Munc13 functions as a Ca2+ regulator of short-term synaptic plasticity. The crystal structure of the C2B domain revealed an unusual Ca2+-binding site with an amphipathic alpha-helix. This configuration confers onto the C2B domain unique Ca2+-dependent phospholipid-binding properties that favor phosphatidylinositolphosphates. A mutation that inactivated Ca2+-dependent phospholipid binding to the C2B domain did not alter neurotransmitter release evoked by isolated action potentials, but it did depress release evoked by action-potential trains. In contrast, a mutation that increased Ca2+-dependent phosphatidylinositolbisphosphate binding to the C2B domain enhanced release evoked by isolated action potentials and by action-potential trains. Our data suggest that, during repeated action potentials, Ca2+ and phosphatidylinositolphosphate binding to the Munc13 C2B domain potentiate synaptic vesicle exocytosis, thereby offsetting synaptic depression induced by vesicle depletion.