Figure 6.

Model of how the Munc13–1 C-terminal region controls vesicular release probability and presynaptic plasticity. The model postulates that the Munc13–1 C-terminal region (cyan) can bridge the vesicle and plasma membranes in two orientations: i) an approximately perpendicular orientation that is favored in the absence of Ca²⁺ and allows initiation of SNARE complex assembly, but hinders C-terminal zippering and membrane fusion (a); and ii) a slanted orientation that allows full zippering of the SNARE complex and membrane fusion, and that is favored by Ca²⁺-binding to the C₂B domain and DAG binding to the C₁ domain (b) (116, 177). These two orientations have been proposed to underlie the formation of two primed states (LS and TS), with TS having a much higher probability for release upon Ca²⁺ influx (104). The equilibrium can be shifted toward TS before Ca²⁺ influx by factors such as complexins (Figure 1e,f), and by accumulation of DAG and Ca²⁺ during repetitive stimulation, leading to enhanced release probability.