Ca²⁺/calmodulin and protein kinase C (PKC) reverse the vesicle fusion arrest by unmasking PIP₂

Vesicle fusion is a key process in cellular communication and membrane trafficking. Soluble N-ethylmaleimide–sensitive factor attachment protein receptor (SNARE) proteins drive vesicle fusion, and SNARE proteins seem to be partially assembled before fusion occurs. However, the molecular mechanisms of the vesicle fusion arrest and how vesicle fusion is rescued from the arrest remain not fully understood. We have previously shown that as a lipid catalyst, phosphatidylinositol 4,5-bisphosphate (PIP2) electrostatically triggers vesicle fusion by lowering the hydration energy, and masking PIP2 arrests vesicle fusion in a state of the partial SNARE assembly. In this study, we show that calmodulin and protein kinase C–epsilon unmask PIP2 through the dissociation of myristoylated alanine-rich C-kinase substrate from membranes and, thus, rescue basal fusion and potentiate synaptotagmin-1–mediated Ca²⁺-dependent vesicle fusion. We provide the model in which the arrest of vesicle fusion can be rescued by the unmasking of PIP2, a lipid catalyst for fusion.