Role of activation of PIP5Kγ661 by AP-2 complex in synaptic vesicle endocytosis

Synaptic vesicles (SVs) are retrieved by clathrin-mediated endocytosis at the nerve terminals. Phosphatidylinositol 4,5-bisphosphate [PI(4,5)P ₂] drives this event by recruiting the components of the endocytic machinery. However, the molecular mechanisms that result in local generation of PI(4,5)P₂ remain unclear. We demonstrate here that AP-2 complex directly interacts with phosphatidylinositol 4-phosphate 5-kinase γ661 (PIP5Kγ661), the major PI(4,5)P₂-producing enzyme in the brain. The β2 subunit of AP-2 was found to bind to the C-terminal tail of PIP5Kγ661 and cause PIP5Kγ661 activation. The interaction is regulated by PIP5Kγ661 dephosphorylation, which is triggered by depolarization in mouse hippocampal neurons. Finally, overexpression of the PIP5Kγ661 C-terminal region in hippocampal neurons suppresses depolarization-dependent SV endocytosis. These findings provide evidence for the molecular mechanism through which PIP5Kγ661 locally generates PI(4,5)P₂ in hippocampal neurons and suggest a model in which the interaction trigger SV endocytosis.