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

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Abstract
Synaptic vesicles (SVs) are retrieved by clathrin‐mediated endocytosis at the nerve terminals. Phosphatidylinositol 4,5‐bisphosphate [PI(4,5)P2] 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.