Role of activation of PIP5Kgamma661 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)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 gamma661 (PIP5Kgamma661), the major PI(4,5)P2-producing enzyme in the brain. The beta2 subunit of AP-2 was found to bind to the C-terminal tail of PIP5Kgamma661 and cause PIP5Kgamma661 activation. The interaction is regulated by PIP5Kgamma661 dephosphorylation, which is triggered by depolarization in mouse hippocampal neurons. Finally, overexpression of the PIP5Kgamma661 C-terminal region in hippocampal neurons suppresses depolarization-dependent SV endocytosis. These findings provide evidence for the molecular mechanism through which PIP5Kgamma661 locally generates PI(4,5)P2 in hippocampal neurons and suggest a model in which the interaction trigger SV endocytosis.
Nakano-Kobayashi
Akiko
A
Department of Physiological Chemistry, Graduate School of Comprehensive Human Sciences and Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Japan.
Yamazaki
Masakazu
M
Unoki
Takamitsu
T
Hongu
Tsunaki
T
Murata
Chie
C
Taguchi
Ryo
R
Katada
Toshiaki
T
Frohman
Michael A
MA
Yokozeki
Takeaki
T
Kanaho
Yasunori
Y
D033962:Adaptor Protein Complex 2 / Q000378:metabolism*; D000818:Animals; D004705:Endocytosis / Q000502:physiology*; D004789:Enzyme Activation / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism*; D007150:Immunohistochemistry; D051379:Mice; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism*; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D013572:Synaptic Vesicles / Q000378:metabolism* / Q000502:physiology
D033962:Adaptor Protein Complex 2; D019269:Phosphatidylinositol 4,5-Diphosphate; D017853:Phosphotransferases (Alcohol Group Acceptor); C020077:1-phosphatidylinositol-4-phosphate 5-kinase