Dynamin I phosphorylation by GSK3 controls activity-dependent bulk endocytosis of synaptic vesicles

Nat Neurosci. 2010 Jul;13(7):845-51. doi: 10.1038/nn.2571. Epub 2010 Jun 6.


Glycogen synthase kinase 3 (GSK3) is a critical enzyme in neuronal physiology; however, it is not yet known whether it has any specific role in presynaptic function. We found that GSK3 phosphorylates a residue on the large GTPase dynamin I (Ser-774) both in vitro and in primary rat neuronal cultures. This was dependent on prior phosphorylation of Ser-778 by cyclin-dependent kinase 5. Using both acute inhibition with pharmacological antagonists and silencing of expression with short hairpin RNA, we found that GSK3 was specifically required for activity-dependent bulk endocytosis (ADBE) but not clathrin-mediated endocytosis. Moreover we found that the specific phosphorylation of Ser-774 on dynamin I by GSK3 was both necessary and sufficient for ADBE. These results demonstrate a presynaptic role for GSK3 and they indicate that a protein kinase signaling cascade prepares synaptic vesicles for retrieval during elevated neuronal activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Cerebellum / cytology
  • Cerebellum / metabolism
  • Cyclin-Dependent Kinase 5 / metabolism
  • Dynamin I / metabolism*
  • Endocytosis / physiology*
  • Glycogen Synthase Kinase 3 / metabolism*
  • Hippocampus / cytology
  • Hippocampus / metabolism
  • In Vitro Techniques
  • Male
  • Neurons / cytology
  • Neurons / metabolism*
  • Phosphorylation / physiology
  • Presynaptic Terminals / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / physiology
  • Synaptic Vesicles / metabolism*


  • Cyclin-Dependent Kinase 5
  • Glycogen Synthase Kinase 3
  • Dynamin I