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

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Abstract
After neurotransmitter release evoked by intense stimulation, synaptic vesicles are retrieved either by clathrin-mediated endocytosis or by activity-dependent bulk endocytosis (ADBE), both of which require the GTPase dynamin I. Here the authors show that presynaptic glycogen synthase kinase-3 specifically regulates synaptic vesicle retrieval during ADBE via phosphorylation of dynamin I. 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.

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