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

TY - JOUR

T1 - Dynamin I phosphorylation by GSK3 controls activity-dependent bulk endocytosis of synaptic vesicles

AU - Clayton, Emma L.

AU - Sue, Nancy

AU - Smillie, Karen J.

AU - O'Leary, Timothy

AU - Bache, Nicolai

AU - Cheung, Giselle

AU - Cole, Adam R.

AU - Wyllie, David J.

AU - Sutherland, Calum

AU - Robinson, Phillip J.

AU - Cousin, Michael A.

PY - 2010/7

Y1 - 2010/7

N2 - 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.

AB - 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.

KW - GLYCOGEN-SYNTHASE KINASE-3

KW - MEMBRANE RETRIEVAL

KW - STIMULATION

KW - INHIBITORS

KW - DISCOVERY

KW - CDK5

KW - VIVO

KW - WNT

U2 - 10.1038/nn.2571

DO - 10.1038/nn.2571

M3 - Article

C2 - 20526333

SN - 1097-6256

VL - 13

SP - 845-U85

JO - Nature Neuroscience

JF - Nature Neuroscience

IS - 7

ER -