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The Journal of Neuroscience, January 10, 2007, 27(2):401-411; doi:10.1523/JNEUROSCI.3809-06.2007
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Cellular/Molecular
Activity-Dependent Control of Slow Synaptic Vesicle Endocytosis by Cyclin-Dependent Kinase 5
Gareth J. O. Evans andMichael A. Cousin Membrane Biology Group, Centre for Integrative Physiology, University of Edinburgh, Edinburgh EH8 9XD, United Kingdom
Correspondence should be addressed to Michael A. Cousin, Membrane Biology Group, Centre for Integrative Physiology, George Square, University of Edinburgh, Edinburgh EH8 9XD, UK. Email: M.Cousin{at}ed.ac.uk
The stimulated dephosphorylation of the dephosphin group of endocytic proteins by calcineurin and their subsequent rephosphorylation by cyclin-dependent kinase 5 (cdk5) is required for synaptic vesicle (SV) retrieval in central nerve terminals. However, the specific endocytic pathway(s) controlled by these enzymes is unknown. To address this issue, we combined functional and morphological assays of endocytosis in primary neuronal cultures with pharmacological and molecular ablation of calcineurin and cdk5 activity. During strong stimulation, inhibition of calcineurin or cdk5 blocked uptake of the activity-dependent membrane marker FM1–43, but not the more hydrophilic FM2–10. However, FM2–10 uptake-measured poststimulation was sensitive to cdk5 and calcineurin inhibition, indicating that a slow form of endocytosis persists after termination of stimulation. In parallel EM studies, inhibition of cdk5 during strong stimulation greatly reduced horseradish peroxidase labeling of plasma membrane-derived nerve terminal endosomes, but not SVs. Furthermore, during mild stimulation, FM1–43 uptake was unaffected by cdk5 inhibition and the SV membrane was exclusively retrieved via a single SV route, suggesting that recruitment of the endosomal route of membrane retrieval is activity dependent. Thus, we propose that the calcineurin/cdk5-dependent phosphorylation cycle of the dephosphins specifically controls a slow endocytic pathway that proceeds via endosomal intermediates and is activated by strong physiological stimulation in central nerve terminals.
Key words: endocytosis; synaptic vesicle; nerve terminal; FM1–43; cdk5; dynamin
Received Sept. 1, 2006; revised Dec. 7, 2006; accepted Dec. 7, 2006.
Correspondence should be addressed to Michael A. Cousin, Membrane Biology Group, Centre for Integrative Physiology, George Square, University of Edinburgh, Edinburgh EH8 9XD, UK. Email: M.Cousin{at}ed.ac.uk
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