title: The phospho-dependent dynamin-syndapin interaction triggers activity-dependent bulk endocytosis of synaptic vesicles.
abstract: Synaptic vesicles (SVs) are retrieved by more than one mode in central nerve terminals. During mild stimulation, the dominant SV retrieval pathway is classical clathrin-mediated endocytosis (CME). During elevated neuronal activity, activity-dependent bulk endocytosis (ADBE) predominates, which requires activation of the calcium-dependent protein phosphatase calcineurin. We now report that calcineurin dephosphorylates dynamin I in nerve terminals only above the same activity threshold that triggers ADBE. ADBE was arrested when the two major phospho-sites on dynamin I were perturbed, suggesting that dynamin I dephosphorylation is a key step in its activation. Dynamin I dephosphorylation stimulates a specific dynamin I-syndapin I interaction. Inhibition of this interaction by competitive peptides or by site-directed mutagenesis exclusively inhibited ADBE but did not affect CME. The results reveal that the phospho-dependent dynamin-syndapin interaction recruits ADBE to massively increase SV endocytosis under conditions of elevated neuronal activity.
authors.affiliation: Membrane Biology Group, Centre for Integrative Physiology, George Square, University of Edinburgh, Edinburgh EH8 9XD, United Kingdom.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Clayton
authors.forename: Victor
authors.initials: V
authors.lastname: Anggono
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Smillie
authors.forename: Ngoc
authors.initials: N
authors.lastname: Chau
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Robinson
authors.forename: Michael A
authors.initials: MA
authors.lastname: Cousin
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D003598:Cytoskeletal Proteins; D003911:Dextrans / Q000378:metabolism; D034284:Dynamin I / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004558:Electric Stimulation / Q000379:methods; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology*; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006735:Horseradish Peroxidase / Q000378:metabolism; D006835:Hydrazones / Q000494:pharmacology; D016253:Microscopy, Immunoelectron / Q000379:methods; D016297:Mutagenesis, Site-Directed / Q000379:methods; D009433:Neural Inhibition / Q000502:physiology; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D009841:Oligonucleotides / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012694:Serine / Q000378:metabolism; D013572:Synaptic Vesicles / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D016708:Synaptophysin / Q000378:metabolism; D013997:Time Factors; D014162:Transfection / Q000379:methods
chemical_list: D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D003911:Dextrans; D006835:Hydrazones; C511794:N'-(3,4-dihydroxybenzylidene)-3-hydroxy-2-naphthahydrazide; D009841:Oligonucleotides; C117738:Pacsin1 protein, rat; D016708:Synaptophysin; D012694:Serine; D011189:Potassium Chloride; D006735:Horseradish Peroxidase; D019703:Calcineurin; D034284:Dynamin I; D020558:GTP Phosphohydrolases; D002118:Calcium