title: Distinct endocytic pathways control the rate and extent of synaptic vesicle protein recycling.
abstract: Synaptic vesicles have been proposed to form through two mechanisms: one directly from the plasma membrane involving clathrin-dependent endocytosis and the adaptor protein AP2, and the other from an endosomal intermediate mediated by the adaptor AP3. However, the relative role of these two mechanisms in synaptic vesicle recycling has remained unclear. We now find that vesicular glutamate transporter VGLUT1 interacts directly with endophilin, a component of the clathrin-dependent endocytic machinery. In the absence of its interaction with endophilin, VGLUT1 recycles more slowly during prolonged, high-frequency stimulation. Inhibition of the AP3 pathway with brefeldin A rescues the rate of recycling, suggesting a competition between AP2 and -3 pathways, with endophilin recruiting VGLUT1 toward the faster AP2 pathway. After stimulation, however, inhibition of the AP3 pathway prevents the full recovery of VGLUT1 by endocytosis, implicating the AP3 pathway specifically in compensatory endocytosis.
authors.affiliation: Department of Neurology, Graduate Programs in Cell Biology, Neuroscience and Biomedical Sciences, UCSF School of Medicine, 600 16th Street, San Francisco, California 94143, USA.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Voglmaier
authors.forename: Kaiwen
authors.initials: K
authors.lastname: Kam
authors.forename: Hua
authors.initials: H
authors.lastname: Yang
authors.forename: Doris L
authors.initials: DL
authors.lastname: Fortin
authors.forename: Zhaolin
authors.initials: Z
authors.lastname: Hua
authors.forename: Roger A
authors.initials: RA
authors.lastname: Nicoll
authors.forename: Robert H
authors.initials: RH
authors.lastname: Edwards
mesh_terms: D000217:Acyltransferases / Q000378:metabolism*; D033962:Adaptor Protein Complex 2 / Q000378:metabolism; D033963:Adaptor Protein Complex 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D020816:Amino Acid Motifs / Q000502:physiology; D000818:Animals; D020126:Brefeldin A / Q000494:pharmacology; D004705:Endocytosis / Q000502:physiology*; D018698:Glutamic Acid / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000378:metabolism* / Q000648:ultrastructure; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013572:Synaptic Vesicles / Q000378:metabolism* / Q000648:ultrastructure; D050598:Vesicular Glutamate Transport Protein 1 / Q000737:chemistry / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000378:metabolism
chemical_list: D033962:Adaptor Protein Complex 2; D033963:Adaptor Protein Complex 3; D011500:Protein Synthesis Inhibitors; C493466:Slc17a7 protein, rat; D050598:Vesicular Glutamate Transport Protein 1; D033921:Vesicular Transport Proteins; D020126:Brefeldin A; D018698:Glutamic Acid; D000217:Acyltransferases; C018764:2-acylglycerophosphate acyltransferase