Distinct Endocytic Pathways Control the Rate and Extent of Synaptic Vesicle Protein Recycling

• Published in: Neuron (Cambridge, Mass.) Vol. 51; no. 1; pp. 71 - 84
• Main Authors: Voglmaier, Susan M., Kam, Kaiwen, Yang, Hua, Fortin, Doris L., Hua, Zhaolin, Nicoll, Roger A., Edwards, Robert H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.07.2006; Elsevier Limited
• Subjects: Acyltransferases - metabolism; Adaptor Protein Complex 2 - metabolism; Adaptor Protein Complex 3 - antagonists & inhibitors; Adaptor Protein Complex 3 - metabolism; Amino Acid Motifs - physiology; Animals; Brefeldin A - pharmacology; CELLBIO; Endocytosis; Endocytosis - physiology; Glutamic Acid - metabolism; MOLNEURO; Plasma; Presynaptic Terminals - metabolism; Presynaptic Terminals - ultrastructure; Protein Binding - physiology; Protein Structure, Tertiary - physiology; Protein Synthesis Inhibitors - pharmacology; Proteins; Rats; Rats, Sprague-Dawley; Rodents; Signal Transduction - drug effects; Signal Transduction - physiology; Synaptic Vesicles - metabolism; Synaptic Vesicles - ultrastructure; Vesicular Glutamate Transport Protein 1 - chemistry; Vesicular Glutamate Transport Protein 1 - metabolism; Vesicular Transport Proteins - metabolism; CELLBIO; MOLNEURO
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2006.05.027

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.