VAMP4 Is an Essential Cargo Molecule for Activity-Dependent Bulk Endocytosis.

Jessica C Nicholson-Fish, Alexandros C Kokotos, Thomas H Gillingwater, Karen J Smillie, Michael A Cousin

Neuron 2015 Dec 2

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The accurate formation of synaptic vesicles (SVs) and incorporation of their protein cargo during endocytosis is critical for the maintenance of neurotransmission. During intense neuronal activity, a transient and acute accumulation of SV cargo occurs at the plasma membrane. Activity-dependent bulk endocytosis (ADBE) is the dominant SV endocytosis mode under these conditions; however, it is currently unknown how ADBE mediates cargo retrieval. We examined the retrieval of different SV cargo molecules during intense stimulation using a series of genetically encoded pH-sensitive reporters in neuronal cultures. The retrieval of only one reporter, VAMP4-pHluorin, was perturbed by inhibiting ADBE. This selective recovery was confirmed by the enrichment of endogenous VAMP4 in purified bulk endosomes formed by ADBE. VAMP4 was also essential for ADBE, with a cytoplasmic di-leucine motif being critical for this role. Therefore, VAMP4 is the first identified ADBE cargo and is essential for this endocytosis mode to proceed. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Citation

Jessica C Nicholson-Fish, Alexandros C Kokotos, Thomas H Gillingwater, Karen J Smillie, Michael A Cousin. VAMP4 Is an Essential Cargo Molecule for Activity-Dependent Bulk Endocytosis. Neuron. 2015 Dec 2;88(5):973-84