A Ca2+ channel differentially regulates Clathrin-mediated and activity-dependent bulk endocytosis.

Chi-Kuang Yao,Yu-Tzu Liu,I-Chi Lee,Ping-Yen Wu,You-Tung Wang,Sandra Schmid

doi:10.1371/journal.pbio.2000931

Abstract

Clathrin-mediated endocytosis (CME) and activity-dependent bulk endocytosis (ADBE) are two predominant forms of synaptic vesicle (SV) endocytosis, elicited by moderate and strong stimuli, respectively. They are tightly coupled with exocytosis for sustained neurotransmission. However, the underlying mechanisms are ill defined. We previously reported that the Flower (Fwe) Ca2+ channel present in SVs is incorporated into the periactive zone upon SV fusion, where it triggers CME, thus coupling exocytosis to CME. Here, we show that Fwe also promotes ADBE. Intriguingly, the effects of Fwe on CME and ADBE depend on the strength of the stimulus. Upon mild stimulation, Fwe controls CME independently of Ca2+ channeling. However, upon strong stimulation, Fwe triggers a Ca2+ influx that initiates ADBE. Moreover, knockout of rodent fwe in cultured rat hippocampal neurons impairs but does not completely abolish CME, similar to the loss of Drosophila fwe at the neuromuscular junction, suggesting that Fwe plays a regulatory role in regulating CME across species. In addition, the function of Fwe in ADBE is conserved at mammalian central synapses. Hence, Fwe exerts different effects in response to different stimulus strengths to control two major modes of endocytosis.

Highlights

In the presynaptic terminal, continuous release of synaptic vesicles (SVs) results in vesicle pool depletion, plasma membrane expansion, and SV protein overloading at the release site [1]
The arrival of an action potential at the nerve end induces synaptic vesicle (SV) exocytosis to allow the release of chemical neurotransmitters and the rapid transmission of signals
SV endocytosis is in turn elicited in order to rapidly replenish the vesicle pool in neurons

Summary

Introduction

Continuous release of synaptic vesicles (SVs) results in vesicle pool depletion, plasma membrane expansion, and SV protein overloading at the release site [1]. Endocytosis is tightly coupled to exocytosis [2]. Among the different modes of SV endocytosis, Clathrin-mediated endocytosis (CME) and activity-dependent bulk endocytosis (ADBE) are well characterized [3,4]. CME is the prevalent mode of retrieving exocytic SVs in the form of a single SV [5,6]. ADBE promotes the uptake of large pieces of fused membranes in bulk endosomes or cisternae [7,8]. Small SVs are formed from these membranous structures

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Discussion

Conclusion