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

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.

A Presynaptic Glutamate Receptor Subunit Confers Robustness to Neurotransmission and Homeostatic Potentiation

“…Conventional presynaptic calcium imaging uses action-potential evoked stimulation to elicit presynaptic calcium influx through voltage gated calcium channels at active zones (Muller and Davis, 2012; Yao et al, 2017). This standard approach would be unlikely to specifically detect the calcium signal through DKaiR1D receptors for two reasons.…”

The Synaptic Vesicle Cycle Revisited: New Insights into the Modes and Mechanisms

“…Some cargoes, such as VAMP4, are preferentially accumulated by ADBE, perhaps explaining why VAMP4 is also essential for this mode of endocytosis (Nicholson-Fish et al, 2015). Interestingly, the SV-associated calcium channel Flower, which is deposited into the plasma membrane during high activity, may provide calcium influx to trigger ADBE and thus facilitate the coupling of neuronal activity to ADBE (Yao et al, 2009(Yao et al, , 2017. Therefore, specific vesicle proteins may play direct roles in ADBE rather than being passively retrieved.…”

Interplay between morphogen‐directed positional information systems and physiological signaling

“…The receiving cells of the ASP require Synaptotagmin‐4 and the glutamate receptor GluRII. This is noteworthy given that Ca 2+ is a crucial regulator of endocytosis and neurotransmitter regulation . Huang et al further demonstrated that Ca 2+ transients observed in cytonemes correlate with Dpp uptake.…”

“…This is noteworthy given that Ca 2+ is a crucial regulator of endocytosis and neurotransmitter regulation. [77][78][79] Huang et al further demonstrated that Ca 2+ transients observed in cytonemes correlate with Dpp uptake. This suggests that signal uptake and transport within cytonemes depends on local Ca 2+ concentrations.…”

“…77 Recent work has shown that Ca 2+ channels regulate bulk endocytosis, a form of endocytosis of synaptic vesicles at nerve terminals, in addition to coupling exo-and endocytosis. 78,79 Further, Rab5-dependent endocytosis requires Ca 2+ signaling to increase the rate of membrane capacitance, which determines how quickly the membrane potential can respond to a change in current and is linearly related to changes in membrane surface area. 81 The converse was also shown in which low Ca 2+ concentrations decreased membrane capacitance.…”