Doc2 Is a Ca2+ Sensor Required for Asynchronous Neurotransmitter Release

Abstract

SUMMARY Synaptic transmission involves a fast synchronous phase and a slower asynchronous phase of neurotransmitter release that are regulated by distinct Ca2+ sensors. While the Ca2+ sensor for rapid exocytosis, synaptotagmin I, has been studied in depth, the sensor for asynchronous release remains unknown. In a screen for neuronal Ca2+ sensors that respond to changes in [Ca2+] with markedly slower kinetics than synaptotagmin I, we observed that Doc2, another Ca2+, SNARE, and lipid binding protein, operates on time scales consistent with asynchronous release. Moreover, up- and down-regulation of Doc2 expression levels in hippocampal neurons increased or decreased, respectively, the slow phase of synaptic transmission. Synchronous release, when triggered by single action potentials, was unaffected by manipulation of Doc2, but was enhanced during repetitive stimulation in Doc2 knockdown neurons potentially due to greater vesicle availability. In summary, we propose that Doc2 is a Ca2+ sensor that is kinetically tuned to regulate asynchronous neurotransmitter release.

Structural insights into the Ca 2+ and PI(4,5)P 2 binding modes of the C2 domains of rabphilin 3A and synaptotagmin 1

“…S2C), making difficult to predict whether these domains might adopt the closed or open conformation without further experimentation. However, it is clear that the similarity of DOC2B to rabphilin 3A is higher than to syt1, and this might explain the different behaviors found for it in recent studies using KO mice (38)(39)(40).…”

Spontaneous Vesicle Release Is Not Tightly Coupled to Voltage-Gated Calcium Channel-Mediated Ca2+ Influx and Is Triggered by a Ca2+ Sensor Other Than Synaptotagmin-2 at the Juvenile Mice Calyx of Held Synapses

“…It was suggested previously that spontaneous vesicle release is triggered by the Ca 2ϩ sensors for asynchronous release (Sun et al, 2007). Doc2 protein was proposed to be such a Ca 2ϩ sensor, because Doc2 deficiency significantly reduced both spontaneous and asynchronous release without altering synchronous release (Groffen et al, 2010;Yao et al, 2011). However, this notion was challenged by the result that Doc2 modulates spontaneous vesicle release by a Ca 2ϩ -independent mechanism (Pang et al, 2011).…”

“…It was shown previously that synchronous vesicle release is triggered by synaptotagmin (Syt)-1, Syt-2, and Syt-9 (defined as fast sensors; Geppert et al, 1994;Sun et al, 2007;Xu et al, 2007), whereas the Ca 2ϩ -sensing mechanisms for asynchronous vesicle release are still under investigation. Syt-7 and Doc2 were proposed recently as the candidate Ca 2ϩ sensors for asynchronous release (Sun et al, 2007;Yao et al, 2011;Bacaj et al, 2013). In contrast, the mechanisms behind Ca 2ϩ sensing during spontaneous vesicle release is far from elucidated (Kavalali et al, 2011).…”

16p11.2 is required for neuronal polarity

“…Doc2a is specifically expressed in neuronal cells and localized on synaptic vesicles [33,34]. In vitro experiments indicate that Doc2a is kinetically tuned to function as a Ca 2+ sensor for asynchronous neurotransmitter release [35]. Mice deleted for Doc2a show alterations in synaptic transmission and long-term potentiation and exhibit learning and behavioral deficits that include an abnormal passive avoidance task [36].We conclude that DOC2a controls neuronal polarity (structure) and synaptic transmission (function) to facilitate information flow.…”