Synaptotagmin 7 docks synaptic vesicles to support facilitation and Doc2α-triggered asynchronous release
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Synaptotagmin 7 docks synaptic vesicles to support facilitation and Doc2α-triggered asynchronous release. / Wu, Zhenyong; Kusick, Grant F; Berns, Manon Mm; Raychaudhuri, Sumana; Itoh, Kie; Walter, Alexander M; Chapman, Edwin R; Watanabe, Shigeki.
I: eLife, Bind 12, RP90632, 2024.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Synaptotagmin 7 docks synaptic vesicles to support facilitation and Doc2α-triggered asynchronous release
AU - Wu, Zhenyong
AU - Kusick, Grant F
AU - Berns, Manon Mm
AU - Raychaudhuri, Sumana
AU - Itoh, Kie
AU - Walter, Alexander M
AU - Chapman, Edwin R
AU - Watanabe, Shigeki
PY - 2024
Y1 - 2024
N2 - Despite decades of intense study, the molecular basis of asynchronous neurotransmitter release remains enigmatic. Synaptotagmin (syt) 7 and Doc2 have both been proposed as Ca2+ sensors that trigger this mode of exocytosis, but conflicting findings have led to controversy. Here, we demonstrate that at excitatory mouse hippocampal synapses, Doc2α is the major Ca2+ sensor for asynchronous release, while syt7 supports this process through activity-dependent docking of synaptic vesicles. In synapses lacking Doc2α, asynchronous release after single action potentials is strongly reduced, while deleting syt7 has no effect. However, in the absence of syt7, docked vesicles cannot be replenished on millisecond timescales. Consequently, both synchronous and asynchronous release depress from the second pulse onward during repetitive activity. By contrast, synapses lacking Doc2α have normal activity-dependent docking, but continue to exhibit decreased asynchronous release after multiple stimuli. Moreover, disruption of both Ca2+ sensors is non-additive. These findings result in a new model whereby syt7 drives activity-dependent docking, thus providing synaptic vesicles for synchronous (syt1) and asynchronous (Doc2 and other unidentified sensors) release during ongoing transmission.
AB - Despite decades of intense study, the molecular basis of asynchronous neurotransmitter release remains enigmatic. Synaptotagmin (syt) 7 and Doc2 have both been proposed as Ca2+ sensors that trigger this mode of exocytosis, but conflicting findings have led to controversy. Here, we demonstrate that at excitatory mouse hippocampal synapses, Doc2α is the major Ca2+ sensor for asynchronous release, while syt7 supports this process through activity-dependent docking of synaptic vesicles. In synapses lacking Doc2α, asynchronous release after single action potentials is strongly reduced, while deleting syt7 has no effect. However, in the absence of syt7, docked vesicles cannot be replenished on millisecond timescales. Consequently, both synchronous and asynchronous release depress from the second pulse onward during repetitive activity. By contrast, synapses lacking Doc2α have normal activity-dependent docking, but continue to exhibit decreased asynchronous release after multiple stimuli. Moreover, disruption of both Ca2+ sensors is non-additive. These findings result in a new model whereby syt7 drives activity-dependent docking, thus providing synaptic vesicles for synchronous (syt1) and asynchronous (Doc2 and other unidentified sensors) release during ongoing transmission.
U2 - 10.7554/eLife.90632
DO - 10.7554/eLife.90632
M3 - Journal article
C2 - 38536730
VL - 12
JO - eLife
JF - eLife
SN - 2050-084X
M1 - RP90632
ER -
ID: 387428646