Munc13-1 and Munc18-1 together prevent NSF-dependent de-priming of synaptic vesicles

He, Enqi; Wierda, Keimpe; Westen, Rhode van; Broeke, Jurjen H.; Toonen, Ruud F.; Cornelisse, L. Niels; Verhage, Matthijs

doi:10.1038/ncomms15915

Cited by 88 publications

(104 citation statements)

References 60 publications

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“…There is indeed evidence for binding of the SNARE four-helix bundle to Munc18-1 85,86,88 (see above) and to the Munc13-1 MUN domain. 104,105 Such binding might prevent disassembly of trans SNARE complexes by NSF-aSNAP and thus stabilize the primed state of readily releasable vesicles, as suggested by a recent study, 106 and could also mediate a direct involvement of Munc18-1 and/or Munc13-1 in membrane fusion as proposed in the models of Figure 1(G,H), but these models need further testing.…”

Section: Rizomentioning

confidence: 86%

Mechanism of neurotransmitter release coming into focus

2018

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Research for three decades and major recent advances have provided crucial insights into how neurotransmitters are released by Ca -triggered synaptic vesicle exocytosis, leading to reconstitution of basic steps that underlie Ca -dependent membrane fusion and yielding a model that assigns defined functions for central components of the release machinery. The soluble N-ethyl maleimide sensitive factor attachment protein receptors (SNAREs) syntaxin-1, SNAP-25, and synaptobrevin-2 form a tight SNARE complex that brings the vesicle and plasma membranes together and is key for membrane fusion. N-ethyl maleimide sensitive factor (NSF) and soluble NSF attachment proteins (SNAPs) disassemble the SNARE complex to recycle the SNAREs for another round of fusion. Munc18-1 and Munc13-1 orchestrate SNARE complex formation in an NSF-SNAP-resistant manner by a mechanism whereby Munc18-1 binds to synaptobrevin and to a self-inhibited "closed" conformation of syntaxin-1, thus forming a template to assemble the SNARE complex, and Munc13-1 facilitates assembly by bridging the vesicle and plasma membranes and catalyzing opening of syntaxin-1. Synaptotagmin-1 functions as the major Ca sensor that triggers release by binding to membrane phospholipids and to the SNAREs, in a tight interplay with complexins that accelerates membrane fusion. Many of these proteins act as both inhibitors and activators of exocytosis, which is critical for the exquisite regulation of neurotransmitter release. It is still unclear how the actions of these various proteins and multiple other components that control release are integrated and, in particular, how they induce membrane fusion, but it can be expected that these fundamental questions can be answered in the near future, building on the extensive knowledge already available.

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Section: Rizomentioning

confidence: 86%

Mechanism of neurotransmitter release coming into focus

2018

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“…A second recent study highlighting the dynamic nature of the primed SV state (He et al, 2017) demonstrated ''de-priming'', i.e., a progressive loss of the primed SV state in the absence of the SNARE-regulating proteins Munc13-1 and Munc18-1. At rest, only a very small primed SV pool can be generated when Munc13-1 is deleted so that only the low endogenous Munc13-2-levels are remaining, or else, when Munc18-1 is replaced by Munc18-2.…”

mentioning

confidence: 99%

Dynamically Primed Synaptic Vesicle States: Key to Understand Synaptic Short-Term Plasticity

Neher

Brose

2018

Neuron

183

218

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Based on evidence that the docked and primed synaptic vesicle state is very dynamic, we propose a three-step process for the buildup of the molecular machinery that mediates synaptic vesicle fusion: (1) loose tethering and docking of vesicles to release sites, forming the nucleus of SNARE-complex assembly, (2) tightening of the complex by association of additional proteins, and partial SNARE-complex zippering, and (3) Ca 2+ -triggered fusion. We argue that the distinction between ''phasic synapses'' and ''tonic synapses'' reflects differences in resting occupancy and stability of the loosely and tightly docked states, and we assign corresponding timescales: with high-frequency synaptic activity and concomitantly increased Ca 2+ -concentrations, step (1) can proceed within 10-50 ms, step (2) within 1-5 ms, and step (3) within 0.2-1 ms.Synaptic signaling between nerve cells is initiated by the presynaptic release of neurotransmitters, which is mediated by the successive processes of synaptic vesicle (SV) tethering, SV priming and concomitant membrane attachment (docking) at the active zone (AZ), and Ca 2+ -triggered SV fusion. Like most other cellular membrane fusion events, the SV fusion reaction itself is executed by soluble N-ethylmaleimide-factor attachment receptor (SNARE) complexes, which are formed by Synaptobrevin on SVs and Syntaxin and SNAP-25 at the AZ plasma membrane. Ca 2+ -triggering at synapses, mediated by the Synaptotagmins (S€ udhof, 2013, 2014) can transiently increase the SV fusion rate by many orders of magnitude. The processes leading up to SV fusion are tightly controlled by multiple soluble and AZ proteins that regulate SV docking and priming (e.g., Munc13s and CAPSs) (Wojcik and Brose, 2007) Traditionally, electrophysiological analyses of neurotransmitter release at synapses have been interpreted in terms of AZ release sites, at which SVs are docked and primed and then fuse with a certain probability upon arrival of an action potential (AP) due to the concomitant increase in the intracellular Ca 2+ concentration [Ca 2+ ] i . In this regard, the docked and primed SV state has mostly been assumed as static and irreversible, but recent discoveries have provided a new perspective with evidence that even at rest the docked and primed SV states may be labile and very dynamic. In particular, the new results indicate that docked SVs fluctuate between a loosely docked and primed state (LS), in which SNARE complexes are only partially zippered, and a tightly docked and primed one (TS), in which zippering has progressed much further (Figure 1).Synaptotagmin-1 (Syt-1) is the Ca 2+ sensor that triggers synchronous SV fusion in response to an AP. A recent study on the ''synchronizing'' action of Syt-1 in AP-induced SV fusion (Chang et al., 2018) showed that transmitter release in Syt-1deficient synapses is desynchronized, a phenotype that can be partially rescued by Syt-1 mutants that lack the ability to bind to membranes and/or to the SNARE fusion complex. Unlike rescue with wild-type (WT) Syt-1, these...

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“…It was demonstrated that Munc13-1 catalyzes the transition of the Munc18-1/syntaxin-1 complex to the SNARE complex in the presence of SNAP-25 and synaptobrevin-2 [12,13]. Supporting such a scenario, increasing evidence revealed that Munc18-1 and Munc13-1 cooperate to ensure proper SNARE complex assembly [14], and stabilize primed synaptic vesicles (SV) in a manner resistant to NSF/a-SNAP [15,16]. These results illustrate a Munc18-Munc13 route to SNARE complex formation and suggest that the Munc18-1/syntaxin-1 complex may constitute a welldefined starting point amenable to exquisite regulation of exocytosis.…”

mentioning

confidence: 99%

Tomosyn guides SNARE complex formation in coordination with Munc18 and Munc13

Wang

et al. 2018

FEBS Letters

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As a SNARE binding protein, tomosyn has been reported to negatively regulate synaptic exocytosis via arresting syntaxin-1 and SNAP-25 into a nonfusogenic product that precludes synaptobrevin-2 entry, raising the question how the assembly of the SNARE complex is achieved. Here, we have investigated new functions of tomosyn in SNARE complex formation and SNARE-mediated vesicle fusion. Assisted by NSF/α-SNAP, syntaxin-1 escapes tomosyn arrest and assembles into the Munc18-1/syntaxin-1 complex. Munc13-1 then catalyzes the transit of syntaxin-1 from the Munc18-1/syntaxin-1 complex to the SNARE complex in a manner specific to synaptobrevin-2 but resistant to tomosyn. Our data suggest that tomosyn ensures SNARE assembly in a way amenable to tight regulation by Munc18-1 and Munc13-1.

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Munc13-1 and Munc18-1 together prevent NSF-dependent de-priming of synaptic vesicles

Cited by 88 publications

References 60 publications

Mechanism of neurotransmitter release coming into focus

Mechanism of neurotransmitter release coming into focus

Dynamically Primed Synaptic Vesicle States: Key to Understand Synaptic Short-Term Plasticity

Tomosyn guides SNARE complex formation in coordination with Munc18 and Munc13

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