scholarly journals The decoy SNARE Tomosyn sets tonic versus phasic release properties and is required for homeostatic synaptic plasticity

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Chad W Sauvola ◽  
Yulia Akbergenova ◽  
Karen L Cunningham ◽  
Nicole A Aponte-Santiago ◽  
J Troy Littleton
Keyword(s):  
Synaptic Plasticity ◽  
Synaptic Vesicle ◽  
Snare Complex ◽  
Neuronal Populations ◽  
Homeostatic Synaptic Plasticity ◽  
Enhanced Resistance ◽  
Synaptic Vesicle Release ◽  
Synaptic Vesicle Fusion ◽  
Snare Complex Formation ◽  
Phasic Release

Synaptic vesicle release probability (Pr) is a key presynaptic determinant of synaptic strength established by cell intrinsic properties and further refined by plasticity. To characterize mechanisms that generate Pr heterogeneity between distinct neuronal populations, we examined glutamatergic tonic (Ib) and phasic (Is) motoneurons in Drosophila with stereotyped differences in Pr and synaptic plasticity. We found the decoy SNARE Tomosyn is differentially expressed between these motoneuron subclasses and contributes to intrinsic differences in their synaptic output. Tomosyn expression enables tonic release in Ib motoneurons by reducing SNARE complex formation and suppressing Pr to generate decreased levels of synaptic vesicle fusion and enhanced resistance to synaptic fatigue. In contrast, phasic release dominates when Tomosyn expression is low, enabling high intrinsic Pr at Is terminals at the expense of sustained release and robust presynaptic potentiation. In addition, loss of Tomosyn disrupts the ability of tonic synapses to undergo presynaptic homeostatic potentiation (PHP).

scholarly journals The decoy SNARE Tomosyn sets tonic versus phasic release properties and is required for homeostatic synaptic plasticity

2021 ◽  
Author(s):  
Chad W. Sauvola ◽  
Yulia Akbergenova ◽  
Karen L Cunningham ◽  
Nicole A. Aponte-Santiago ◽  
J. Troy Littleton
Keyword(s):  
Synaptic Plasticity ◽  
Synaptic Vesicle ◽  
Snare Complex ◽  
Neuronal Populations ◽  
Homeostatic Synaptic Plasticity ◽  
Enhanced Resistance ◽  
Synaptic Vesicle Release ◽  
Synaptic Vesicle Fusion ◽  
Snare Complex Formation ◽  
Phasic Release

Synaptic vesicle release probability (Pr) is a key presynaptic determinant of synaptic strength established by cell intrinsic properties and further refined by plasticity. To characterize mechanisms that generate Pr heterogeneity between distinct neuronal populations, we examined glutamatergic tonic (Ib) and phasic (Is) motoneurons in Drosophila with stereotyped differences in Pr and synaptic plasticity. We found the decoy SNARE Tomosyn is differentially expressed between these motoneuron subclasses and contributes to intrinsic differences in their synaptic output. Tomosyn expression enables tonic release in Ib motoneurons by reducing SNARE complex formation and suppressing Pr to generate decreased levels of synaptic vesicle fusion and enhanced resistance to synaptic fatigue. In contrast, phasic release dominates when Tomosyn expression is low, enabling high intrinsic Pr at Is terminals at the expense of sustained release and robust presynaptic potentiation. In addition, loss of Tomosyn disrupts the ability of tonic synapses to undergo presynaptic homeostatic potentiation (PHP).

scholarly journals A new life for an old pump: V-ATPase and neurotransmitter release

2014 ◽  
Vol 205 (1) ◽  
pp. 7-9 ◽  
Author(s):  
Stefano Vavassori ◽  
Andreas Mayer
Keyword(s):  
Plasma Membrane ◽  
Complex Formation ◽  
Membrane Fusion ◽  
Synaptic Vesicle ◽  
Neurotransmitter Release ◽  
Synaptic Vesicles ◽  
Snare Complex ◽  
Spontaneous Release ◽  
Synaptic Vesicle Fusion ◽  
Snare Complex Formation

Neurons fire by releasing neurotransmitters via fusion of synaptic vesicles with the plasma membrane. Fusion can be evoked by an incoming signal from a preceding neuron or can occur spontaneously. Synaptic vesicle fusion requires the formation of trans complexes between SNAREs as well as Ca2+ ions. Wang et al. (2014. J. Cell Biol. http://dx.doi.org/jcb.201312109) now find that the Ca2+-binding protein Calmodulin promotes spontaneous release and SNARE complex formation via its interaction with the V0 sector of the V-ATPase.

scholarly journals Munc18-1 is crucial to overcome the inhibition of synaptic vesicle fusion by αSNAP

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Karolina P. Stepien ◽  
Eric A. Prinslow ◽  
Josep Rizo
Keyword(s):  
Nmr Spectroscopy ◽  
Complex Formation ◽  
Synaptic Vesicle ◽  
Active Zone ◽  
Neurotransmitter Release ◽  
Snare Complex ◽  
Inhibitory Activities ◽  
Liposome Fusion ◽  
Synaptic Vesicle Fusion ◽  
Snare Complex Formation

Abstract Munc18-1 and Munc13-1 orchestrate assembly of the SNARE complex formed by syntaxin-1, SNAP-25 and synaptobrevin, allowing exquisite regulation of neurotransmitter release. Non-regulated neurotransmitter release might be prevented by αSNAP, which inhibits exocytosis and SNARE-dependent liposome fusion. However, distinct mechanisms of inhibition by αSNAP were suggested, and it is unknown how such inhibition is overcome. Using liposome fusion assays, FRET and NMR spectroscopy, here we provide a comprehensive view of the mechanisms underlying the inhibitory functions of αSNAP, showing that αSNAP potently inhibits liposome fusion by: binding to syntaxin-1, hindering Munc18-1 binding; binding to syntaxin-1-SNAP-25 heterodimers, precluding SNARE complex formation; and binding to trans-SNARE complexes, preventing fusion. Importantly, inhibition by αSNAP is avoided only when Munc18-1 binds first to syntaxin-1, leading to Munc18-1-Munc13-1-dependent liposome fusion. We propose that at least some of the inhibitory activities of αSNAP ensure that neurotransmitter release occurs through the highly-regulated Munc18-1-Munc13-1 pathway at the active zone.

scholarly journals Dual inhibition of SNARE complex formation by tomosyn ensures controlled neurotransmitter release

2008 ◽  
Vol 183 (2) ◽  
pp. 323-337 ◽  
Author(s):  
Toshiaki Sakisaka ◽  
Yasunori Yamamoto ◽  
Sumiko Mochida ◽  
Michiko Nakamura ◽  
Kouki Nishikawa ◽  
...  
Keyword(s):  
Complex Formation ◽  
Neurotransmitter Release ◽  
Snare Complex ◽  
Protein Receptor ◽  
Repeat Domain ◽  
Dual Inhibition ◽  
Presynaptic Nerve Terminals ◽  
Synaptic Vesicle Fusion ◽  
Deficient Mice ◽  
Snare Complex Formation

Neurotransmitter release from presynaptic nerve terminals is regulated by soluble NSF attachment protein receptor (SNARE) complex–mediated synaptic vesicle fusion. Tomosyn inhibits SNARE complex formation and neurotransmitter release by sequestering syntaxin-1 through its C-terminal vesicle-associated membrane protein (VAMP)–like domain (VLD). However, in tomosyn-deficient mice, the SNARE complex formation is unexpectedly decreased. In this study, we demonstrate that the N-terminal WD-40 repeat domain of tomosyn catalyzes the oligomerization of the SNARE complex. Microinjection of the tomosyn N-terminal WD-40 repeat domain into neurons prevented stimulated acetylcholine release. Thus, tomosyn inhibits neurotransmitter release by catalyzing oligomerization of the SNARE complex through the N-terminal WD-40 repeat domain in addition to the inhibitory activity of the C-terminal VLD.

scholarly journals SNARE-complex disassembly by NSF follows synaptic-vesicle fusion

2001 ◽  
Vol 98 (21) ◽  
pp. 12233-12238 ◽  
Author(s):  
J. T. Littleton ◽  
R. J. O. Barnard ◽  
S. A. Titus ◽  
J. Slind ◽  
E. R. Chapman ◽  
...  
Keyword(s):  
Synaptic Vesicle ◽  
Vesicle Fusion ◽  
Snare Complex ◽  
Synaptic Vesicle Fusion

scholarly journals Munc18-1 binding to the neuronal SNARE complex controls synaptic vesicle priming

2009 ◽  
Vol 184 (5) ◽  
pp. 751-764 ◽  
Author(s):  
Ferenc Deák ◽  
Yi Xu ◽  
Wen-Pin Chang ◽  
Irina Dulubova ◽  
Mikhail Khvotchev ◽  
...  
Keyword(s):  
Synaptic Vesicle ◽  
Tight Binding ◽  
Point Mutations ◽  
Snare Complex ◽  
Attachment Protein ◽  
Macromolecular Assembly ◽  
Closed Conformation ◽  
Protein Receptors ◽  
Primed State ◽  
Synaptic Vesicle Fusion

Munc18-1 and soluble NSF attachment protein receptors (SNAREs) are critical for synaptic vesicle fusion. Munc18-1 binds to the SNARE syntaxin-1 folded into a closed conformation and to SNARE complexes containing open syntaxin-1. Understanding which steps in fusion depend on the latter interaction and whether Munc18-1 competes with other factors such as complexins for SNARE complex binding is critical to elucidate the mechanisms involved. In this study, we show that lentiviral expression of Munc18-1 rescues abrogation of release in Munc18-1 knockout mice. We describe point mutations in Munc18-1 that preserve tight binding to closed syntaxin-1 but markedly disrupt Munc18-1 binding to SNARE complexes containing open syntaxin-1. Lentiviral rescue experiments reveal that such disruption selectively impairs synaptic vesicle priming but not Ca2+-triggered fusion of primed vesicles. We also find that Munc18-1 and complexin-1 bind simultaneously to SNARE complexes. These results suggest that Munc18-1 binding to SNARE complexes mediates synaptic vesicle priming and that the resulting primed state involves a Munc18-1–SNARE–complexin macromolecular assembly that is poised for Ca2+ triggering of fusion.

scholarly journals Conformational Change of Syntaxin-3b in Regulating SNARE Complex Assembly in the Ribbon Synapses

2021 ◽  
Author(s):  
Claire Gething ◽  
Joshua Ferrar ◽  
Bishal Misra ◽  
Giovanni Howells ◽  
Ucheor B. Choi
Keyword(s):  
Plasma Membrane ◽  
Complex Formation ◽  
Synaptic Vesicle ◽  
Conformational Change ◽  
Single Molecule ◽  
Conformational Changes ◽  
Snare Complex ◽  
Complex Assembly ◽  
Ribbon Synapses ◽  
Snare Complex Formation

AbstractNeurotransmitter release of synaptic vesicles relies on the assembly of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex, consisting of syntaxin and SNAP-25 on the plasma membrane and synaptobrevin on the synaptic vesicle. The formation of the SNARE complex progressively zippers towards the membranes, which drives membrane fusion between the plasma membrane and the synaptic vesicle. However, the underlying molecular mechanism of SNARE complex regulation is unclear. In this study, we investigate the syntaxin-3b isoform found in the retinal ribbon synapses using single-molecule fluorescence resonance energy transfer (smFRET) to monitor the conformational changes of syntaxin-3b that modulate the SNARE complex formation. We found that syntaxin-3b is predominantly in a self-inhibiting closed conformation, inefficiently forming the ternary SNARE complex. Conversely, a phosphomimetic mutation (T14E) at the N-terminal region of syntaxin-3b promoted the open conformation, similar to the constitutively open form of syntaxin LE mutant. When syntaxin-3b is bound to Munc18-1, SNARE complex formation is almost completely blocked. Surprisingly, the T14E mutation of syntaxin-3b partially abolishes Munc18-1 regulation, acting as a conformational switch to trigger SNARE complex assembly. Thus, we suggest a model where the conformational change of syntaxin-3b induced by phosphorylation initiates the release of neurotransmitters in the ribbon synapses.

scholarly journals Alpha-Synuclein and Calpains Disrupt SNARE-Mediated Synaptic Vesicle Fusion During Manganese Exposure in SH-SY5Y Cells

Cells ◽  
2018 ◽  
Vol 7 (12) ◽  
pp. 258 ◽  
Author(s):  
Can Wang ◽  
Zhuo Ma ◽  
Dong-Ying Yan ◽  
Chang Liu ◽  
Yu Deng ◽  
...  
Keyword(s):  
Synaptic Vesicle ◽  
Vesicle Fusion ◽  
Alpha Synuclein ◽  
Convincing Evidence ◽  
Snare Complex ◽  
Attachment Protein ◽  
Over Expression ◽  
Synaptic Vesicle Fusion

Synaptic vesicle fusion is mediated by an assembly of soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptors (SNAREs), composed of syntaxin 1, soluble NSF-attachment protein (SNAP)-25, and synaptobrevin-2/VAMP-2. Previous studies have suggested that over-exposure to manganese (Mn) could disrupt synaptic vesicle fusion by influencing SNARE complex formation, both in vitro and in vivo. However, the mechanisms underlying this effect remain unclear. Here we employed calpeptin, an inhibitor of calpains, along with a lentivirus vector containing alpha-synuclein (α-Syn) shRNA, to examine whether specific SNAP-25 cleavage and the over-expression of α-Syn disturbed the formation of the SNARE complex in SH-SY5Y cells. After cells were treated with Mn for 24 h, fragments of SNAP-25-N-terminal protein began to appear; however, this effect was reduced in the group of cells which were pre-treated with calpeptin. FM1-43-labeled synaptic vesicle fusion decreased with Mn treatment, which was consistent with the formation of SNARE complexes. The interaction of VAMP-2 and α-Syn increased significantly in normal cells in response to 100 μM Mn treatment, but decreased in LV-α-Syn shRNA cells treated with 100 μM Mn; similar results were observed in terms of the formation of SNARE complexes and FM1-43-labeled synaptic vesicle fusion. Our data suggested that Mn treatment could increase [Ca2+]i, leading to abnormally excessive calpains activity, which disrupted the SNARE complex by cleaving SNAP-25. Our data also provided convincing evidence that Mn could induce the over-expression of α-Syn; when combined with VAMP-2, α-Syn prevented VAMP-2 from joining the SNARE complex cycle.

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