Conformational Switch of Syntaxin-1 Controls Synaptic Vesicle Fusion

Gerber, Stefan; Rah, Jong‐Cheol; Min, Sang-Won; Liu, Xinran; Wit, Heidi de; Dulubova, Irina; Meyer, Alexander; Rizo, Josep; Arancillo, Marife; Hammer, Robert E.; Verhage, Matthijs; Rosenmund, Christian; Südhof, Thomas C.

doi:10.1126/science.1163174

Cited by 262 publications

(392 citation statements)

References 22 publications

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“…S6), thereby limiting the number of v-vesicles available for docking. Recently, it was suggested that synaptobrevin-2 is not required for the initial docking of synaptic vesicles to the plasma membrane in vivo (46,47). Our results show that large α-Syn oligomers specifically inhibit SNARE complex formation between synaptobrevin-2 and t-SNAREs after initial docking by other synaptic factors, such as synaptotagmin-1, in the neuron.…”

Section: Discussionsupporting

confidence: 56%

Large α-synuclein oligomers inhibit neuronal SNARE-mediated vesicle docking

Choi

Kim

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

251

237

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Parkinson disease and dementia with Lewy bodies are featured with the formation of Lewy bodies composed mostly of α-synuclein (α-Syn) in the brain. Although evidence indicates that the large oligomeric or protofibril forms of α-Syn are neurotoxic agents, the detailed mechanisms of the toxic functions of the oligomers remain unclear. Here, we show that large α-Syn oligomers efficiently inhibit neuronal SNARE-mediated vesicle lipid mixing. Large α-Syn oligomers preferentially bind to the N-terminal domain of a vesicular SNARE protein, synaptobrevin-2, which blocks SNARE-mediated lipid mixing by preventing SNARE complex formation. In sharp contrast, the α-Syn monomer has a negligible effect on lipid mixing even with a 30-fold excess compared with the case of large α-Syn oligomers. Thus, the results suggest that large α-Syn oligomers function as inhibitors of dopamine release, which thus provides a clue, at the molecular level, to their neurotoxicity.

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Section: Discussionsupporting

confidence: 56%

Large α-synuclein oligomers inhibit neuronal SNARE-mediated vesicle docking

Choi

Kim

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

251

237

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“…Besides participating in SNARE complexes, syntaxin (Synt) is also involved in docking of granules. Synt1A knockout mice have a reduced number of docked granules (14), a fact that is in line with studies in chromaffin cells (31) and with the findings that interaction between Munc18-1, granuphilin and Syntaxin-1 is involved in docking of granules in insulin-secreting cells (32,33), and that the Munc18 -1-Syntaxin-1 complex is crucial for docking of granules in chromaffin cells (34)(35)(36).…”

supporting

confidence: 73%

Newcomer insulin secretory granules as a highly calcium-sensitive pool

Pedersen

Sherman

2009

Proc. Natl. Acad. Sci. U.S.A.

118

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Insulin secretion is biphasic in response to a step in glucose stimulation. Recent experiments suggest that 2 different mechanisms operate during the 2 phases, with transient first-phase secretion due to exocytosis of docked granules but the second sustained phase due largely to newcomer granules. Another line of research has shown that there exist 2 pools of releasable granules with different Ca 2؉ sensitivities. An immediately releasable pool (IRP) is located in the vicinity of Ca 2؉ channels, whereas a highly Ca 2؉ -sensitive pool (HCSP) resides mainly away from Ca 2؉ channels. We extend a previous model of exocytosis and insulin release by adding an HCSP and show that the inclusion of this pool naturally leads to insulin secretion mainly from newcomer granules during the second phase of secretion. We show that the model is compatible with data from single cells on the HCSP and from stimulation of islets by glucose, including L-and R-type Ca 2؉ channel knockouts, as well as from Syntaxin-1A-deficient cells. We also use the model to investigate the relative contribution of calcium signaling and pool depletion in controlling biphasic secretion.␤-cells ͉ biphasic secretion ͉ exocytosis ͉ pancreatic islets ͉ vesicles

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“…Membrane proteins extracted from the LDCV-enriched fractions, which were confirmed by electron microscopy (Supplementary information, Figure S1B), were processed by LC-MS. A total of 294 proteins were identified by LC-MS ( Figure 1B). Thirty-six of these proteins were trafficking-related proteins, including the well-known LDCV residents (Supplementary information, Table S1) syntaxin 1B, Rab3a, Rab3c, synaptotagmin 2 and vesicle-associated membrane protein 1 (VAMP1) [18][19][20][21]. Importantly, 8 GPCRs, 10 ion channels, 6 transporters and 70 signaling molecules were detected in the LDCVenriched fractions (Supplementary information, Table S1).…”

Section: Analysis Of the Protein Composition Of Ldcvsmentioning

confidence: 99%

Transport of receptors, receptor signaling complexes and ion channels via neuropeptide-secretory vesicles

Zhao

Wang

et al. 2011

Cell Res

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Stimulus-induced exocytosis of large dense-core vesicles (LDCVs) leads to discharge of neuropeptides and fusion of LDCV membranes with the plasma membrane. However, the contribution of LDCVs to the properties of the neuronal membrane remains largely unclear. The present study found that LDCVs were associated with multiple receptors, channels and signaling molecules, suggesting that neuronal sensitivity is modulated by an LDCV-mediated mechanism. Liquid chromatography-mass spectrometry combined with immunoblotting of subcellular fractions identified 298 proteins in LDCV membranes purified from the dorsal spinal cord, including G-protein-coupled receptors, G-proteins and other signaling molecules, ion channels and trafficking-related proteins. Morphological assays showed that δ-opioid receptor 1 (DOR1), β2 adrenergic receptor (AR), G αi2 , voltage-gated calcium channel α2δ1 subunit and P2X purinoceptor 2 were localized in substance P (SP)-positive LDCVs in small-diameter dorsal root ganglion neurons, whereas β1 AR, Wnt receptor frizzled 8 and dishevelled 1 were present in SP-negative LDCVs. Furthermore, DOR1/G αi2 /G β1γ5 /phospholipase C β2 complexes were associated with LDCVs. Blockade of the DOR1/ G αi2 interaction largely abolished the LDCV localization of G αi2 and impaired stimulation-induced surface expression of G αi2 . Thus, LDCVs serve as carriers of receptors, ion channels and preassembled receptor signaling complexes, enabling a rapid, activity-dependent modulation of neuronal sensitivity.

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Conformational Switch of Syntaxin-1 Controls Synaptic Vesicle Fusion

Cited by 262 publications

References 22 publications

Large α-synuclein oligomers inhibit neuronal SNARE-mediated vesicle docking

Large α-synuclein oligomers inhibit neuronal SNARE-mediated vesicle docking

Newcomer insulin secretory granules as a highly calcium-sensitive pool

Transport of receptors, receptor signaling complexes and ion channels via neuropeptide-secretory vesicles

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