Synaptophysin 1 Clears Synaptobrevin 2 from the Presynaptic Active Zone to Prevent Short-Term Depression

Rajappa, Rajit; Gauthier-Kemper, Anne; Böning, Daniel; Hüve, Jana; Klingauf, Jürgen

doi:10.1016/j.celrep.2016.01.031

Cited by 43 publications

(52 citation statements)

References 57 publications

(99 reference statements)

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“…Synaptobrevin also interacts with synaptophysin in the synaptic vesicles with six synaptophysin molecules binding to synaptobrevin dimers to form a hexameric ring that directionally orients synaptobrevin toward the presynaptic membrane . Exocytosed synaptobrevin and synaptophysin homo‐ or hetero‐oligomerize into clusters which clears synaptobrevin from the active zone preventing short term depression …”

Section: Discussionmentioning

confidence: 99%

Novel synaptobrevin‐1 mutation causes fatal congenital myasthenic syndrome

Shen

Scola

Lorenzoni

et al. 2017

Ann Clin Transl Neurol

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ObjectiveTo identify the molecular basis and elucidate the pathogenesis of a fatal congenital myasthenic syndrome.MethodsWe performed clinical electrophysiology studies, exome and Sanger sequencing, and analyzed functional consequences of the identified mutation.ResultsClinical electrophysiology studies of the patient revealed several‐fold potentiation of the evoked muscle action potential by high frequency nerve stimulation pointing to a presynaptic defect. Exome sequencing identified a homozygous c.340delA frameshift mutation in synaptobrevin 1 (SYB1), one of the three SNARE proteins essential for synaptic vesicle exocytosis. Analysis of both human spinal cord gray matter and normal human muscle revealed expression of the SYB1A and SYB1D isoforms, predicting expression of one or both isoforms in the motor nerve terminal. The identified mutation elongates the intravesicular C‐terminus of the A isoform from 5 to 71, and of the D isoform from 4 to 31 residues. Transfection of either mutant isoform into bovine chromaffin cells markedly reduces depolarization‐evoked exocytosis, and transfection of either mutant isoform into HEK cells significantly decreases expression of either mutant compared to wild type.InterpretationThe mutation is pathogenic because elongation of the intravesicular C‐terminus of the A and D isoforms increases the energy required to move their C‐terminus into the synaptic vesicle membrane, a key step for fusion of the synaptic vesicle with the presynaptic membrane, and because it is predicted to reduce expression of either isoform in the nerve terminal.

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Section: Discussionmentioning

confidence: 99%

Novel synaptobrevin‐1 mutation causes fatal congenital myasthenic syndrome

Shen

Scola

Lorenzoni

et al. 2017

Ann Clin Transl Neurol

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“…This we attribute to two factors. First, in some studies, the glycine was replaced by residues that should not increase the structural rigidity of the TMD 10, 44, 45 . Second, toxins were used in some studies to inhibit the exocytosis supported by the endogenous VAMP2 but in such systems remaining endogenous TMD may dimerize and compensate for the effects of the studied mutations 8, 11 .…”

Section: Discussionmentioning

confidence: 99%

A Central Small Amino Acid in the VAMP2 Transmembrane Domain Regulates the Fusion Pore in Exocytosis

Hastoy

Scotti

Milochau

et al. 2017

Sci Rep

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Exocytosis depends on cytosolic domains of SNARE proteins but the function of the transmembrane domains (TMDs) in membrane fusion remains controversial. The TMD of the SNARE protein synaptobrevin2/VAMP2 contains two highly conserved small amino acids, G100 and C103, in its central portion. Substituting G100 and/or C103 with the β-branched amino acid valine impairs the structural flexibility of the TMD in terms of α-helix/β-sheet transitions in model membranes (measured by infrared reflection-absorption or evanescent wave spectroscopy) during increase in protein/lipid ratios, a parameter expected to be altered by recruitment of SNAREs at fusion sites. This structural change is accompanied by reduced membrane fluidity (measured by infrared ellipsometry). The G100V/C103V mutation nearly abolishes depolarization-evoked exocytosis (measured by membrane capacitance) and hormone secretion (measured biochemically). Single-vesicle optical (by TIRF microscopy) and biophysical measurements of ATP release indicate that G100V/C103V retards initial fusion-pore opening, hinders its expansion and leads to premature closure in most instances. We conclude that the TMD of VAMP2 plays a critical role in membrane fusion and that the structural mobility provided by the central small amino acids is crucial for exocytosis by influencing the molecular re-arrangements of the lipid membrane that are necessary for fusion pore opening and expansion.

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“…Using genetically-encoded reporters of SV cargo in conjunction with super-resolution microscopy, it was demonstrated that freshly deposited cargo was freely diffusible within the plasma membrane, but was prevented from leaving the presynapse by the presence of adaptor proteins and potentially other unidentified factors which retarded diffusion (Gimber et al, 2015 ). Interestingly, the iTRAP synaptophysin has recently been proposed to aid clearance of sybII from active zone regions during action potential stimulation (Rajappa et al, 2016 ). This suggests that a number of SV cargo clustering mechanisms participate in forming and maintaining the readily retrievable pool.…”

Section: How Does Cargo Clustering Integrate With Known Endocytosis Mmentioning

confidence: 99%

Integration of Synaptic Vesicle Cargo Retrieval with Endocytosis at Central Nerve Terminals

Cousin

2017

Front. Cell. Neurosci.

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Central nerve terminals contain a limited number of synaptic vesicles (SVs) which mediate the essential process of neurotransmitter release during their activity-dependent fusion. The rapid and accurate formation of new SVs with the appropriate cargo is essential to maintain neurotransmission in mammalian brain. Generating SVs containing the correct SV cargo with the appropriate stoichiometry is a significant challenge, especially when multiple modes of endocytosis exist in central nerve terminals, which occur at different locations within the nerve terminals. These endocytosis modes include ultrafast endocytosis, clathrin-mediated endocytosis (CME) and activity-dependent bulk endocytosis (ADBE) which are triggered by specific patterns of neuronal activity. This review article will assess the evidence for the role of classical adaptor protein complexes in SV retrieval, discuss the role of monomeric adaptors and how interactions between specific SV cargoes can facilitate retrieval. In addition it will consider the evidence for preassembled plasma membrane cargo complexes and their role in facilitating these endocytosis modes. Finally it will present a unifying model for cargo retrieval at the presynapse, which integrates endocytosis modes in time and space.

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Synaptophysin 1 Clears Synaptobrevin 2 from the Presynaptic Active Zone to Prevent Short-Term Depression

Cited by 43 publications

References 57 publications

Novel synaptobrevin‐1 mutation causes fatal congenital myasthenic syndrome

Novel synaptobrevin‐1 mutation causes fatal congenital myasthenic syndrome

A Central Small Amino Acid in the VAMP2 Transmembrane Domain Regulates the Fusion Pore in Exocytosis

Integration of Synaptic Vesicle Cargo Retrieval with Endocytosis at Central Nerve Terminals

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