Calcium-dependent docking of synaptic vesicles

Silva, Melissa; Tran, Van; Marty, Alain

doi:10.1016/j.tins.2021.04.003

Cited by 60 publications

(50 citation statements)

References 106 publications

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“…The exact geometric arrangement of replacement SVs and docked SVs is still uncertain (review: ref. 55 ), making the position of IP vesicles also uncertain. If replacement SVs are located in a second row of SVs, behind docked SVs, IP vesicles would be placed further back, at a distance of >80 nm from release sites.…”

Section: Discussionmentioning

confidence: 99%

“…If replacement SVs are located in a second row of SVs, behind docked SVs, IP vesicles would be placed further back, at a distance of >80 nm from release sites. If, however, replacement and docked SVs are all located within the first row of SVs above the plasma membrane, as suggested by the “two-state model” ( 26 ), IP vesicles would correspond to the second row of vesicles and could be attached to the plasma membrane by Munc13 links ( 55 ).…”

Section: Discussionmentioning

confidence: 99%

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Three small vesicular pools in sequence govern synaptic response dynamics during action potential trains

Tran

Miki

Marty

2022

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

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During prolonged trains of presynaptic action potentials (APs), synaptic release reaches a stable level that reflects the speed of replenishment of the readily releasable pool (RRP). Determining the size and filling dynamics of vesicular pools upstream of the RRP has been hampered by a lack of precision of synaptic output measurements during trains. Using the recent technique of tracking vesicular release in single active zone synapses, we now developed a method that allows the sizes of the RRP and upstream pools to be followed in time. We find that the RRP is fed by a small-sized pool containing approximately one to four vesicles per docking site at rest. This upstream pool is significantly depleted by short AP trains, and reaches a steady, depleted state for trains of >10 APs. We conclude that a small, highly dynamic vesicular pool upstream of the RRP potently controls synaptic strength during sustained stimulation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Three small vesicular pools in sequence govern synaptic response dynamics during action potential trains

Tran

Miki

Marty

2022

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

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“…The fusion of vesicles with other lipid bilayers is essential for intracellular trafficking and release of neurotransmitters and hormones [1][2][3][4]. Release of neurotransmitters and hormones involves the active transport of the vesicles using cytoskeletal elements such as F-actin and microtubules [5,6], tethering and docking of the vesicles with the target membrane [7,8], and finally calcium-induced fusion of the membranes, resulting in the release of vesicular contents to the extracellular media via exocytosis [9,10].…”

Section: Lipids and Exocytosismentioning

confidence: 99%

“…To study the way sphingolipids affect the secretory process, it is important to appreciate that this is a multi-step process starting with the translocation of the vesicles to the plasma membrane using active transport involving cytoskeletal elements [43,44], maturation of the docked vesicles to be competent for membrane fusion [8,45], and finally the fusion process itself that includes the opening of a fusion pore, subsequent dilation, and then the release of active substances that ends in full collapse of the vesicle into the plasma membrane [46][47][48] (Figure 2). Therefore, the use of biophysical techniques such as membrane capacitance methods [49,50], and amperometry [51,52], which resolve distinct stages of exocytosis, is essential for better understanding how sphingolipids alter the secretory pathway.…”

Section: Sphingolipids Alter the Single Fusion Properties Of Neurotransmitter Releasementioning

confidence: 99%

Vesicle Fusion as a Target Process for the Action of Sphingosine and Its Derived Drugs

Villanueva

Giménez-Molina

Davletov

et al. 2022

IJMS

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The fusion of membranes is a central part of the physiological processes involving the intracellular transport and maturation of vesicles and the final release of their contents, such as neurotransmitters and hormones, by exocytosis. Traditionally, in this process, proteins, such SNAREs have been considered the essential components of the fusion molecular machinery, while lipids have been seen as merely structural elements. Nevertheless, sphingosine, an intracellular signalling lipid, greatly increases the release of neurotransmitters in neuronal and neuroendocrine cells, affecting the exocytotic fusion mode through the direct interaction with SNAREs. Moreover, recent studies suggest that FTY-720 (Fingolimod), a sphingosine structural analogue used in the treatment of multiple sclerosis, simulates sphingosine in the promotion of exocytosis. Furthermore, this drug also induces the intracellular fusion of organelles such as dense vesicles and mitochondria causing cell death in neuroendocrine cells. Therefore, the effect of sphingosine and synthetic derivatives on the heterologous and homologous fusion of organelles can be considered as a new mechanism of action of sphingolipids influencing important physiological processes, which could underlie therapeutic uses of sphingosine derived lipids in the treatment of neurodegenerative disorders and cancers of neuronal origin such neuroblastoma.

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“…SV fusion is coupled to presynaptic elevations of Ca 2+ concentration by the vesicular Ca 2+ sensor synaptotagmin (syt) which interacts with the SNAREs (Brewer et al, 2015; Littleton et al, 1993; Mohrmann et al, 2013; Schupp et al, 2016; Zhou et al, 2015; Zhou et al, 2017). Besides a role in fusion, both the SNARE complex and syt are involved in docking and priming of SVs (Chen et al, 2021; Imig et al, 2014; Neher and Brose, 2018; Silva et al, 2021; Walter et al, 2010; Weber et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Allosteric stabilization of calcium and phosphoinositide dual binding engages three synaptotagmins in fast exocytosis

Kobbersmed

Berns

Ditlevsen

et al. 2021

Preprint

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The release of neurotransmitters from presynaptic terminals is a strongly Ca2+-dependent process controlled by synaptotagmins, especially by their C2B domains. Biochemical measurements have reported Ca2+ affinities of synaptotagmin too low to account for synaptic function. However, binding of the C2B domain to the membrane phospholipid PI(4,5)P2 increases the Ca2+ affinity and vice versa, indicating a positive allosteric stabilization of simultaneous binding. Here, we construct a mathematical model of the release-triggering mechanism of synaptotagmin based on measured Ca2+/PI(4,5)P2 affinities and reported protein copy numbers. The model reproduced the kinetics of synaptic transmission observed at the calyx of Held over the full range of Ca2+ stimuli, with each C2B domain crosslinking Ca2+ and PI(4,5)P2 lowering the energy barrier for fusion by 4.85 kBT. The allosteric stabilization of simultaneous Ca2+ and PI(4,5)P2 binding was crucial to form multiple crosslinks which enabled fast fusion rates. Only three crosslinking C2B domains were needed to reproduce physiological responses, but high copy numbers per vesicle sped up the collision-limited formation of crosslinks. In silico evaluation of theoretical mutants revealed that affection of the allosteric properties might be a determinant of the severity of synaptotagmin mutations and may underlie dominant-negative, disease-causing effects. We conclude that allostericity is a crucial feature of synaptotagmin action.

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Calcium-dependent docking of synaptic vesicles

Cited by 60 publications

References 106 publications

Three small vesicular pools in sequence govern synaptic response dynamics during action potential trains

Three small vesicular pools in sequence govern synaptic response dynamics during action potential trains

Vesicle Fusion as a Target Process for the Action of Sphingosine and Its Derived Drugs

Allosteric stabilization of calcium and phosphoinositide dual binding engages three synaptotagmins in fast exocytosis

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