Additive effects on the energy barrier for synaptic vesicle fusion cause supralinear effects on the vesicle fusion rate

Schotten, Sebastiaan; Meijer, Marieke; Walter, Alexander; Huson, Vincent; Mamer, Lauren; Kalogreades, Lawrence; Veer, Mirelle ter; Ruiter, Marvin; Brose, Nils; Rosenmund, Christian; Sørensen, Jakob B.; Verhage, Matthijs; Cornelisse, L. Niels

doi:10.7554/elife.05531

Cited by 67 publications

(123 citation statements)

References 78 publications

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“…On the other hand, recent evidence assigns decisive roles to specific isoforms of PKC (6,28) and PKC-mediated phosphorylation of Munc18 (29) to the induction of PTP. However, assuming that PTP and PdBu-induced potentiation act through the same mechanism (evidence provided here) and given the finding that all effects of PdBu are eliminated by disrupting its interaction with Munc13 (26), we may conclude that Munc13 executes both forms of potentiation by regulating the energy barrier for SV fusion (54). PKC, on the other hand, may enable such regulation through targets, which are part of the release machinery.…”

Section: Discussionmentioning

confidence: 99%

Superpriming of synaptic vesicles as a common basis for intersynapse variability and modulation of synaptic strength

Taschenberger

Woehler

Neher

2016

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

113

156

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Glutamatergic synapses show large variations in strength and shortterm plasticity (STP). We show here that synapses displaying an increased strength either after posttetanic potentiation (PTP) or through activation of the phospholipase-C-diacylglycerol pathway share characteristic properties with intrinsically strong synapses, such as (i) pronounced short-term depression (STD) during high-frequency stimulation; (ii) a conversion of that STD into a sequence of facilitation followed by STD after a few conditioning stimuli at low frequency; (iii) an equalizing effect of such conditioning stimulation, which reduces differences among synapses and abolishes potentiation; and (iv) a requirement of long periods of rest for reconstitution of the original STP pattern. These phenomena are quantitatively described by assuming that a small fraction of "superprimed" synaptic vesicles are in a state of elevated release probability (p ∼ 0.5). This fraction is variable in size among synapses (typically about 30%), but increases after application of phorbol ester or during PTP. The majority of vesicles, released during repetitive stimulation, have low release probability (p ∼ 0.1), are relatively uniform in number across synapses, and are rapidly recruited. In contrast, superprimed vesicles need several seconds to be regenerated. They mediate enhanced synaptic strength at the onset of burst-like activity, the impact of which is subject to modulation by slow modulatory transmitter systems.posttetanic potentiation | short-term plasticity | calyx of Held | Munc13 | phorbol ester G lutamatergic synapses display a variety of dynamic changes in response to stimulation with action potential (AP) trains, ranging from immediate short-term depression to facilitation followed by depression (1). Both pharmacological (2-6) and molecular (7-9) perturbations have been described, which change such patterns from one to the other in a given synapse. Short-term plasticity (STP) has been shown to underlie many basic signal processing tasks of circuits in the central nervous system (10-13) and rapid changes of STP have been considered "... to be an almost necessary condition for the existence of (short-lived) activity states in the central nervous system" (ref. 14, p. 247). The balance between facilitation and depression is shifted during posttetanic potentiation (PTP) (15) and behavioral states are dynamically regulated by STP (16). Regulation occurs through slow, modulatory transmitter systems (17, 18). However, many open questions regarding the mechanisms underlying such changes remain. Modulation of presynaptic voltage-gated Ca 2+ channels by slow transmitter systems is probably the most powerful mechanism of changing release probability (p) of synaptic vesicles (SVs) (19)(20)(21). Changes in intrinsic [Ca 2+ ] i sensitivity of the release apparatus also contribute and have been investigated in the context of the phospholipase-C-diacylglycerol (PLC-DAG) signaling pathway (22-26) and posttetanic potentiation (15,(27)(28)(29)(30), but the infl...

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Section: Discussionmentioning

confidence: 99%

Superpriming of synaptic vesicles as a common basis for intersynapse variability and modulation of synaptic strength

Taschenberger

Woehler

Neher

2016

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

113

156

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“…The RRP size is underestimated if RRP depletion is incomplete, and overestimated if replenished vesicles contribute to the measure of RRP. One approach that has been used extensively in cultured cells is to apply high osmolarity solutions (usually 500 mM sucrose) to release the RRP [14–17]. It is thought that high osmolarity solutions result in fusion of the RRP.…”

Section: Definitions and Measurements Of Rrpmentioning

confidence: 99%

The readily releasable pool of synaptic vesicles

Kaeser

Regehr

2017

Current Opinion in Neurobiology

206

166

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Each presynaptic bouton is densely packed with many vesicles, only a small fraction of which are available for immediate release. These vesicles constitute the readily releasable pool (RRP). The RRP size, and the probability of release of each vesicle within the RRP, together determine synaptic strength. Here, we discuss complications and recent advances in determining the size of the physiologically relevant RRP. We consider molecular mechanisms to generate and regulate the RRP, and discuss the relationship between vesicle docking and the RRP. We conclude that many RRP vesicles are docked, that some docked vesicles may not be part of the RRP, and that undocked vesicles can contribute to the RRP by rapid recruitment to unoccupied, molecularly activated ready-torelease sites.

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“…The cross‐binding of membranes is particularly interesting because it might lower the energy barrier for fusion (Schotten et al . ) and explain why Munc13 proteins directly modify fusogenicity (Basu et al . ; Shin et al .…”

Section: Unc13/munc13 and Caps Proteinsmentioning

confidence: 99%

C2‐domain containing calcium sensors in neuroendocrine secretion

Pinheiro

Houy

Sørensen

2016

Journal of Neurochemistry

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The molecular mechanisms for calcium-triggered membrane fusion have long been sought for, and detailed models now exist that account for at least some of the functions of the many proteins involved in the process. Key players in the fusion reaction are a group of proteins that, upon binding to calcium, trigger the merger of cargo-filled vesicles with the plasma membrane. Low-affinity, fast-kinetics calcium sensors of the synaptotagmin family -especially synaptotagmin-1 and synaptotagmin-2 -are the main calcium sensors for fast exocytosis triggering in many cell types. Their functions extend beyond fusion triggering itself, having been implicated in the calcium-dependent vesicle recruitment during activity, docking of vesicles to the plasma membrane and priming, and even in post-fusion steps, such as fusion pore expansion and endocytosis. Furthermore, synaptotagmin diversity imparts distinct properties to the release process itself. Other calcium-sensing proteins such as Munc13s and protein kinase C play important, but more indirect roles in calcium-triggered exocytosis. Because of their higher affinity, but intrinsic slower kinetics, they operate on longer temporal and spatial scales to organize assembly of the release machinery. Finally, the high-affinity synaptotagmin-7 and Doc2 (Double C2-domain) proteins are able to trigger membrane fusion in vitro, but cellular measurements in different systems show that they may participate in either fusion or vesicle priming. Here, we summarize the properties and possible interplay of (some of) the major C2-domain containing calcium sensors in calcium-triggered exocytosis. Keywords: calcium sensor, exocytosis, Munc13, neuroendocrine, synaptic transmission, synaptotagmin. This article is part of a mini review series: "Synaptic Function and Dysfunction in Brain Diseases". Cellular processes as distinct as neurotransmitter release, mast cell degranulation, and hormone release are brought about by calcium-dependent exocytosis (Lindau and Gomperts 1991;Bean et al. 1994;Sudhof 2013). Extensive research over several decades has elucidated the general mechanism behind those processes, and the functions of the key players involved. It is now clearly established that, both in synaptic and endocrine secretion, the vesicle fusion machinery is composed, at its core, by a set of proteins forming the soluble N-ethylmaleimide sensitive factor attachment receptor (SNARE) complex. The canonical (neuronal) SNARE complex consists of the vesicular SNARE protein synaptobrevin 2/VAMP-2 and the plasma membrane SNAREs synaptosomal-associated protein of 25 kDa (SNAP-25) and syntaxin-1 (Sollner et al. 1993). The~65-residue heptad-repeat SNARE motifs of these proteins form a parallel four-stranded helix bundle (Hanson et al. 1997;Sutton et al. 1998) that can zipper-up from its Nto C-terminus (Hua and Charlton 1999;Sorensen et al. 2006) in a stepwise manner (Gao et al. 2012;Min et al. 2013) to bring the two opposing membranes together. The formation of this trans alpha-helical ternary complex...

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Additive effects on the energy barrier for synaptic vesicle fusion cause supralinear effects on the vesicle fusion rate

Cited by 67 publications

References 78 publications

Superpriming of synaptic vesicles as a common basis for intersynapse variability and modulation of synaptic strength

Superpriming of synaptic vesicles as a common basis for intersynapse variability and modulation of synaptic strength

The readily releasable pool of synaptic vesicles

C2‐domain containing calcium sensors in neuroendocrine secretion

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