Regulation of Neurotransmitter Release Kinetics by NSF

Schweizer, Felix E.; Dresbach, Thomas; DeBello, William M.; O’Connor, Vincent; Augustine, George J; Betz, Heinrich

doi:10.1126/science.279.5354.1203

Cited by 94 publications

(69 citation statements)

References 47 publications

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“…This is unexpected, given the established role of NSF in the sustained component of secretion in neuroendocrine cells (Eliasson et al, 1997;Xu et al, 1999); however, the roles of NSF in synapses are controversial. For example, Schweizer et al (1998) showed that NSF is involved in supporting rapid kinetics of transmitter release in squid giant synapses. In some synapses, it has been shown that NEM increases the frequency of spontaneous fusion events (Morishima et al, 1997).…”

Section: Roles Of Nsf and Protein Kinases In Vesicle Recruitmentmentioning

confidence: 99%

Involvement of Actin Polymerization in Vesicle Recruitment at the Calyx of Held Synapse

2003

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Depletion and replenishment of pools of synaptic vesicles are important determinants of short-term synaptic plasticity, but the underlying molecular mechanisms are not yet clear. As a first step toward understanding the process of vesicle recruitment, we have applied various specific agents directly to the presynaptic terminal of the calyx of Held synapse. Here we show that the nonhydrolyzable ATP analog ATP-␥S retards the recovery from vesicle pool depletion, as does latrunculin A. Phalloidin has no effects on recovery, suggesting that dynamic actin reorganization is not necessary. Unexpectedly, neither N-ethylmaleimide nor staurosporine affected the recovery, calling into question the role of N-ethylmaleimide-sensitive factor and protein kinases. The results suggest that intact actin polymerization is involved in vesicle recruitment.

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Section: Roles Of Nsf and Protein Kinases In Vesicle Recruitmentmentioning

confidence: 99%

Involvement of Actin Polymerization in Vesicle Recruitment at the Calyx of Held Synapse

2003

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“…Until recently, modulation of release kinetics had been a rare observation. However, it now has been demonstrated that blocking or deleting N-ethylmaleimide-sensitive factor retards release kinetics (Schweizer et al, 1998;Kawasaki et al, 1998) and that synaptic depression at the calyx of Held is associated with decelerated release (Wu and Borst, 1999). Moreover, serotonin can modulate release kinetics in Aplysia (Klein, 1994) and crayfish (Vyshedskiy et al, 1998).…”

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confidence: 99%

Analysis of Presynaptic Ca²⁺ Influx and Transmitter Release Kinetics during Facilitation at the Inhibitor of the Crayfish Neuromuscular Junction

2000

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The inhibitory synapse of the crayfish neuromuscular junction was used to examine mechanisms underlying the F2 component of synaptic facilitation. Because previous studies have shown accelerated transmitter release during facilitation, we examined whether an activity-dependent plasticity in I Ca could underlie this acceleration. We established that fluorescent transients generated by Magnesium Green can resolve small differences in presynaptic Ca 2ϩ influx that correlate with changes in IPSC waveform. However, there was no change in Ca 2ϩ transients associated with the accelerated release. Analyzing the initial rise of IPSC and the duration of the presynaptic spike yielded a depolarization-release coupling plot that captures the impact of spike waveform on the initial rate of release. We conclude that accelerated release during F2 facilitation cannot be attributed to plasticity of I Ca or modulation of spike waveform. Kinetic analysis showed a reduction in synaptic delay during facilitation only when broad action potentials were used. In unfacilitated release, synaptic delay increased as spike duration lengthened. We propose that small single Ca 2ϩ channel currents during the plateau phase of broad action potentials raise local Ca 2ϩ concentration only enough to fill a high-affinity site. Occupation of this site in itself, or events downstream, would convert a vesicle from control to facilitated state. If the conversion were a slow process, it could explain the changes in synaptic delay reported here. This hypothesis can also account for a number of observations related to Ca 2ϩ cooperativity and synaptic facilitation.

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“…These results, together with appropriate controls, are the first evidence that NSF is crucial for neurotransmitter release under physiological conditions. 8 To our surprise, we found that both NSF peptides not only reduced neurotransmitter release but also slowed the time course of release from the presynaptic terminal. This became clear when we measured the postsynaptic currents resulting from neurotransmitter release; the NSF peptides not only reduced the amplitude of these currents but also slowed both the onset and the decay of the currents (Figure 2c).…”

mentioning

confidence: 80%

“…This became clear when we measured the postsynaptic currents resulting from neurotransmitter release; the NSF peptides not only reduced the amplitude of these currents but also slowed both the onset and the decay of the currents (Figure 2c). 8 This observation indicates that NSF influences a reaction that occurs during the release of neurotransmitters. This was a surprise because neurotransmitter release at this synapse lasts for only a millisecond or two, which is quite fast relative to the speed of NSF and most other enzymes.…”

mentioning

confidence: 95%

“…We synthesized peptides derived from various regions of NSF and found that two of these peptides, termed NSF2 and NSF3, prevented NSF from hydrolyzing ATP despite the presence of SNAP. 8 Therefore, these peptides prevent some molecular rearrangement, either within NSF or between NSF and SNAP, that is needed for NSF to act as an enzyme to catalyze the dissociation of the 20S SNARE complex. We next microinjected these peptides into the giant presynaptic terminal of a squid giant synapse to determine the effect of these peptides on neurotransmitter release.…”

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confidence: 99%

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SNARE proteins and the timing of neurotransmitter release

Schweizer¹,

Augustine

1998

Mol Psychiatry

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The SNARE complex proteins have been implicated in exocytotic neurotransmitter release and other forms of membrane fusion. Recent work shows that NSF, the ATPase of the SNARE complex, regulates the kinetics of neurotransmitter release and can thereby control the integrative properties of synapses.Time is one of the most critical parameters in the functioning of the brain. Information transfer on the timescale of milliseconds (10 −3 seconds) is typical throughout the brain and in certain brain regions, such as the auditory brainstem, time differences on the order of microseconds (10 −6 seconds) are used to define the frequency and location of perceived sounds. Thus information processing not only depends on a fast underlying process but also on the precise timing of synaptic activity. Such high temporal fidelity must rely upon very finely-regulated molecular mechanisms. However, until recently the identity of these mechanisms has been remarkably elusive. We summarize here our recent experiments that provide the first clues about the identity of the molecular timers of synaptic transmission.Synaptic transmission occurs when synaptic vesicles containing neurotransmitters fuse with the plasma membrane of a neuron, causing the neurotransmitters to be released onto downstream neurons and other target cells. Biochemical and molecular biological approaches have identified a group of presynaptic proteins that may be key players in neurotransmitter release. A soluble ATPase, called NSF (N-ethylmaleimide Sensitive Factor) binds, via another protein called SNAP (Soluble NSF Attachment Protein) to its membrane receptors, known as SNAREs (SNAP Receptors). Two of these SNAREs-syntaxin and SNAP-25 (for synaptosome-associated protein of 25-kDa molecular weight)-are found on the plasma membrane and another SNARE-synaptobrevin or VAMP (vesicleassociated membrane protein)-is in the membrane of the synaptic vesicles. In vitro experiments indicate that these proteins associate in various combinations 1 (Figure 1). The SNAREs can bind together to form the so-called 7S complex and addition of the soluble NSF and SNAP leads to the formation of a larger, 20S complex. This 20S complex breaks apart when NSF Correspondence: FE Schweizer, Dept Neurobiology, UCLA, Box 951763, Los Angeles, CA 90095-1763, USA. E-mail: felixsȰ-ucla.edu hydrolyzes ATP. Because SNAREs are found on both the synaptic vesicle membrane and the plasma membrane, it has been postulated that the various SNARE complexes mediate the interaction between the two membranes before fusion and thus may be necessary for neurotransmitter release. 2 Evidence for a role for SNARE proteins in neurotransmitter release has come from a variety of sources. The most compelling indication of the central importance of the three membrane SNARE proteins is that these proteins are remarkably specific targets of tetanus and botulinum toxins, a group of potent neurotoxins that completely paralyze neurotransmitter release. These toxins act as proteases that cleave one of the SNARE proteins, either...

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Regulation of Neurotransmitter Release Kinetics by NSF

Cited by 94 publications

References 47 publications

Involvement of Actin Polymerization in Vesicle Recruitment at the Calyx of Held Synapse

Involvement of Actin Polymerization in Vesicle Recruitment at the Calyx of Held Synapse

Analysis of Presynaptic Ca²⁺ Influx and Transmitter Release Kinetics during Facilitation at the Inhibitor of the Crayfish Neuromuscular Junction

SNARE proteins and the timing of neurotransmitter release

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Regulation of Neurotransmitter Release Kinetics by NSF

Cited by 94 publications

References 47 publications

Involvement of Actin Polymerization in Vesicle Recruitment at the Calyx of Held Synapse

Involvement of Actin Polymerization in Vesicle Recruitment at the Calyx of Held Synapse

Analysis of Presynaptic Ca2+ Influx and Transmitter Release Kinetics during Facilitation at the Inhibitor of the Crayfish Neuromuscular Junction

SNARE proteins and the timing of neurotransmitter release

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Analysis of Presynaptic Ca²⁺ Influx and Transmitter Release Kinetics during Facilitation at the Inhibitor of the Crayfish Neuromuscular Junction