Loading and recycling of synaptic vesicles in the Torpedo electric organ and the vertebrate neuromuscular junction

Kloot, William Van der

doi:10.1016/j.pneurobio.2003.10.003

Cited by 74 publications

(65 citation statements)

References 245 publications

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“…Previous experiments with munc18-1 null mice, which have no regulated secretion of a neurotransmitter, also suggested that NMJ development is reg- ulated by synaptic vesicle exocytosis, although for these mutants, it has not been established whether ACh synthesis and storage are affected (28). A number of previously reported studies suggested that distinct pathways of ACh secretion might exist at cholinergic synapses (56,60,61,64). Moreover, vesamicol-independent ACh release, presumably from synaptic vesicles, can be detected in response to pharmacological treatments (2,7,10,11,46).…”

Section: Discussionmentioning

confidence: 99%

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The Vesicular Acetylcholine Transporter Is Required for Neuromuscular Development and Function

Castro

Jaeger

Martins-Silva

et al. 2009

Molecular and Cellular Biology

116

114

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The vesicular acetylcholine (ACh) transporter (VAChT) mediates ACh storage by synaptic vesicles. However, the VAChT-independent release of ACh is believed to be important during development. Here we generated VAChT knockout mice and tested the physiological relevance of the VAChT-independent release of ACh. Homozygous VAChT knockout mice died shortly after birth, indicating that VAChT-mediated storage of ACh is essential for life. Indeed, synaptosomes obtained from brains of homozygous knockouts were incapable of releasing ACh in response to depolarization. Surprisingly, electrophysiological recordings at the skeletalneuromuscular junction show that VAChT knockout mice present spontaneous miniature end-plate potentials with reduced amplitude and frequency, which are likely the result of a passive transport of ACh into synaptic vesicles. Interestingly, VAChT knockouts exhibit substantial increases in amounts of choline acetyltransferase, high-affinity choline transporter, and ACh. However, the development of the neuromuscular junction in these mice is severely affected. Mutant VAChT mice show increases in motoneuron and nerve terminal numbers. End plates are large, nerves exhibit abnormal sprouting, and muscle is necrotic. The abnormalities are similar to those of mice that cannot synthesize ACh due to a lack of choline acetyltransferase. Our results indicate that VAChT is essential to the normal development of motor neurons and the release of ACh.

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Section: Discussionmentioning

confidence: 99%

“…Previously reported electrophysiological studies showed that quantal size is decreased by vesamicol, an inhibitor of VAChT, but only in nerve terminals that have been electrically stimulated (19,59,60,63). VAChT overexpression in developing Xenopus MNs increases both the size and frequency of miniature-end-plate currents (54).…”

mentioning

confidence: 95%

The Vesicular Acetylcholine Transporter Is Required for Neuromuscular Development and Function

Castro

Jaeger

Martins-Silva

et al. 2009

Molecular and Cellular Biology

116

114

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“…Additionally, they are essentially "sealed off" (they are inert in terms of neurotransmitter flow), implying that the neurotransmitter contained within nonrecycling vesicles is never used (reviewed in ref. 4), thus rejecting this first hypothesis. A second possibility has been suggested recently in cultured hippocampal neurons, with "reserve" vesicles perhaps participating in spontaneous release (5).…”

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confidence: 83%

“…However, vesicles contain only a minority of all neurotransmitter molecules in a neuron (4). Additionally, they are essentially "sealed off" (they are inert in terms of neurotransmitter flow), implying that the neurotransmitter contained within nonrecycling vesicles is never used (reviewed in ref.…”

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confidence: 99%

The reserve pool of synaptic vesicles acts as a buffer for proteins involved in synaptic vesicle recycling

Denker

Kröhnert²,

Bückers

et al. 2011

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

111

108

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Presynaptic nerve terminals contain between several hundred vesicles (for example in small CNS synapses) and several tens of thousands (as in neuromuscular junctions). Although it has long been assumed that such high numbers of vesicles are required to sustain neurotransmission during conditions of high demand, we found that activity in vivo requires the recycling of only a few percent of the vesicles. However, the maintenance of large amounts of reserve vesicles in many evolutionarily distinct species suggests that they are relevant for synaptic function. We suggest here that these vesicles constitute buffers for soluble accessory proteins involved in vesicle recycling, preventing their loss into the axon. Supporting this hypothesis, we found that vesicle clusters contain a large variety of proteins needed for vesicle recycling, but without an obvious function within the clusters. Disrupting the clusters by application of black widow spider venom resulted in the diffusion of numerous soluble proteins into the axons. Prolonged stimulation and ionomycin application had a similar effect, suggesting that calcium influx causes the unbinding of soluble proteins from vesicles. Confirming this hypothesis, we found that isolated synaptic vesicles in vitro sequestered soluble proteins from the cytosol in a process that was inhibited by calcium addition. We conclude that the reserve vesicles support neurotransmission indirectly, ensuring that soluble recycling proteins are delivered upon demand during synaptic activity.buffering | clathrin | synapsin | stimulated emission depletion microscopy | latrotoxin

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“…The VAChT is responsible for loading presynaptic vesicles with the neurotransmitter ACh and has been shown to be a reliable marker of ACh activity in vivo. 9 This tracer has been most extensively studied in the brain, where increased uptake of [ 18 …”

Section: Introductionmentioning

confidence: 99%

Enhanced Cholinergic Response in Pancreata of Nonhuman Primates with Impaired Glucose Tolerance Shown on [¹⁸F]Fluorobenzyltrozamicol Positron Emission Tomography

Clark

Kavanagh

Gage

et al. 2009

Diabetes Technology & Therapeutics

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Background: Islet cell adaptation to insulin resistance in type 2 diabetes mellitus may be due in part to increased stimulation of beta cells by the autonomic nervous system. The parasympathetic neurotransmitter acetylcholine (ACh) mediates insulin release via M3 muscarinic receptors on islet beta cells. The vesicular ACh transporter (VAChT) receptor correlates with cholinergic activity in vivo. The positron emission tomography (PET) radiotracer (+)-4-[18 F]fluorobenzyltrozamicol ([ 18 F]FBT) binds to the VAChT receptor on presynaptic cholinergic neurons and can be quantified by PET. In this study, we utilize [18 F]FBT PET to demonstrate pancreatic cholinergic activity before and after dextrose infusion in nonhuman primates with normal (NGT) and impaired (IGT) glucose tolerance. Methods: Seven adult female vervet (Chlorocebus aethiops) monkeys were maintained on an atherogenic Western diet. They were divided into two groups: four with NGT and three with IGT. Each subject underwent [

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Loading and recycling of synaptic vesicles in the Torpedo electric organ and the vertebrate neuromuscular junction

Cited by 74 publications

References 245 publications

The Vesicular Acetylcholine Transporter Is Required for Neuromuscular Development and Function

The Vesicular Acetylcholine Transporter Is Required for Neuromuscular Development and Function

The reserve pool of synaptic vesicles acts as a buffer for proteins involved in synaptic vesicle recycling

Enhanced Cholinergic Response in Pancreata of Nonhuman Primates with Impaired Glucose Tolerance Shown on [¹⁸F]Fluorobenzyltrozamicol Positron Emission Tomography

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Loading and recycling of synaptic vesicles in the Torpedo electric organ and the vertebrate neuromuscular junction

Cited by 74 publications

References 245 publications

The Vesicular Acetylcholine Transporter Is Required for Neuromuscular Development and Function

The Vesicular Acetylcholine Transporter Is Required for Neuromuscular Development and Function

The reserve pool of synaptic vesicles acts as a buffer for proteins involved in synaptic vesicle recycling

Enhanced Cholinergic Response in Pancreata of Nonhuman Primates with Impaired Glucose Tolerance Shown on [18F]Fluorobenzyltrozamicol Positron Emission Tomography

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Enhanced Cholinergic Response in Pancreata of Nonhuman Primates with Impaired Glucose Tolerance Shown on [¹⁸F]Fluorobenzyltrozamicol Positron Emission Tomography