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Quantal Nature of Transmitter Release

Quantal neurotransmitter release

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On the quantal hypothesis of neurotransmitter release: …

In this article, we shall review data from experiments dealing with reconstitution of quantal and Ca2+-dependent acetylcholine release in: i) proteoliposomes, ii) Xenopus oocytes, and iii) release-deficient cell lines.

Mechanisms of Neurotransmitter Release (Section 1, …

C. Katz and Miledi. d. Eccles and Miledi. 216. The person(s) largely responsible for describing the quantal nature of neuromuscular transmission was (were) a. Ochs. b. Golgi. c. Katz Miledi. d. Eccles. 217. The vesicular hypothesis of synaptic transmission states that a. the presence of vesicles in an electron micrograph of.

Chapter 5: Mechanisms of Neurotransmitter Release

Based on these results Katz proposed the quantal hypothesis for chemical synaptic transmission.

The illustration below (Figure 5.4) shows one of these vesicles in the process of fusing with the membrane and releasing its contents into the synaptic cleft through a process called exocytosis. For illustrative purposes, each synaptic vesicle is shown to contain three molecules of transmitter. In reality, each vesicle contains about 10,000 molecules of transmitter. Vesicles ready to be released are found in a region near the presynaptic terminal membrane called the readily releaseable pool. Newly synthesized vesicles are found in the storage or reserve pool. The process by which a vesicle migrates from the reserve pool to the readily releaseable pool is called mobilization. After fusing with the membrane and releasing its contents, the membrane is recycled to form new synaptic vesicles. This process is called recycling. Additional details of this process are found in .

An experiment by Katz that further supported the quantal hypothesis for chemical synaptic transmission is shown above. The extracellular concentration of calcium was lowered to reduce the size of the evoked endplate potential. Because less Ca2+ is in the extracellular medium, less Ca2+ will be available to enter through the voltage-dependent Ca2+ channels. At the arrow, the electrical shock was delivered to the motor axon. Eight successive stimuli were delivered to the presynaptic terminal. EPSPs with stars are the miniature endplate potentials (MEPPs). Note that they are uncorrelated with the stimulus. The evoked endplate potentials are small and highly variable. Sometimes the EPP was 1.6 mV in amplitude; sometimes there was no EPP at all. Sometimes the EPP was 0.4 mV. Katz noticed that these amplitudes showed a specific kind of distribution. The smallest evoked responses were 0.4 mV. He called these responses "units". Other times he recorded EPPs that were about 0.8 mV and called such responses "doubles" because they were twice the unit, and sometimes responses were 1.6 mV. Figure 5.5 is a plot of the number of times an EPP of various amplitudes was observed. Katz noticed that the amplitude of the smallest EPP that could be evoked was the same amplitude (0.5 mV) as the amplitude of the MEPP.

Quantal neurotransmitter release - Wikipedia - Thyquo

Bernard Katz, quantal transmitter release and the foundations of ..

There is a large body of literature describing the study of bioactive compounds in and the proposal to use it for the study of anthelmintics precedes the publication of the genome sequence by nearly 20 years. ) coined the term ‘genetic pharmacology’ to describe this approach. These studies generally hinge on the ability of a drug to elicit a significant, ideally quantifiable, change in the worm's growth, development, metabolism, and/or behaviour. Pharmacokinetic considerations include the method and duration of drug exposure. For the vast majority of experiments the anthelmintics are applied to intact . There are thus two ways in which the drug can gain access to target tissues, namely by ingestion or by diffusion across the cuticle. In this regard it should be noted that for many drugs the cuticle presents a significant permeability barrier. Thus the lipophilicity of drugs has a strong bearing on the concentration that is achieved in target tissues following external application. It is not uncommon for polar drugs to be applied at a concentration 1000 fold higher than their predicted affinity for the target. It may be possible to ameliorate this problem to some extent by employing animals that have a compromised cuticle (). Once the effect of a particular drug on has been defined, two different strategies may be adopted to investigate the molecular basis for its biological activity. The first follows a hypothesis led approach in which strains with mutations in genes of known function are tested for altered sensitivity to the drug. The alternate strategy is to conduct a forward genetic screen. This is a powerful and objective approach that provides novel insight into the signalling pathways that mediate anthelmintic action. Often the impact of these studies extends beyond the interests of parasitologists and into the broader context of cellular and molecular neuroscience. This is because the vast majority of anthelmintics exert their effects in the neuromuscular system and key transduction molecules in the nervous system are highly conserved across the phyla from worm to human. Thus anthelmintic resistance screens can promote the discovery and characterisation of genes that have important roles in neurotransmission. An excellent example of the utility of this approach is provided by genetic screens employing the organophosphate cholinesterase inhibitors, in particular aldicarb. The detail of these studies is beyond the scope of this review as organophosphates are not widely used as anthelmintics. (Toxicity limits their use to highly regulated applications for plant parasitic nematodes). However, aldicarb screens provide an excellent example of ‘genetic pharmacology’ and the interested reader is directed to ; ; and .

Anthelmintics are separated into classes on the basis of similar chemical structure and mode of action. There are only a few main classes and each is briefly discussed in turn below. For the most part, information on the physiological and pharmacological actions of anthelmintics has been obtained from studies on the large parasitic nematode . , on the other hand, has been valuable in defining molecular targets.

Splitting the quantum: regulation of quantal release during ..
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    One and a half decades have gone by since the concept of quantal secretion of neurotransmitter ..

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Quantal Release of ATP in Mouse Cortex | JGP

Ivermectin elicits a potent and persistent paralysis of nematode pharyngeal (; ) and body wall musculature (; ). It has been shown to interact with a range of ligand-gated ion channels including 7 nACh receptors (), acetylcholine-gated chloride channels (), GABA-gated chloride channels (; ), histamine-gated chloride channels (), glycine receptors () and P2X4 receptors (). However, it is its high affinity for nematode glutamate-gated chloride channels (GluCl) that correlates with its potent anthelmintic activity. This was defined by the team at Merck which succeeded in expression cloning GluCl and GluCl ion channel subunits from (). Both subunits were expressed either singly, or together, in oocytes. GluCl responds to micromolar ivermectin, but not to glutamate whilst GluCl responds to glutamate but not ivermectin. Co-expression of GluCl and GluCl yields a channel which responds to glutamate and is positively allosterically modulated by nanomolar ivermectin. Subsequently a small family of nematode genes encoding GluCl channels has been identified (see ). The nomenclature is confusing as the same genes have been discovered by both homology screening approaches and from forward genetic screens for ivermectin resistance genes. Essentially there are four genes encoding GluCl subunits, two of which are alternately spliced yielding the GluCl channels: GluCl1 encoded by ; GluCl2A and B encoded by ; GluCl3A and B encoded by ; GluCl4 encoded by . There is just one GluCl subunit encoded by and a further gene, , which is divergent from the genes encoding and subunits. Although the pharmacology of channels assembled from these GluCl subunits has been defined in heterologous expression systems, the important question of the subunit stoichiometry and pharmacology of the native channels is much more poorly defined. Further studies on are providing a better understanding of this by delineating the expression pattern for GluCl subunits in the nervous system. For example, the pharyngeal muscle expresses and , (; ). Thus it might be expected that GluCl2 and GluCl subunits co-assemble to form a native ivermectin sensitive channel. Whether or not other subunits contribute to the functional receptor is not yet clear. However, the pharyngeal muscle of mutants does not respond to ivermectin (; ) clearly indicating an involvement of GluCl2. An important point to note in terms of the site of anthelmintic action of ivermectin is that although the pharynxes of mutants are not inhibited by ivermectin, populations of mutants exposed to ivermectin are still paralyzed. Thus GluCl channels in the pharynx are not required for the paralytic effect. This may also be true for parasitic nematodes. For example, ivermectin has anthelmintic activity against and yet the pharynx of this species is not inhibited by the drug (). In order to obtain a better understanding of the role of GluCl channels in mediating the paralytic actions of ivermectin it is probably more informative to consider their role in the motornervous system. Currently most information is available for and . These genes are expressed in the motor nervous system of (; ) and there is immunostaining for GluCl3A and B in motorneurones of the parasitic nematode , (). One role of these GluCl channels in involves regulation of the duration of forward movement, a well established glutamatergic-regulated behaviour (). This function may be conserved between and as GluCl3 subunits expressed in mutants restore the wild type pattern of movement (). It is most likely that the paralytic action of ivermectin derives from its potent activation of GluCl in the motornervous system of nematodes. However, the precise role of individual GluCl channels in mediating the effects of ivermectin on these circuits is yet to be established. The mechanism of resistance to ivermectin has also been studied in . High level resistance is a complex phenomenon which requires mutations in at least three genes, namely in , and . Further genes, regulating membrane permeability () and gap junctions ( and ), are also involved (). Defining the role of GluCl mutations in conferring ivermectin resistance to parasitic nematodes in the field is a less tractable and more controversial problem ().

Quantal Release of ATP in Mouse ..

The cyclodepsipeptide molecule, emodepside, is a semi-synthetic derivative of PF1022A, a fermentation product obtained from the fungus, , of . Its discovery and anthelmintic activity has recently been reviewed (). It is effective against isolates of parasites that are resistant to benzimidazole, levamisole and ivermectin indicating, importantly, that it has a novel mode of action. The molecule has pore-forming properties in planar lipids, however, this does not appear to be important in conferring its anthelmintic potency as an optical isomer of emodepside, with similar pore forming properties, does not have anthelmintic action. Thus it would appear that it may act through stereospecific binding to a receptor. Studies in have highlighted muscle paralysis and point to a calcium- and potassium-dependent mechanism of action (). A candidate receptor for the cyclodepsipeptides has been cloned from a cDNA library by immunoscreening with an antibody to PF1022 A. This receptor, designated HC110R, has been expressed in HEK293 cells and shown to gate calcium flux in a PF1022 A-dependent manner (). It has homology to mammalian latrophilins, a class of G protein-coupled receptors which bind the neurotoxin, latrotoxin. Latrotoxin paralyses mammals by triggering neurotransmitter release, and thus the identification of latrophilin as an emodepside receptor raised the intriguing possibility that emodepside may cause paralysis of nematodes by stimulating excessive neurotransmitter release at neuromuscular sites.

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