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Different mechanism of blockade of neuroexocytosis by presynaptic neurotoxins
No full textNerve terminals are specific sites of action of a very large number of toxins
produced by many different organisms. The presynaptic neurotoxins which interfere
directly with the process of neurotransmitter release can be grouped in three
large families: (1) the clostridial neurotoxins which act inside nerves and block
neurotransmitter release via their metalloproteolytic activity directed
specifically on SNARE proteins; (2) the snake presynaptic neurotoxins with
phospholipase A2 activity whose site of action is still undefined and which
induce the release of acetylcholine followed by impairment of synaptic functions;
(3) the excitatory latrotoxin-like neurotoxins which induce a massive release of
neurotransmitter at peripheral and central synapses. In this paper, the first two
families are considered in terms of their modes of action and in relation to
their potential use in cell biology and neuroscience as well as the therapeutic
utilisation of the botulinum neurotoxins in human diseases characterised by
hyperfunction of cholinergic terminals
Extra-pineal melatonin in perisynaptic Schwann cell-muscle fiber cross talk at the regenerating neuromuscular junction
Full text linkCellular Mechanisms of Action of Snake Phospholipase A2 Toxins
No full textSnake venoms contain a large amount of toxins endowed with phospholipase A2 (PLA2) activity. Despite an overall conserved structure, snake PLA2s display a variety of pharmacological activities that are the result of different cell targets and mode of actions. Here follows an overview of the present knowledge on the mechanism of action of the two main classes of snake PLA2s, myotoxins and neurotoxins, derived from in vivo, ex vivo, and in vitro models, along with a comparison with mammalian secreted PLA2 (sPLA2) homologues. In spite of many qualified efforts, several aspects of snake envenomation are still undefined, including the identification of specific receptors on nerve and muscle membranes. Further studies are required to elucidate the unclear molecular steps of snakebite intoxication that might contribute to shed light also on the mode of action of mammalian PLA2 counterparts. There is a high degree of homology in terms of primary structure between snake and mammalian sPLA2s, suggesting that snake PLA2 receptors might be also candidates for mammalian sPLA2s; this topic is of high relevance, in the light of the emerging involvement of mammalian sPLA2s in many human disorders
Animal models for studying motor axon terminal paralysis and recovery
No full textAn extraordinary property of the peripheral nervous system is that nerve terminals can regenerate after damage caused by different physical, chemical, or biological pathogens. Regeneration is the result of a complex and ill-known interplay among the nerve, the glia, the muscle, the basal lamina and, in some cases, the immune system. This phenomenon has been studied using different injury models mainly in rodents, particularly in mice, where a lesion can be produced in a chosen anatomical area. These approaches differ significantly among them for the nature of the lesion and the final outcomes. We have reviewed here the most common experimental models employed to induce motor axon injury, the relative advantages and drawbacks, and the principal read-outs used to monitor the regenerative process. Recently introduced tools for inducing reversible damage to the motor axon terminal that overcome some of the drawbacks of the more classical approaches are also discussed. Animal models have provided precious information about the cellular components involved in the regenerative process and on its electrophysiological features. Methods and tools made available recently allow one to identify and study molecules that are involved in the crosstalk among the components of the endplate. The time-course of the intercellular signaling and of the intracellular pathways activated will draw a picture of the entire process of regeneration as seen from a privileged anatomical site of observation. This is an article for the special issue XVth International Symposium on Cholinergic Mechanisms
An update on the mechanism of action of tetanus and botulinum neurotoxins.
Full text linkTetanus and botulinum neurotoxins, produced by anaerobic bacteria of the genus Clostridium, are the most toxic proteins
known and are the sole responsible for the pathogenesis of tetanus and botulism. They enter peripheral cholinergic
nerve terminals and cleave proteins of the neuroexocytosis apparatus causing a persistent, but reversible, inhibition of
neurotransmitter release. Botulinum neurotoxins are used in the therapy of many human syndromes caused by hyperactive
cholinergic nerve terminals. Here we focus on the many advances that were recently made on the understanding of
their molecular mechanism of action and on their use in human therapy
Calpains participate in nerve terminal degeneration induced by spider and snake presynaptic neurotoxins
No full textalpha-latrotoxin and snake presynaptic phospholipases A2 neurotoxins target the presynaptic membrane of axon terminals of the neuromuscular junction causing paralysis. These neurotoxins display different biochemical activities, but similarly alter the presynaptic membrane permeability causing Ca2+ overload within the nerve terminals, which in turn induces nerve degeneration. Using different methods, here we show that the calcium-activated proteases calpains are involved in the cytoskeletal rearrangements that we have previously documented in neurons exposed to ch-latrotoxin or to snake presynaptic phospholipases A2 neurotoxins. These results indicate that calpains, activated by the massive calcium influx from the extracellular medium, target fundamental components of neuronal cytoskeleton such as spectrin and neurofilaments, whose cleavage is functional to the ensuing nerve terminal fragmentation. (C) 2013 Elsevier Ltd. All rights reserved
Studies of the mechanism of blockade of acetylcholine release by snake presynaptic PLA2 neurotoxins
No full textSite-directed mutagenesis identifies active-site residues of the light chain of botulinum neurotoxin type A
No full textIF 2.93
Presynaptic enzymatic neurotoxins
No full textBotulinum neurotoxins produced by anaerobic bacteria of the genus Clostridium are
the most toxic proteins known, with mouse LD50 values in the 1-5 ng/kg range, and
are solely responsible for the pathophysiology of botulism. These
metalloproteinases enter peripheral cholinergic nerve terminals and cleave
proteins of the neuroexocytosis apparatus, causing a persistent, but reversible,
inhibition of neurotransmitter release. They are used in the therapy of many
human syndromes caused by hyperactive nerve terminals. Snake presynaptic PLA2
neurotoxins block nerve terminals by binding to the nerve membrane and catalyzing
phospholipid hydrolysis with production of lysophospholipids and fatty acids.
These compounds change the membrane conformation, causing enhanced fusion of
synaptic vesicle via hemifusion intermediate with release of neurotransmitter
and, at the same time, inhibition of vesicle fission and recycling. It is
possible to envisage clinical applications of the lysophospholipid/fatty acid
mixture to inhibit hyperactive superficial nerve terminals
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