1,721,104 research outputs found
Peculiar binding of botulinum neurotoxins
No full textBotulinum neurotoxin (BoNT) is a bacterial toxin that causes paralysis. Recent models have suggested that BoNT recognizes and enters nerve endings by interacting with protein receptors and gangliosides, which are glycosphingolipid components of the cell membrane that modulate cell signaling. Recent structures provide insight into how BoNT interacts with these cell surface components and open the door for the development of inhibitors against this neurotoxin
On the quaternary structure of taipoxin and textilotoxin: The advantage of being multiple
No full textMany presynaptic neurotoxins endowed with a phospholipase A2 activity are produced by a variety of snake species (Harris, 1991; Kini, 1997). These toxins have evolved from PLA2 enzymes mainly implicated in digestive functions (Davidson and Dennis, 1990). The evolutionary transition from a hydrolytic enzyme to a toxin has been achieved without significant modifications to the stable multi-disulfide-bridged protein PLA2 scaffold, apart from the loss of the so-called “pancreatic loop” (Alape-Girón et al., 1999; Kini, 1997). Rather, subsequent mutations have generated the ability of some of these toxins to bind and act at the presynaptic membrane of motoneurons end plates (Fletcher and Jiang, 1995). This evolution has been driven by a very strong selection pressure, as prey immobilisation greatly improves the extent of feeding and therefore the fitness of the toxin-producing species. The acquisition of neurospecific binding properties by mutation and selection is at the basis of the transformation of a generic PLA2 enzyme into a presynaptic neurotoxin as it concentrates their phospholipid hydrolytic activity within selected portions of the plasma membrane, whose alteration results in loss of neurotransmission (Kini and Evans, 1989; Fletcher and Jiang, 1995; Kini, 2003). The ensuing change of membrane structure and the increased permeability to Ca2+ causes a sustained blockade of the transmission of the nerve impulse to the muscle ( [Rigoni et al., 2005] and [Rigoni et al., 2007]; Rossetto and Montecucco, 2008)
Clostridial Neurotoxins: Mechanism of Action of Tetanus and Botulinum Neurotoxins
No full textTetanus and botulinum neurotoxins are the most potent toxins known as few nanograms are sufficient to kill most mammals. Their exceptional toxicity derives from: a) the absolute specificity for the nervous tissue, whose complete functionality is essential for survival, particularly in the wilderness, and b) their enzymatic activity in the cytosol of nerve terminals where they cleave one after the other all the copies of the core proteins of the neuroexocytosis apparatus causing a persistent blockade of neurotransmitter release.
The seven botulinum neurotoxins cause the flaccid paralysis of botulism by acting on peripheric cholinergic nerve terminals. At variance, tetanus neurotoxins enters inside the axon terminals of motoneurons and moves retroaxonally to the spinal cord where it impairs inhibitory interneurons causing the spastic paralysis of tetanus.
Because of their specificity of action botulinum neurotoxins are increasingly used in the therapy of diseases caused by hyperfunction of cholinergic nerve terminals and to correct defects due to muscle hyperactivity
Neurotoxigenic Clostridia
No full textCertain bacterial species belonging to the genus Clostridium are characterized by their ability to produce extremely potent neurotoxins. Classified as either tetanus neurotoxin (TeNT) or botulinum neurotoxin (BoNT), they act by inhibiting neurotransmitter release at CNS synapses (TeNT) and neuromuscular junctions (BoNT), leading to the spastic (tetanus) or flaccid (botulism) paralysis. To date, eight different neurotoxin types have been recognized; these are single form of TeNT, and seven (A-G) serologically distinct BoNTs. One of the most important factors to emphasize is that while production of TeNT is confined to a single clostridial species, Clostridium tetani, BoNT is produced by a range of species.
The deadly nature of the diseases these toxins cause has assured them some considerable attention from the scientific community. As a result, much is now known of their mode of action
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
Neurotoxicity of inverted-cone shaped lipids
No full textMany amphipatic molecules are characterized by an inverted-cone shape capable of altering the curvature and other properties of the plasma membrane of cells. We have recently shown that several lysophospholipids which have this shape impair nerve terminals by promoting neuroexocytosis and inhibiting endocytosis. This results in a bulging of neurites and nerve terminals and block of neurotransmission with paralysis of the neuromuscular junction. Here, we have determined the neurotoxicity of four inverted-cone shaped molecules of great interest because of their biological and pharmacological activities: miltefosine, perifosine, lysoPAF and lysophosphatidylcholine. These compounds were found to cause a complete, but reversible, paralysis of the nerve-hemidiaphragm preparation and to induce bulging of neurons in culture with entry of calcium from the external medium
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