Neurotoxins Affecting Neuroexocytosis

Abstract

Nerve terminals are specific sites of action of a very large number of toxins produced by many different organisms. The mechanism of action of three groups of presynaptic neurotoxins that interfere directly with the process of neurotransmitter release is reviewed, whereas presynaptic neurotoxins acting on ion channels are not dealt with here. These neurotoxins can be grouped in three large families: 1) the clostridial neurotoxins that act inside nerves and block neurotransmitter release via their metalloproteolytic activity directed specifically on SNARE proteins; 2) the snake presynaptic neurotoxins with phospholipase A(2) activity, whose site of action is still undefined and which induce the release of acethylcholine followed by impairment of synaptic functions; and 3) the excitatory latrotoxin-like neurotoxins that induce a massive release of neurotransmitter at peripheral and central synapses. Their modes of binding, sites of action, and biochemical activities are discussed in relation to the symptoms of the diseases they cause. The use of these toxins in cell biology and neuroscience is considered as well as the therapeutic utilization of the botulinum neurotoxins in human diseases characterized by hyperfunction of cholinergic terminals.

Sensing the Deadliest Toxin: Technologies for Botulinum Neurotoxin Detection

“…Lethality of the disease is then connected with muscle paralysis-caused respiratory failure. On a molecular level, BoNTs are zinc-dependent metallo¬proteases that cleave SNARE (soluble N -ethylmaleimide-sensitive factor attachment protein receptor) complex proteins that are critical for the release of the neurotransmitter acetylcholine from neuronal cells [3]. …”

“…It is believed that as the pH in the endosome lowers, it triggers a subsequent conformation change in the toxin, resulting in the HC acting as a transport channel and chaperone, facilitating LC translocation through the endosome membrane and into the cytosol [14,15]. Finally, inside the cytosol, the LC acts as zinc-dependent metallo¬protease and cleaves proteins of the SNARE complex, which are the part of exocytosis apparatus, effectively destroying this apparatus and leading to inhibition of neurotransmitter release [3]. In this last step of SNARE complex protein cleavage, each of the seven different BoNT serotypes cleaves a unique peptide bond located on one of the SNARE proteins [16,17,18].…”

Botulinum Neurotoxin Serotype F: Identification of Substrate Recognition Requirements and Development of Inhibitors with Low Nanomolar Affinity

“…In the United States, there are ∼200 cases of human botulism each year, due to ingestion of toxin-contaminated food, wound infections, or colonization of the intestinal tract by C. botulinum (5-7). However, much of the current interest in BoNTs 1 stems from their use as tools in research on the mechanisms of neurotransmission (1,8,9), an ever-expanding number of applications in the treatment of human muscle dysfunctions (10-13), and their potential for use as bioterrorist weapons (14).Intoxication resulting in the flaccid paralysis of botulism or the spastic paralysis of tetanus has been described as a four-step process, consisting of (1) toxin binding to specific receptors on neurons, (2) receptor-mediated toxin endocytosis, (3) translocation through the endosomal membrane, and (4) proteolytic inactivation of neuronal proteins critical to the mechanism of neurotransmitter release. The first three steps are mediated by the heavy chain, while the fourth is effected by the zinc metalloprotease activity of the light chain (15,16).…”

“…In the United States, there are ∼200 cases of human botulism each year, due to ingestion of toxin-contaminated food, wound infections, or colonization of the intestinal tract by C. botulinum (5)(6)(7). However, much of the current interest in BoNTs 1 stems from their use as tools in research on the mechanisms of neurotransmission (1,8,9), an ever-expanding number of applications in the treatment of human muscle dysfunctions (10)(11)(12)(13), and their potential for use as bioterrorist weapons (14).…”

“…BoNT C also cleaves syntaxin (1,10,12,25). Because identical bonds occur at multiple sites in the neuronal proteins and in many other proteins as well, substrate recognition must include sequences and structures both adjacent to and at some distance from the cleavage sites.…”