How does this neurotoxin affect the nervous system's ability to stimulate skeletal muscle contraction? How does it affect the ability of skeletal muscle fibers to respond to stimulation? (Be sure to explain how ligand-gated channels work in your response.) Choose any other organism that utilizes a neurotoxin in its defense and explain it mode of neuronal action and the overall effect on the nervous system. There are several to choose from so be creative and discuss something interesting or intriguing that we may not encounter often or some organism that may not be a part of our environment. You can choose from any of the six kingdoms of life as well.

The neuroselectivity of BoNT and TeNT is probably due to the following aspects: (1) The C-terminal part of the HC mediates the interaction of the toxins with their receptors, and the receptors are mainly enriched in the neuronal terminals. (2) The receptor-mediated endocytosis makes them enter the neuronal cells, but BoNT and TeNT enter in different endocytic vesicles. (3) SNAREs, the target molecules of BoNT and TeNT, are expressed in the neuronal cells of almost all vertebrate phylla [30,31,32]. However, the neuroselectivity of BoNT is not absolute and it can act on the non-neuronal cells to exert some functions, such as glial cells [33].

Up to now, there are eight BoNT serotypes that have been identified and named as A–G and X. They are classified due to lack of cross-neutralization by different antisera against each toxin type [34,35]. Over 40 subtypes have been identified [36]. They bind to different receptors to drive the process of internalization [19]. The flaccid paralysis induced by BoNTs occurs primarily due to the blockade of peripheral cholinergic nerve endings [21,37,38,39], whereas TeNT, produced by a Gram-positive bacillus, Clostridium tetani [40], has only one type [18]. The release of neurotransmitters, such as GABA and glycine, is blocked by TeNT which can lead to spastic paralysis [41,42,43]. With prolonged action, it causes death when muscular hypertonus occurs in the respiratory muscle and leads to breathing failure [44].

The two clostridium neurotoxins act in a similar way, but they cause very different diseases. The reason for this is that TeNT travels retroaxonally and is transferred via a trans-synaptic movement to inhibitory interneurons in the CNS to block the release of neurotransmitters, which results in motor neuron hyperactivity and spastic paralysis. However, BoNT mainly acts on the NMJs to inhibit the release of acetylcholine and then induce flaccid paralysis [18,41,45]. Specifically, TeNT moves retroaxonally along the axons of motor neurons into the cell body, releases and thereby enters the connecting inhibitor neurons, and then the LC exerts the function of blocking neurotransmitter release [46]. TeNT can bind to not only the connecting inhibitor neurons but also the dendrites of sensory and adrenergic neurons [41].

2.2. Excitatory Latrotoxin-like Neurotoxins

There are high-molecular neurotoxins extracted from the venom of black widow spiders called latrotoxin-like neurotoxins (LaTXs). They consist of various specific types: one vertebrate-specific toxin (α-latrotoxin (α-LTX)) [47], five highly specific insecticidal toxins (α-, β-, γ-, δ-, and ε-latroinsectotoxin (LITs)) [48], and one crustacean-specific toxin (α-latrocrustatoxin (α-LCT)) [49]. LaTXs are secreted into the gland lumen as 160 kDa inactive precursor polypeptides. In the gland lumen, the N-terminal signal peptide and a C-terminal inhibitory domain are cleaved and proteolyzed, which produces the final mature 130 kDa toxin [39,40].

Among the above-mentioned toxins, there are a number of studies on α-LTX. α-LTX causes a syndrome called lactrodectism in the clinic, which has the feature of serious muscle spasm and lots of other effects, for example, hypertension, sweating, and vomiting [50,51]. The α-LTX also affects the process of exocytosis and has a high affinity for three types of receptors: cell adhesion protein neurexin (NRX) [52,53,54]; G-protein-coupled receptor latrophilin (LPHN or CIRL) [55,56]; and the receptor-like protein tyrosine phosphatase σ (PTPσ) [57]. The α-LTX initiates the release of neurotransmitters by two distinct mechanisms, both of them relying on the binding of the toxin to three types of receptors [58,59,60]: (1) in a Ca2+-dependent manner: α-LTX binds to the cell adhesion protein neurexin in the presence of Ca2+ and then inserts into the plasma membrane to form the pore and thereby induces the influx of Ca2+ [61], and (2) in a Ca2+-independent manner: it binds to the other two receptors without Ca2+. Furthermore, LPHN may mediate the process of stimulating PLC, producing IP3 and diacyl glycerol, releasing the stored Ca2+, and activating PKC. This cascade promotes the release of neurotransmitters form vesicles [60,62] (Figure 1).

2.3. Presynaptic Neurotoxins from Snakes

Most snake venoms contain both pre- and postsynaptic neurotoxins [63], whereas some snake venoms contain only presynaptic neurotoxins [64]. These presynaptic neurotoxins belong to phospholipases A2 (PLA2), which are Ca2+-dependent enzymes [63]. They can hydrolyze the sn-2 ester bond of 1,2-diacyl-3-sn-phosphoglycerides to produce fatty acids and lysophospholipids [11,65]. Various snake presynaptic PLA2 neurotoxins have a similar secondary structure with three larger α-helices and a short two-stranded β-sheet [66,67]. The pharmacological effects of these neurotoxins are also attributed to their PLA2 enzymatic activity, including antibacterial, cardiotoxic, and neurotoxic actions [68,69,70,71,72,73,74,75].