Neurotoxin toxic site

V-Na+ CH activator (neurotoxin binding site 2 of a-subunit) (abolishes inactivation causes channel to stay open) [1] (nACh-R) [antinociceptive (0.1), arrhythmic (at 10 nM), hypotensive, slows heart rate, very toxic]... 

Almost aU publications on the metabolites of marine reptiles are devoted to snake venoms. Like their terrestrial homologs, these venoms are mixtures of proteins. The most studied are netirotoxins, particularly erabutoxins A and B, isolated from species of the genus Laticauda, the amino acid sequences of which have been determined (Gttinea, Tamiya, and Cogger, 1983 Tamiya et al., 1983). The toxic sites of snake neurotoxin molecules from marine and land snakes always include a number of invariant amino adds (Menez et al., 1986). 

Figure 2. Schematic diagram of botulinum neurotoxin showing its light and heavy chains. The two different domains of the heavy chain shaded with different patterns indicate the N-terminal and C-terminal halves (about 50 kDa each). These two domains are believed to play different functional roles during the intoxication process. The light chain has been shown to contain the toxic site.

Research in this area advanced in the 1970 s as several groups reported the isolation of potent toxins from P. brevis cell cultures (2-7). To date, the structures of at least eight active neurotoxins have been elucidated (PbTx-1 through PbTx-8) (8). Early studies of toxic fractions indicated diverse pathophysiological effects in vivo as well as in a number of nerve and muscle tissue preparations (reviewed in 9-11). The site of action of two major brevetoxins, PbTx-2 and PbTx-3, has been shown to be the voltage-sensitive sodium channel (8,12). These compounds bind to a specific receptor site on the channel complex where they cause persistent activation, increased Na flux, and subsequent depolarization of excitable cells at resting... 

Superfund sites are sites that emit numerous neurotoxins into the air and water environments. Love Canal studies have shown nervous system effects that can be attributed to living near a toxic waste site. I36 Elevated neural tube defects in offspring were identified with mothers residing proximate to hazardous waste sites. I49 50 It has also been shown that people residing close to industrial facilities that emit solvents or metals have offspring with increased CNS defects J51l... 

Demonstration of this activity was initially difficult because the toxins are very specific for their substrates. However, it is now clear that (a) the clostridial neurotoxins express proteolytic activity and (b) this activity is absolutely required for toxicity.30 The substrate proteins for this action appear to be part of a hetero-oligomeric assembly associated with the synaptic vesicles. Interestingly, the specific target site for cleavage seems to be different for each serotype of the botulinum toxins in some cases, different locations on the same protein in others, different proteins of the assembly.30 The basis of this marked specificity is not yet clear and remains fascinating to scientists interested in neurosecretion. 

Distribution often follows blood flow. Organs that receive the most blood, therefore, are at heightened risk of toxicant exposure. Some toxicants may have special affinity for certain tissues regardless of blood circulation levels. The body also possesses several barriers such as the blood-brain barrier or placental barrier that specifically limit distribution. Distribution is not a uniformly beneficial or detrimental process. A toxicant may be distributed to its site of toxic action or it may be transported to an inert storage tissue. For example, lead is a potent neurotoxin when it reaches the brain. It is chemically similar to calcium, however, and may safely be taken up and stored by bone. 

One question that has never been properly answered is What is the biological function of CVF in cobra venom Cobra venom factor in purified form can be considered nontoxic. When introduced into the bloodstream of an animal, complement activation with consumption of complement component occurs (41). Intravascular complement activation may have some side effects, such as sequestration of neutrophils to the lungs with subsequent injury to lung tissue (42). However, unless massive amounts of CVF are administered i.v., the consequences of intravascular complement activation by CVF are insignificant compared with the toxic effects of the other venom components, particularly the neurotoxins and membrane toxins. It appears, therefore, that local complement activation at the site of venom injection into the prey animal may be the beneficial effect of CVF for the cobra. Local complement activation by CVF will release the anaphylatoxins C3a and C5a which, in turn, will cause the degranulation of mast cells and basophils, with subsequent increase of the vascular permeability. The increased vascular permeability locally at the site of venom... 

---