Medical Aspects of Chemical Warfare (2008) - The Black Vault

Toxins: Established and Emergent ThreatsFig. 19-4. Structure of the α-subunit of the voltage-gated sodium channel. The six transmembrane portions for each coloreddomain (I-IV) insert into the cell membrane and form the charged pore (shown above) through which ions can travel. Theknown toxin binding sites are color-coded and numbered, as are the phosphorylation sites and charged residues that formthe selectivity filter of the channel. The lipid bilayer is illustrated in orange. Transmembrane segments 5 and 6 from eachdomain contribute to the channel pore and contributions from segment 4 form the voltage sensor. Amino acids betweensegments 5 and 6 from each domain form the filter (or gate) for ionic selectivity. The α-subunit illustrated here folds intofour transmembrane domains (I–IV), colored green, blue, orange, and purple. The transmembrane domains are themselvescomprised of six α-helical segments designated S1 through S6. Within each domain, the S4 segment has a primary structurecontaining positive charged amino acid residues at every third position. The S4 segment functions as the voltage sensor,detecting the depolarization of the cell membrane and initiating channel opening. When the α-subunit is properly foldedin three dimensions, segments S5 and S6 form the channel pore. Amino acid residues between transmembrane segments S5and S6 are predominately acidic (negatively charged) or neutral, which creates an electrically favorable tunnel to allow thepassage of positively charged ions (eg, sodium ions) of a particular radius.Six different binding sites on the voltage-gated sodium channel have been identified, each site corresponding to a locuson the protein where groups of neurotoxins can bind. TTX and STX bind to site 1 on the extracellular face of the sodiumchannel, occluding the pore and thereby preventing the movement of sodium ions through the pore. Batrachotoxin and thebrevetoxins have similar physiological effects, mainly causing activation of the channel at more negative membrane potentials.Batrachotoxin binds to site 2 and brevetoxins to site 5.STX: saxitoxinTTX: tetrodotoxinxanthid crabs, and various fish that have consumedthe toxic marine algae dinoflagellates. Eating shellfishcontaminated with STX, readily absorbed through theoral and gastrointestinal mucosa, can cause paralytic,neurotoxic, and amnestic symptoms. 80,84 STX causessymptoms very similar to several other dinoflagellatetoxins (eg, PbTxs). Because STX and TTX share verysimilar mechanisms of action, as discussed above, it isnot surprising that the symptoms of STX intoxicationare almost indistinguishable from TTX intoxication.PSP can produce paralytic, neurotoxic, and amnesticsymptoms in the range of mild to severe. Neurologicsymptoms can include sensory, cerebellar, and motor.Mild symptoms of STX intoxication begin withparesthesia of the lips, tongue, and fingertips. Thesesymptoms start within minutes of toxin ingestion.Nausea, headache, and the initial spread of paresthesiasto the neck and extremities are common features.Moderate symptoms include limb weakness, dyspnea,hypersalivation, diaphoresis, and more neurologicinvolvement (eg, incoherent speech, ataxia, floatingsensation, extremity paresthesias). Giddiness, rash,fever, tachycardia, hypertension, dizziness, and temporaryblindness have been reported. Severe symptomsinclude muscle paralysis, severe dyspnea, chokingsensation, and respiratory failure. As STX poisoningprogresses, muscular paralysis and respiratory distressdevelop, and death from respiratory arrest occurs625