Taicatoxin

Taicatoxin (TCX) is a snake toxin that blocks voltage-dependent L-type calcium channels and small conductance Ca2+-activated K+ channels.

Etymology
The name Taicatoxin comes from its source, taipan snake (Tai-), the site of its action, calcium channels (Ca-), and from being a toxin.

Source
Taicatoxin was isolated from the venom of Australian taipan snake, Oxyuranus scutellatus scutellatus. It is a secreted protein, expressed by the venom gland.

Chemistry
This toxin is an oligomer composed of a α-neurotoxin-like peptide, a neurotoxic phospholipase and a serine protease inhibitor, bond by non-covalent bonds, with a stoichiometry of 1:1:4 of the 16-, 8- and 7- kDa polypeptides. This information was obtained through SDS-PAGE analysis. The active complex was isolated by ion exchange chromatography through DE-Cellulose and two steps of Cm-Cellulose chromatography at pH4.7 and pH6.0, respectively. It migrates in beta-alanine-acetate-urea gel electrophoresis as a single compound. The phospholipase activity can be separated by affinity chromatography, using a phospholipid analog (PC-Sepharose). The alpha-neurotoxin-like peptide can be separated from the protease inhibitor, Sephadex G-50 gel filtration chromatography can be used, in the presence of high salt (1M NaCl) at alkaline pH (8.2). By using the automatic Edman degradation method the amino sequence of the protease inhibitor was determined. Taicatoxin can be found in the Swiss-Prot database under the names Q7LZE4 and Q7LZG2 and in the UniProt database under the names IVBTI OXYSC and Q7LZG2 OXYSC.

Target
Taicatoxin acts on the voltage-dependent L-type calcium channels from the heart, and on the small conductance Ca2+-activated K+ channels in the chromaffin cells and in the brain. It has a high affinity for the 125I-apamin acceptor-binding sites of the rat synaptosomal membranes (Ki=1.45±0.22 nM) and blocks affinity-labeling of a 33-kDa 125I-apamin-binding polypeptide. Other neurotoxins that act on the calcium channels are calcicludine, calciseptine, ω-Conotoxin, ω-Agatoxin.

Mode of action
It lowers the plateau of the action potential, decreasing the duration and the concentration parameters in the heart muscle cells. It has been seen that the 16-kDa subunit exhibits phospholipase activity, inducing a release of acyl CoA and acyl carnitine, fact which has a negative effect on cell’s integrity and function. TCX is involved in the outer hair cell motility too, by blocking the calcium traffic and preventing the cell shortening and elongation. Taicatoxin has an inhibitory effect by reducing the affinity of 125I-apamin for its acceptor and not by alteration of the acceptor binding site density.

Toxicity
1 or 2 μg of taicatoxin can kill a mouse of 20 g in 2 hours. Pretreatment with taicatoxin (0.19 μM) on the outer hair cells of guinea pig prevented the cell shortening induced by high K+ (50 mM) and the cell elongation induced by ionomycine (10 μM). This is due to the fact that taicatoxin blocks the calcium influx through the calcium channels in the cell’s membrane. 50 nM of taicatoxin blocks the apamin-sensitive after-hyperpolarizing slow tail K+ currents in rat chromaffin cells, but not immediately; instead, 5 μM of this toxin immediately blocks the ISK(Ca) tail current. It has been shown that taicatoxin blocks the calcium currents in heart cells with IC50 between 10-500 nM. Also was seen to evoke severe Arrhythmias and prolonged changes in the intercellular electrical coupling.