Taicatoxin

Taicatoxin (TCX) is a snake toxin that blocks voltage-dependent L-type calcium channels and small conductance Ca2+-activated K+ channels. The name taicatoxin (TAIpan + CAlcium + TOXIN) is derived from its natural source, the taipan snake, the site of its action, calcium channels, and from its function as a toxin. Taicatoxin was isolated from the venom of Australian taipan snake, Oxyuranus scutellatus scutellatus. TCX is a secreted protein, produced in the venom gland of the snake.[1]

Chemistry

Through SDS-PAGE analysis, TCX (112154-17-3 ) was determined to be a complex held together by non-covalent forces of the following three polypeptides in a stoichiometry of 1:1:4 respectively:[2]

The active complex was isolated by ion exchange chromatography through DE-Cellulose and two steps of Cm-Cellulose chromatography at pH = 4.7 and pH = 6.0, 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) and alkaline conditions (pH = 8.2). The amino sequence of the protease inhibitor was determined by using the automatic Edman degradation method.

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.[5] 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.[6][7] 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

A dose of 1 to 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).[7] This is because 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 and 500 nM. Also was seen to evoke severe arrhythmias and prolonged changes in the intercellular electrical coupling.[8]

References
  1. Brown AM, Yatani A, Lacerda AE, Gurrola GB, Possani LD (1987). "Neurotoxins that act selectively on voltage-dependent cardiac calcium channels". Circ. Res. 61 (4 Pt 2): I6–9. PMID 2443275.
  2. Possani LD, Martin BM, Yatani A, Mochca-Morales J, Zamudio FZ, Gurrola GB, Brown AM (1992). "Isolation and physiological characterization of taicatoxin, a complex toxin with specific effects on calcium channels". Toxicon. 30 (11): 1343–64. doi:10.1016/0041-0101(92)90511-3. PMID 1485334.
  3. Universal protein resource accession number Q7LZG2 for "Phospholipase A2 taicatoxin" at UniProt.
  4. Universal protein resource accession number Q7LZE4 for "Kunitz-type serine protease inhibitor taicotoxin" at UniProt.
  5. Doorty KB, Bevan S, Wadsworth JD, Strong PN (1997). "A novel small conductance Ca2+-activated K+ channel blocker from Oxyuranus scutellatus taipan venom. Re-evaluation of taicatoxin as a selective Ca2+ channel probe". J. Biol. Chem. 272 (32): 19925–30. doi:10.1074/jbc.272.32.19925. PMID 9242659.
  6. Schnee ME, Ricci AJ (2003). "Biophysical and pharmacological characterization of voltage-gated calcium currents in turtle auditory hair cells". J. Physiol. 549 (Pt 3): 697–717. doi:10.1113/jphysiol.2002.037481. PMC 2342991. PMID 12740421.
  7. Su MC, Lee SY, Tan CT, Su CC, Li SY, Lin RH, Hung CC, Lin MJ (2005). "Taicatoxin inhibits the calcium-dependent slow motility of mammalian outer hair cells" (PDF). Hear. Res. 203 (1–2): 172–9. doi:10.1016/j.heares.2004.12.003. PMID 15855042. S2CID 23849498.
  8. Fantini E, Athias P, Tirosh R, Pinson A (1996). "Effect of TaiCatoxin (TCX) on the electrophysiological, mechanical and biochemical characteristics of spontaneously beating ventricular cardiomyocytes". Mol. Cell. Biochem. 160–161: 61–6. doi:10.1007/BF00240032. PMID 8901456. S2CID 20258431.
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