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8.B.1 The Long (4C-C) Scorpion Toxin (L-ST) Superfamily

The NaC- L-ST superfamily contains a large number of scorpion-derived peptide toxins. These are tabulated below with descriptions. They include the well-characterized scorpion α- and β-toxins that act on tetrodotoxin-inhibitable, voltage-gated Na+ channels (TC #1.A.1.10). While the α-toxins (e.g., from Buthinea venom) prolong the Na+-inactivation phase of the activated action potential-causing channels, thereby blocking neuronal transmission, the β-toxins (e.g., from Centrurinae sculpturatus venom) affect the Na+-activation phase. These toxins are derived from a variety of scorpions. They can affect both insect and mammalian Na+ channel activities (Tian et al., 2007).

In many cases the details of their toxic actions are known. β-scorpion toxin, for example, targets neurotoxin receptor site 4 in Na+ channels and induces a negative shift in the voltage dependence of activation through a voltage sensor-trapping mechanism (Cestèle et al., 2006). A single organism may produce many of these toxins, some closely related, others more distantly related. This superfamily includes hundreds of sequenced members as revealed by PSI-BLAST searches with six iterations, some of which are reported to be non-toxic. They are usually characterized by four disulfide bridges, but some have three or five. 

Among scorpion species, the Buthidae produce the most deadly and painful venoms.  A pain-inducing α-toxin (CvIV4) was isolated from the venom of Centruroides vittatus and tested on five Na+ channel isoforms (Rowe et al. 2011).  CvIV4 slowed the fast inactivation of Na(v)1.7 (TC# 1.A.1.10.5), a Na+ channel expressed in peripheral pain-pathway neurons (nociceptors), but did not affect the Na(v)1.8-based sodium currents of these neurons (TC# 1.A.1.10.6). CvIV4 also slowed the fast inactivation of Na(v)1.2, Na(v)1.3 and Na(v)1.4. The effects of CvIV4 are similar to Old World α-toxins that target Na(v)1.7 (AahII, BmK MI, LqhIII, OD1), but the primary sequence of CvIV4 is not similar to these toxins. Mutant Na(v)1.7 channels (D1586A and E1589Q, DIV S3-S4 linker) reduced but did not abolish the effects of CvIV4.

This family belongs to the: Defensin Superfamily.

References associated with 8.B.1 family:

Cestèle, S., Yarov-Yarovoy, V., Qu, Y., Sampieri, F., Scheuer, T., and Catterall, W.A. (2006). Structure and function of the voltage sensor of sodium channels probed by a β-scorpion toxin. J. Biol. Chem. 281: 21332-21344. 16679310
Cohen, L., Y. Moran, A. Sharon, D. Segal, D. Gordon, and M. Gurevitz. (2009). Drosomycin, an innate immunity peptide of Drosophila melanogaster, interacts with the fly voltage-gated sodium channel. J. Biol. Chem. 284: 23558-23563. 19574227
Fontecilla-Camps, J.C., Habersetzer-Rochat, C., and Rochat, H. (1988). Orthorhombic crystals and three-dimensional structure of the potent toxin II from the scorpion Androctonus australis Hector. Proc. Natl. Acad. Sci. USA 85: 7443-7447. 3174645
Guan, R.J., Xiang, Y., He, X.L., Wang, C.G., Wang, M., Zhang, Y., Sundberg, E.J., and Wang, D.C. (2004). Structural mechanism governing cis and trans isomeric states and an intramolecular switch for cis/trans isomerization of a non-proline peptide bond observed in crystal structures of scorpion toxins. J. Mol. Biol. 341: 1189-1204. 15321715
Ma, Z., J. Kong, D. Gordon, M. Gurevitz, and R.G. Kallen. (2013). Direct Evidence that Scorpion α-Toxins (Site-3) Modulate Sodium Channel Inactivation by Hindrance of Voltage-Sensor Movements. PLoS One 8: e77758. 24302985
Possani, L.D., Becerril, B., Delepierre, M., and Tytgat, J. (1999). Scorpion toxins specific for Na+-channels. Eur. J. Biochem. 264: 287-300. 10491073
Rowe, A.H., Y. Xiao, J. Scales, K.D. Linse, M.P. Rowe, T.R. Cummins, and H.H. Zakon. (2011). Isolation and characterization of CvIV4: a pain inducing α-scorpion toxin. PLoS One 6: e23520. 21887265
Tian, C., Y. Yuan, and S. Zhu. (2008). Positively selected sites of scorpion depressant toxins: possible roles in toxin functional divergence. Toxicon 51(4): 555-562. 18177911
Zhu, S., B. Gao, M. Deng, Y. Yuan, L. Luo, S. Peigneur, Y. Xiao, S. Liang, and J. Tytgat. (2010). Drosotoxin, a selective inhibitor of tetrodotoxin-resistant sodium channels. Biochem Pharmacol 80: 1296-1302. 20637738
Zuo, X.P. and Ji, Y.H. (2004). Molecular mechanism of scorpion neurotoxins acting on sodium channels: insight into their diverse selectivity. Mol. Neurobiol. 30: 265-278. 15655252