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