The selectivity of scorpion α-toxins for sodium channel subtypes is determined by subtle variations at the interacting surface

The voltage-gated sodium channel (NaCh) consists of a large (similar to260 kDa) pore-forming a-subunit, composed of four homologous domains (D1-D4) each with six transmembrane segments (S1-S6), and a hairpin-like pore region between S5 and S6 (Fig. 1). Due to their structural conservation and pivotal role in excitability, NaChs are targeted by many non-selective drugs and insecticides and by a large variety of neurotoxins produced in a wide array of organisms (Catterall, 1992; Gordon, 1997). Among them, some scorpion neurotoxins show specificity for insect NaChs and others are able to differentiate between NaCh subtypes in mammalian neurons (Gordon et al., 2002) This selectivity is attributed to differences of active sites on the toxins and to variations in receptor binding sites on distinct NaChs that, when identified, may be used for design of selective drugs and insecticides.