Receptor site-3 on voltage-gated sodium channels is targeted by a variety of structurally distinct toxins from scorpions, sea anemones, and spiders whose typical action is the inhibition of sodium current inactivation. This site interacts allosterically with other topologically distinct receptors that bind alkaloids, lypophilic polyether toxins, pyrethroids, and site-4 scorpion toxins. These features suggest that design of insecticides with specificity for site-3 might be rewarding due to the positive cooperativity with other toxins or insecticidal agents. Yet, despite the central role of scorpion α-toxins in envenomation and their vast use in the study of channel functions, molecular details on site-3 are scarce. Scorpion α-toxins vary greatly in preference for sodium channels of insects and mammals, and some of them are highly active on insects. This implies that despite its commonality, receptor site-3 varies on insect vs. mammalian channels, and that elucidation of these differences could potentially be exploited for manipulation of toxin preference. This review provides current perspectives on (i) the classification of scorpion α-toxins, (ii) their mode of interaction with sodium channels and pharmacological divergence, (iii) molecular details on their bioactive surfaces and differences associated with preference for channel subtypes, as well as (iv) a summary of the present knowledge about elements involved in constituting receptor site-3. These details, combined with the variations in allosteric interactions between site-3 and the other receptor sites on insect and mammalian sodium channels, may be useful in new strategies of insect control and future design of anti-insect selective ligands.
Bibliographical noteFunding Information:
The work was supported, in part, by the United States-Israel Binational Agricultural Research and Development grant IS-3480-03 and IS-3480-03 (M.G. and D.G.); By the Israeli Science Foundation, grants 733/01 (M.G.) and 1008/05 (D.G.); and by a grant from the G.I.F., the German-Israeli Foundation for Scientific Research and Development No. G-770-242.1/2002 (D.G. and W.S.).
- Allosteric interactions
- Insect sodium channel
- Insecticidal toxins
- Receptor site-3
- Scorpion α-toxins
ASJC Scopus subject areas