title: The differential preference of scorpion alpha-toxins for insect or mammalian sodium channels: implications for improved insect control.
abstract: 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, lipophilic 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 alpha-toxins in envenomation and their vast use in the study of channel functions, molecular details on site-3 are scarce. Scorpion alpha-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 alpha-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.
authors.affiliation: Department of Plant Sciences, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Ramat-Aviv 69978, Tel-Aviv, Israel. dgordon@post.tau.ac.il
authors.forename: Dalia
authors.initials: D
authors.lastname: Gordon
authors.forename: Izhar
authors.initials: I
authors.lastname: Karbat
authors.forename: Nitza
authors.initials: N
authors.lastname: Ilan
authors.forename: Lior
authors.initials: L
authors.lastname: Cohen
authors.forename: Roy
authors.initials: R
authors.lastname: Kahn
authors.forename: Nicolas
authors.initials: N
authors.lastname: Gilles
authors.forename: Ke
authors.initials: K
authors.lastname: Dong
authors.forename: Walter
authors.initials: W
authors.lastname: Stühmer
authors.forename: Jan
authors.initials: J
authors.lastname: Tytgat
authors.forename: Michael
authors.initials: M
authors.lastname: Gurevitz
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D006110:Grasshoppers; D008969:Molecular Sequence Data; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009498:Neurotoxins / Q000737:chemistry / Q000633:toxicity*; D010572:Pest Control, Biological; D011487:Protein Conformation; D051381:Rats; D012604:Scorpion Venoms / Q000737:chemistry / Q000633:toxicity*; D012605:Scorpions / Q000502:physiology*; D015222:Sodium Channels / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D010738:Type C Phospholipases / Q000737:chemistry / Q000633:toxicity*
chemical_list: D009498:Neurotoxins; D012604:Scorpion Venoms; D015222:Sodium Channels; D010738:Type C Phospholipases