Scorpion toxin tells an evolutionary tale.
To thrill visitors at his lab, Herve Rochat sometimes picks up a scorpion and rubs its belly with his finger. Do not try this at home.
The venom that trickles from the tail of the tickled arachnid contains a cocktail of powerful, protein-based toxins that has kept Rochat and his co-workers busy for two decades. In the Jan. 22 BIOCHEMISTRY, the team reports the discovery of a scorpion toxin that may represent a molecular ancestor of the dozens already identified by scientists who study scorpion venom.
Scorpions, notorious for the defnesive stings they inflict when disturbed by humans, also use their poisons offensively to paralyze prey such as insects, other scorpions or small vertebrates. Their specific neurotoxic action makes these chemicals useful as molecular tools for studies of nerve-cell behavior. They may also hold promise as models for safer and more selective insecticides.
Biochemist Erwann P. Loret, working with Rochat's group at the National Center for Scientific Research in Marseilles, France, isolated the new toxin from the venom of the North African speices Androctonus australis Hector. In Greek, Loret notes, androctonus means "killer of man." These large scorpions--some the size of a hand--kill several thousand people each year, estimates biologist Gary A. Polis of Vanderbilt University in Nashville. The molecular diversity of their venomous brew limits the effectiveness of current antivenom treatments, notes Dean D. Watt, a scorpion venom specialist at Creighton University School of Medicine in Omaha, Neb.
Although the newly identified toxin, labeled AaH IT4, doesn't rank among the most potent scorpion poisons, it stands out in its ability to smile both mice and insects, says Loret, now at Oregon State University in Corvallis. Laboratory experiments show that AaH IT4, like anti-insect toxins secreted by other "Old World" scorpions, paralyzes insect larvae by binding to sodium channels on the larvae's nerve-cell membranes. And, like anti-mammal toxins from "New World" scorpions in North and South America, it also kills mice. Although researchers have identified several New World scorpion toxins that show both anti-insect and anti-mammal action, those toxins bind to only one of two possible sites on mammalian sodium channels. AaH IT4, unlike any other scorpion toxin known, can bind to either type of site on mammalian cells while also possessing anti-insect properties.
This unprecedented breadth of action suggests that AaH IT4 is an "ancestral scorpion toxin," Loret and his co-workers assert. According to their reasonin, it's a more primitive, less specialized toxin that covers more ground at the expense of potency.
That flexibility shows up in the toxin's molecular structure: a folded string of 65 amino acids that does not include the amino acid proline. Loret believes the absence of proline allows the molecule to change its shape so that it can conform to any of several sodium-channel sites featuring subtly different configurations. A strict molecular shape would restrict the toxin's versatility.
Loret plans to use AaH IT4 to study why some scorpion toxins affect only insects while others affect only mammals and other vertebrates. In the long run, he and others hope to exploit this natural selectivity to design potent new insecticides. Watt, noting that scorpion toxins appear effective only when injected, suggests that getting scorpion-inspired insecticides into their targets will take some technical creativity.
Most early investigations of scorpion venom focused on the development of antidotes or vaccines, but the various toxins have now become an important research topic in their own right. "In science," says Loret with a laugh, "you begin working on a serum antidote and you may end up with an insecticide."