Learning From Scorpions to Control Impulses

For venomous animals seeking to cripple their prey or defend against predators, voltage-gated sodium (Na_v) channels are attractive targets. These transmembrane proteins, which play a key role in the generation of electrical signals in neurons, consist of four domains that make up the regions that sense changes in membrane voltage as well as the pore through which sodium ions can cross the membrane. Various animal toxins bind to each domain’s “paddle” region, a part of the voltage-sensing domain, so named for the shape created by the helix-turn-helix structure.

Animal toxins can affect Na_v channel function differently based on which paddle they target. Some toxins, that bind to paddles in voltage-sensing domains I to III, for instance, disrupt channel activation to inhibit the propagation of nerve impulses. Certain scorpion toxins, on the other hand, which bind to the paddle in domain IV, prolong nerve impulses by inhibiting channel inactivation. Finding molecules that similarly target the paddle could therefore be useful in developing drugs that correct abnormal channel activity. But techniques to identify such compounds can be time consuming and tedious, requiring expression of the full-length channel.

In the new study, a team of researchers from Aix Marseille Université in France and Johns Hopkins Medicine in Baltimore, Maryland, isolated the domain IV paddle and found that, even when bound to a chip, it remained sensitive to scorpion venom. The results indicate that the isolated paddle could be used to identify other molecules that target this pharmacologically important region, providing a much faster approach. The technique might also be used with other domain paddles to discover molecules that beneficially modify Na_v channel activity.

Martin-Eauclaire, M.-F., et al. 2015. J. Gen. Physiol. doi:10.1085/jgp.201411268

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Research reported in the press release was supported by the Centre National de la Recherche Scientifique and the National Institutes of Health.