Voltage-gated sodium channel modulation by scorpion α-toxins

Voltage-gated Na⁺ channels are integral membrane proteins that function as a gateway for a selective permeation of sodium ions across biological membranes. In this way, they are crucial players for the generation of action potentials in excitable cells. Voltage-gated Na⁺ channels are encoded by at least nine genes in mammals. The different isoforms have remarkably similar functional properties, but small changes in function and pharmacology are biologically well-defined, as underscored by mutations that cause several diseases and by modulation of a myriad of compounds, respectively. This review will stress on the modulation of voltage-gated Na⁺ channels by scorpion α-toxins. Nature has designed these two classes of molecules as if they were predestined to each other: an inevitable 'encounter' between a voltage-gated Na⁺ channel isoform and an α-toxin from scorpion venom indeed results in a dramatically changed Na⁺ current phenotype with clear-cut consequences on electrical excitability and sometimes life or death. This fascinating aspect justifies an overview on scorpion venoms, their alpha-toxins and the Na⁺ channel targets they are built for, as well as on the molecular determinants that govern the selectivity and affinity of this 'inseparable duo'.