Voltage-gated sodium channels (VGSCs) are large transmembrane proteins that 
conduct sodium ions across the membrane and by doing so they generate signals of 
communication between many kinds of tissues. They are responsible for the 
generation and propagation of action potentials in excitable cells, in close 
collaboration with other channels like potassium channels. Therefore, genetic 
defects in sodium channel genes can cause a wide variety of diseases, generally 
called "channelopathies." The first insights into the mechanism of action 
potentials and the involvement of sodium channels originated from Hodgkin and 
Huxley for which they were awarded the Nobel Prize in 1963. These concepts still 
form the basis for understanding the function of VGSCs. When VGSCs sense a 
sufficient change in membrane potential, they are activated and consequently 
generate a massive influx of sodium ions. Immediately after, channels will start 
to inactivate and currents decrease. In the inactivated state, channels stay 
refractory for new stimuli and they must return to the closed state before being 
susceptible to a new depolarization. On the other hand, studies with neurotoxins 
like tetrodotoxin (TTX) and saxitoxin (STX) also contributed largely to our 
today's understanding of the structure and function of ion channels and of VGSCs 
specifically. Moreover, neurotoxins acting on ion channels turned out to be 
valuable lead compounds in the development of new drugs for the enormous range 
of diseases in which ion channels are involved. A recent example of a synthetic 
neurotoxin that made it to the market is ziconotide (Prialt(®), Elan). The 
original peptide, ω-MVIIA, is derived from the cone snail Conus magus and now 
FDA/EMA-approved for the management of severe chronic pain by blocking the 
N-type voltage-gated calcium channels in pain fibers. This review focuses on the 
current status of research on neurotoxins acting on VGSC, their contribution to 
further unravel the structure and function of VGSC and their potential as novel 
lead compounds in drug development.