Neurotoxins and Their Binding Areas on Voltage-Gated Sodium Channels

Abstract

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.

Modular Organization of α-Toxins from Scorpion Venom Mirrors Domain Structure of Their Targets, Sodium Channels

“…Voltage-gated sodium channels (Na v s) 6 are vital components of the nervous system and muscles, playing a central role in the excitability of these tissues (1,2). Dysfunctions of Na v s cause a number of channelopathies (3), and approaches for treatment of these diseases are eagerly awaited.…”

“…the Para protein in Drosophila) (4,5). To date, a host of substances has been described affecting Na v s through binding to different parts of the channels, so-called receptor sites (6). One of the most prominent examples is scorpion ␣-toxins, classical and potent modulators of Na v s, which slow or inhibit channel inactivation, leading to prolongation of the action potential (7).…”

Cyanobacterial Toxins of the Laurentian Great Lakes, their Toxicological Effects, and Numerical Limits in Drinking Water

“…A variety of organisms in nature produce molecules that block, activate, or modulate these ion channels [257]. Among these, saxitoxins and structurally similar compounds (gonyautoxins) bind to voltage gated sodium channels preventing the flow of sodium ions and action potentials [258][259][260].…”

Dinoflagellates: Ecological Approaches and Spatial Distributions in Malaysia Waters

“…The action mechanism of this toxin is totally opposite to the STX as brevetoxins stimulates the opening of sodium channel rather than blocking the inflow [54]. The potential mechanisms of action involve binding of brevetoxins at site 5 of voltage-gated sodium channel as shown in Figure 2 [55]. The binding leads to continuous influx of Na+ thus prolonged the depolarization of action potential [56].…”