REVIEW ARTICLE published: 09 November 2011 doi: 10.3389/fphar.2011.00071 Neurotoxins and their binding areas on voltage-gated sodium channels Marijke Stevens, Steve Peigneur and JanTytgat* Lab ofToxicology, Katholieke Universiteit Leuven, Leuven, Belgium Edited by: Mohamed Chahine, Laval University, Canada Reviewed by: Motohiro Nishida, Kyushu University, Japan Baron Chanda, University of Wisconsin–Madison, USA *Correspondence: Jan Tytgat, Lab of Toxicology, Katholieke Universiteit Leuven, Campus Gasthuisberg O&N 2, Herestraat 49, Box 922, 3000 Leuven, Belgium. e-mail: jan.tytgat@pharm.kuleuven.be 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 neu- rotoxins 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 chan- nels 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 onVGSC, their contribution to further unravel the structure and function ofVGSC and their potential as novel lead compounds in drug development. Keywords: voltage-gated sodium channel, neurotoxin, binding site VOLTAGE-GATED SODIUM CHANNELS Like many other voltage-gated ion channels,VGSCs are transmem- brane complexes consisting of a large core protein, the α-subunit (220–260 kDa, ≈2000 amino acids), associated with one or more smaller regulatory β-subunits (22–36 kDa). Alpha-subunits con- tain the functional ion conduction pore as an aqueous cavity that is selectively permeable for sodium ions. In mammalian cells, nine α-subunit isoforms (classified as Na v 1.1–Na v 1.9) have been characterized so far. Additionally, sodium channel-like proteins, classified as Na x , have been identified but are not yet functionally expressed (Catterall et al., 2005). The VGSC isoforms are distrib- uted differentially throughout electrical excitable cells of the body, which correlates with different functional properties in the cor- responding tissues. Na v 1.1, 1.2, 1.3, and 1.6 are mainly expressed in the central nervous system (CNS); Na v 1.7, 1.8, and 1.9 on the contrary are highly expressed in the peripheral nervous system (PNS) and finally, the Na v 1.4 and 1.5 isoforms are present in adult skeletal muscle and heart muscle, respectively (Goldin, 2001). In contrast to potassium channels, no crystallographic image of a sodium channel could be assessed for a long time and information about the structural composition of the VGSC had to be deduced in an indirect way. Recently however, the group of Catterall enlightened the horizon with the determination of the crystal structure of a bacterial VGSC (Payandeh et al., 2011). In early molecular cloning studies, later confirmed by cryo-electron images (Sato et al., 2001) and the recent crystallographic image, the α-subunit turned out to be composed of four homologous domains, DI–DIV, which all contain six putative transmembrane segments, S1–S6 (Yu and Catterall, 2003). The four domains are connected by three cytoplasmic linker loops of different size and together they form a bell-shaped protein (Sato et al., 2001). All of the four domains consist of two modules, the first being the voltage-sensing module formed by S1–4, the second being the pore-forming module, formed by S5 and S6 and the connect- ing loop. How the voltage-sensing module can “sense” voltage and thereby open the channel is a question that can be answered by looking at one particular segment of this module, the volt- age sensor S4. These cylindrical α-helical structures display highly conserved positive residues at every third position. In the “sliding helix” (Catterall, 1986) or “helical screw” (Guy and Seetharamulu, www.frontiersin.org November 2011 |Volume 2 | Article 71 | 1