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Neurotoxins and Their Binding Areas on Voltage-Gated Sodium Channels

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, i...

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Autores principales: Stevens, Marijke, Peigneur, Steve, Tytgat, Jan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Research Foundation 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3210964/
https://www.ncbi.nlm.nih.gov/pubmed/22084632
http://dx.doi.org/10.3389/fphar.2011.00071
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author Stevens, Marijke
Peigneur, Steve
Tytgat, Jan
author_facet Stevens, Marijke
Peigneur, Steve
Tytgat, Jan
author_sort Stevens, Marijke
collection PubMed
description 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.
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spelling pubmed-32109642011-11-14 Neurotoxins and Their Binding Areas on Voltage-Gated Sodium Channels Stevens, Marijke Peigneur, Steve Tytgat, Jan Front Pharmacol Pharmacology 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. Frontiers Research Foundation 2011-11-09 /pmc/articles/PMC3210964/ /pubmed/22084632 http://dx.doi.org/10.3389/fphar.2011.00071 Text en Copyright © 2011 Stevens, Peigneur and Tytgat. http://www.frontiersin.org/licenseagreement This is an open-access article subject to a non-exclusive license between the authors and Frontiers Media SA, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and other Frontiers conditions are complied with.
spellingShingle Pharmacology
Stevens, Marijke
Peigneur, Steve
Tytgat, Jan
Neurotoxins and Their Binding Areas on Voltage-Gated Sodium Channels
title Neurotoxins and Their Binding Areas on Voltage-Gated Sodium Channels
title_full Neurotoxins and Their Binding Areas on Voltage-Gated Sodium Channels
title_fullStr Neurotoxins and Their Binding Areas on Voltage-Gated Sodium Channels
title_full_unstemmed Neurotoxins and Their Binding Areas on Voltage-Gated Sodium Channels
title_short Neurotoxins and Their Binding Areas on Voltage-Gated Sodium Channels
title_sort neurotoxins and their binding areas on voltage-gated sodium channels
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3210964/
https://www.ncbi.nlm.nih.gov/pubmed/22084632
http://dx.doi.org/10.3389/fphar.2011.00071
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