Structure and function of voltage‐gated sodium channels at atomic resolution
Open Access
- 14 November 2013
- journal article
- review article
- Published by Wiley in Experimental Physiology
- Vol. 99 (1), 35-51
- https://doi.org/10.1113/expphysiol.2013.071969
Abstract
• What is the topic of this review? The central goal of the research reviewed here is to understand the functional properties of voltage‐gated sodium channels at the level of high‐resolution structure of the channel protein. • What advances does it highlight? The key functional properties of voltage‐gated sodium channels, including voltage‐dependent activation. Sodium conductance and selectivity, block by local anesthetics and related drugs, and both fast and slow inactivation, are now understood at the level of protein structure with high resolution. These emerging high‐resolution structural models may lead to development of safer and more efficacious drugs for treatment of epilepsy, chronic pain, and cardiac arrhythmia through structure‐based drug design. Voltage‐gated sodium channels initiate action potentials in nerve, muscle and other excitable cells. Early physiological studies described sodium selectivity, voltage‐dependent activation and fast inactivation, and developed conceptual models for sodium channel function. This review article follows the topics of my 2013 Sharpey‐Schafer Prize Lecture and gives an overview of research using a combination of biochemical, molecular biological, physiological and structural biological approaches that have elucidated the structure and function of sodium channels at the atomic level. Structural models for voltage‐dependent activation, sodium selectivity and conductance, drug block and both fast and slow inactivation are discussed. A perspective for the future envisions new advances in understanding the structural basis for sodium channel function and the opportunity for structure‐based discovery of novel therapeutics.Keywords
This publication has 107 references indexed in Scilit:
- Crystal structure of a voltage-gated sodium channel in two potentially inactivated statesNature, 2012
- Gating charge interactions with the S1 segment during activation of a Na + channel voltage sensorProceedings of the National Academy of Sciences of the United States of America, 2011
- Mapping the receptor site for α-scorpion toxins on a Na + channel voltage sensorProceedings of the National Academy of Sciences, 2011
- The crystal structure of a voltage-gated sodium channelNature, 2011
- Ion Channel Voltage Sensors: Structure, Function, and PathophysiologyNeuron, 2010
- Sequential formation of ion pairs during activation of a sodium channel voltage sensorProceedings of the National Academy of Sciences of the United States of America, 2009
- Disulfide locking a sodium channel voltage sensor reveals ion pair formation during activationProceedings of the National Academy of Sciences of the United States of America, 2008
- Atomic structure of a voltage-dependent K+ channel in a lipid membrane-like environmentNature, 2007
- Two atomic constraints unambiguously position the S4 segment relative to S1 and S2 segments in the closed state of Shaker K channelProceedings of the National Academy of Sciences of the United States of America, 2007
- Voltage sensor conformations in the open and closed states in rosetta structural models of K + channelsProceedings of the National Academy of Sciences, 2006