Journal article
The hitchhiker's guide to the voltage-gated sodium channel galaxy
The Journal of general physiology, Vol.147(1), pp.1-24
01/2016
DOI: 10.1085/jgp.201511492
PMCID: PMC4692491
PMID: 26712848
Abstract
Eukaryotic voltage-gated sodium (Nav) channels contribute to the rising phase of action potentials and served as an early muse for biophysicists laying the foundation for our current understanding of electrical signaling. Given their central role in electrical excitability, it is not surprising that (a) inherited mutations in genes encoding for Nav channels and their accessory subunits have been linked to excitability disorders in brain, muscle, and heart; and (b) Nav channels are targeted by various drugs and naturally occurring toxins. Although the overall architecture and behavior of these channels are likely to be similar to the more well-studied voltage-gated potassium channels, eukaryotic Nav channels lack structural and functional symmetry, a notable difference that has implications for gating and selectivity. Activation of voltage-sensing modules of the first three domains in Nav channels is sufficient to open the channel pore, whereas movement of the domain IV voltage sensor is correlated with inactivation. Also, structure-function studies of eukaryotic Nav channels show that a set of amino acids in the selectivity filter, referred to as DEKA locus, is essential for Na(+) selectivity. Structures of prokaryotic Nav channels have also shed new light on mechanisms of drug block. These structures exhibit lateral fenestrations that are large enough to allow drugs or lipophilic molecules to gain access into the inner vestibule, suggesting that this might be the passage for drug entry into a closed channel. In this Review, we will synthesize our current understanding of Nav channel gating mechanisms, ion selectivity and permeation, and modulation by therapeutics and toxins in light of the new structures of the prokaryotic Nav channels that, for the time being, serve as structural models of their eukaryotic counterparts.
Details
- Title: Subtitle
- The hitchhiker's guide to the voltage-gated sodium channel galaxy
- Creators
- Christopher A Ahern - Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA 52242 christopher-ahern@uiowa.edu payandeh.jian@gene.com frankbosmans@jhmi.edu chanda@wisc.eduJian Payandeh - Department of Structural Biology, Genentech, Inc., South San Francisco, CA 94080 christopher-ahern@uiowa.edu payandeh.jian@gene.com frankbosmans@jhmi.edu chanda@wisc.eduFrank Bosmans - Department of Physiology and Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, School of Medicine, Baltimore, MD 21205 Department of Physiology and Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, School of Medicine, Baltimore, MD 21205 christopher-ahern@uiowa.edu payandeh.jian@gene.com frankbosmans@jhmi.edu chanda@wisc.eduBaron Chanda - Department of Neuroscience and Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705 Department of Neuroscience and Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705 christopher-ahern@uiowa.edu payandeh.jian@gene.com frankbosmans@jhmi.edu chanda@wisc.edu
- Resource Type
- Journal article
- Publication Details
- The Journal of general physiology, Vol.147(1), pp.1-24
- DOI
- 10.1085/jgp.201511492
- PMID
- 26712848
- PMCID
- PMC4692491
- NLM abbreviation
- J Gen Physiol
- ISSN
- 0022-1295
- eISSN
- 1540-7748
- Publisher
- United States
- Grant note
- GM106569 / NIGMS NIH HHS NS081293 / NINDS NIH HHS R01 GM084140 / NIGMS NIH HHS 1R01NS091352 / NINDS NIH HHS GM084140 / NIGMS NIH HHS R01 NS081293 / NINDS NIH HHS U54 GM087519 / NIGMS NIH HHS R01 NS091352 / NINDS NIH HHS AR066802 / NIAMS NIH HHS GM087519 / NIGMS NIH HHS R21 AR066802 / NIAMS NIH HHS R01 GM106569 / NIGMS NIH HHS
- Language
- English
- Date published
- 01/2016
- Academic Unit
- Molecular Physiology and Biophysics; Iowa Neuroscience Institute
- Record Identifier
- 9984065489702771
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