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      The hitchhiker’s guide to the voltage-gated sodium channel galaxy

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          Eukaryotic voltage-gated sodium (Na v) 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 Na v channels and their accessory subunits have been linked to excitability disorders in brain, muscle, and heart; and (b) Na v 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 Na v 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 Na v 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 Na v 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 Na v 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 Na v channel gating mechanisms, ion selectivity and permeation, and modulation by therapeutics and toxins in light of the new structures of the prokaryotic Na v channels that, for the time being, serve as structural models of their eukaryotic counterparts.

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          Most cited references 296

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          The structure of the potassium channel: molecular basis of K+ conduction and selectivity.

          The potassium channel from Streptomyces lividans is an integral membrane protein with sequence similarity to all known K+ channels, particularly in the pore region. X-ray analysis with data to 3.2 angstroms reveals that four identical subunits create an inverted teepee, or cone, cradling the selectivity filter of the pore in its outer end. The narrow selectivity filter is only 12 angstroms long, whereas the remainder of the pore is wider and lined with hydrophobic amino acids. A large water-filled cavity and helix dipoles are positioned so as to overcome electrostatic destabilization of an ion in the pore at the center of the bilayer. Main chain carbonyl oxygen atoms from the K+ channel signature sequence line the selectivity filter, which is held open by structural constraints to coordinate K+ ions but not smaller Na+ ions. The selectivity filter contains two K+ ions about 7.5 angstroms apart. This configuration promotes ion conduction by exploiting electrostatic repulsive forces to overcome attractive forces between K+ ions and the selectivity filter. The architecture of the pore establishes the physical principles underlying selective K+ conduction.
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            A quantitative description of membrane current and its application to conduction and excitation in nerve.

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              Crystal structure of a mammalian voltage-dependent Shaker family K+ channel.

              Voltage-dependent potassium ion (K+) channels (Kv channels) conduct K+ ions across the cell membrane in response to changes in the membrane voltage, thereby regulating neuronal excitability by modulating the shape and frequency of action potentials. Here we report the crystal structure, at a resolution of 2.9 angstroms, of a mammalian Kv channel, Kv1.2, which is a member of the Shaker K+ channel family. This structure is in complex with an oxido-reductase beta subunit of the kind that can regulate mammalian Kv channels in their native cell environment. The activation gate of the pore is open. Large side portals communicate between the pore and the cytoplasm. Electrostatic properties of the side portals and positions of the T1 domain and beta subunit are consistent with electrophysiological studies of inactivation gating and with the possibility of K+ channel regulation by the beta subunit.

                Author and article information

                J Gen Physiol
                J. Gen. Physiol
                The Journal of General Physiology
                The Rockefeller University Press
                January 2016
                : 147
                : 1
                : 1-24
                [1 ]Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA 52242
                [2 ]Department of Structural Biology, Genentech, Inc., South San Francisco, CA 94080
                [3 ]Department of Physiology and [4 ]Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, School of Medicine, Baltimore, MD 21205
                [5 ]Department of Neuroscience and [6 ]Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705
                Author notes
                Correspondence to Christopher A. Ahern: christopher-ahern@ ; Jian Payandeh: payandeh.jian@ ; Frank Bosmans: frankbosmans@ ; or Baron Chanda: chanda@
                © 2016 Ahern et al.

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at


                Anatomy & Physiology


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