53
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      Deconstructing voltage sensor function and pharmacology in sodium channels

      research-article
      1 , 2 , 3 , 1
      Nature

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Voltage-activated sodium (Nav) channels are crucial for the generation and propagation of nerve impulses, and as such are amongst the most widely targeted ion channels by toxins and drugs. The four voltage sensors in Nav channels have distinct amino acid sequences, raising fundamental questions about their relative contributions to the function and pharmacology of the channel. Here we use four-fold symmetric voltage-activated potassium (Kv) channels as reporters to examine the contributions of individual Nav channel S3b-S4 paddle motifs to the kinetics of voltage sensor activation and to forming toxin receptors. Our results uncover binding sites for toxins from tarantula and scorpion venom on each of the four paddle motifs in Nav channels and reveal how paddle-specific interactions can be used to reshape Nav channel activity. One paddle motif is unique in that it slows voltage sensor activation and toxins selectively targeting this motif impede Nav channel inactivation. This reporter approach and the principles that emerge will be useful in developing new drugs for treating pain and Nav channelopathies.

          Related collections

          Most cited references53

          • Record: found
          • Abstract: found
          • Article: not found

          X-ray structure of a voltage-dependent K+ channel.

          Voltage-dependent K+ channels are members of the family of voltage-dependent cation (K+, Na+ and Ca2+) channels that open and allow ion conduction in response to changes in cell membrane voltage. This form of gating underlies the generation of nerve and muscle action potentials, among other processes. Here we present the structure of KvAP, a voltage-dependent K+ channel from Aeropyrum pernix. We have determined a crystal structure of the full-length channel at a resolution of 3.2 A, and of the isolated voltage-sensor domain at 1.9 A, both in complex with monoclonal Fab fragments. The channel contains a central ion-conduction pore surrounded by voltage sensors, which form what we call 'voltage-sensor paddles'-hydrophobic, cationic, helix-turn-helix structures on the channel's outer perimeter. Flexible hinges suggest that the voltage-sensor paddles move in response to membrane voltage changes, carrying their positive charge across the membrane.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            The principle of gating charge movement in a voltage-dependent K+ channel.

            The steep dependence of channel opening on membrane voltage allows voltage-dependent K+ channels to turn on almost like a switch. Opening is driven by the movement of gating charges that originate from arginine residues on helical S4 segments of the protein. Each S4 segment forms half of a 'voltage-sensor paddle' on the channel's outer perimeter. Here we show that the voltage-sensor paddles are positioned inside the membrane, near the intracellular surface, when the channel is closed, and that the paddles move a large distance across the membrane from inside to outside when the channel opens. KvAP channels were reconstituted into planar lipid membranes and studied using monoclonal Fab fragments, a voltage-sensor toxin, and avidin binding to tethered biotin. Our findings lead us to conclude that the voltage-sensor paddles operate somewhat like hydrophobic cations attached to levers, enabling the membrane electric field to open and close the pore.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Evidence for voltage-dependent S4 movement in sodium channels.

              The mutation R1448C substitutes a cysteine for the outermost arginine in the fourth transmembrane segment (S4) of domain 4 in skeletal muscle sodium channels. We tested the accessibility of this cysteine residue to hydrophilic methanethiosulfonate reagents applied to the extracellular surface of cells expressing these mutant channels. The reagents irreversibly increase the rate of inactivation of R1448C, but not wild-type, channels. Cysteine modification is voltage dependent, as if depolarization extends this residue into the extracellular space. The rate of cysteine modification increases with depolarization and has the voltage dependence and kinetics expected for the movement of a voltage sensor controlling channel gating.
                Bookmark

                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                0028-0836
                1476-4687
                2 October 2008
                13 November 2008
                13 May 2009
                : 456
                : 7219
                : 202-208
                Affiliations
                [1 ]Molecular Physiology and Biophysics Section, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892 USA
                [2 ]Laboratory of Toxicology, University of Leuven, 3000 Leuven, Belgium
                [3 ]CNRS UMR 6132, CRN2M, Institut Jean Roche, Université de la Méditerranée, Marseille Cedex 20, France
                Author notes
                Correspondence and requests for materials should be addressed to K.J.S. ( swartzk@ 123456ninds.nih.gov ).

                Author Information Reprints and permissions information is available at . The authors declare no competing financial interests.

                Article
                nihpa71930
                10.1038/nature07473
                2587061
                19005548
                8c4fdb6f-64fa-4db1-8f9e-0df0a563346f
                History
                Funding
                Funded by: National Institute of Neurological Disorders and Stroke : NINDS
                Award ID: ZIA NS003017-03 ||NS
                Categories
                Article

                Uncategorized
                Uncategorized

                Comments

                Comment on this article