{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T06:33:31Z","timestamp":1792737211234,"version":"4.5.0"},"reference-count":36,"publisher":"Rockefeller University Press","issue":"3","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2013,3,1]]},"abstract":"<jats:p>The number of voltage-gated sodium (NaV) channels available to generate action potentials in muscles and nerves is adjusted over seconds to minutes by prior electrical activity, a process called slow inactivation (SI). The basis for SI is uncertain. NaV channels have four domains (DI\u2013DIV), each with a voltage sensor that moves in response to depolarizing stimulation over milliseconds to activate the channels. Here, SI of the skeletal muscle channel NaV1.4 is induced by repetitive stimulation and is studied by recording of sodium currents, gating currents, and changes in the fluorescence of probes on each voltage sensor to assess their movements. The magnitude, voltage dependence, and time course of the onset and recovery of SI are observed to correlate with voltage-sensor movements 10,000-fold slower than those associated with activation. The behavior of each voltage sensor is unique. Development of SI over 1\u2013160 s correlates best with slow immobilization of the sensors in DI and DII; DIII tracks the onset of SI with less fidelity. Showing linkage to the sodium conduction pathway, pore block by tetrodotoxin affects both SI and immobilization of all the sensors, with DI and DII significantly suppressed. Recovery from SI correlates best with slow restoration of mobility of the sensor in DIII. The findings suggest that voltage-sensor movements determine SI and thereby mediate NaV channel availability.<\/jats:p>","DOI":"10.1085\/jgp.201210909","type":"journal-article","created":{"date-parts":[[2013,2,12]],"date-time":"2013-02-12T04:03:51Z","timestamp":1360641831000},"page":"309-321","update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":31,"title":["Voltage-sensor movements describe slow inactivation of voltage-gated sodium channels I: Wild-type skeletal muscle NaV1.4"],"prefix":"10.1085","volume":"141","author":[{"given":"Jonathan R.","family":"Silva","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Brandeis University, Waltham, MA 02453"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve A.N.","family":"Goldstein","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Brandeis University, Waltham, MA 02453"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2013,2,11]]},"reference":[{"key":"2023072622462018200_bib1","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1113\/jphysiol.1996.sp021503","article-title":"External pore residue mediates slow inactivation in mu 1 rat skeletal muscle sodium channels","volume":"494","author":"Balser","year":"1996","journal-title":"J. Physiol."},{"key":"2023072622462018200_bib2","doi-asserted-by":"publisher","first-page":"1266","DOI":"10.1212\/WNL.58.8.1266","article-title":"Impairment of slow inactivation as a common mechanism for periodic paralysis in DIIS4-S5","volume":"58","author":"Bendahhou","year":"2002","journal-title":"Neurology."},{"key":"2023072622462018200_bib3","doi-asserted-by":"publisher","first-page":"2648","DOI":"10.1073\/pnas.1115575109","article-title":"Gating transitions in the selectivity filter region of a sodium channel are coupled to the domain IV voltage sensor","volume":"109","author":"Capes","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072622462018200_bib4","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1124\/pr.57.4.4","article-title":"International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels","volume":"57","author":"Catterall","year":"2005","journal-title":"Pharmacol. Rev."},{"key":"2023072622462018200_bib5","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/S0896-6273(00)80680-7","article-title":"Voltage sensors in domains III and IV, but not I and II, are immobilized by Na+ channel fast inactivation","volume":"22","author":"Cha","year":"1999","journal-title":"Neuron."},{"key":"2023072622462018200_bib6","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1085\/jgp.20028679","article-title":"Tracking voltage-dependent conformational changes in skeletal muscle sodium channel during activation","volume":"120","author":"Chanda","year":"2002","journal-title":"J. Gen. Physiol."},{"key":"2023072622462018200_bib7","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1085\/jgp.200308971","article-title":"Coupling interactions between voltage sensors of the sodium channel as revealed by site-specific measurements","volume":"123","author":"Chanda","year":"2004","journal-title":"J. Gen. Physiol."},{"key":"2023072622462018200_bib8","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1016\/0896-6273(93)90168-Q","article-title":"Functional consequences of a Na+ channel mutation causing hyperkalemic periodic paralysis","volume":"10","author":"Cummins","year":"1993","journal-title":"Neuron."},{"key":"2023072622462018200_bib9","doi-asserted-by":"publisher","first-page":"3098","DOI":"10.1016\/S0006-3495(96)79504-8","article-title":"Interaction between fast and slow inactivation in Skm1 sodium channels","volume":"71","author":"Featherstone","year":"1996","journal-title":"Biophys. J."},{"key":"2023072622462018200_bib10","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1085\/jgp.201010487","article-title":"The contribution of individual subunits to the coupling of the voltage sensor to pore opening in Shaker K channels: Effect of ILT mutations in heterotetramers","volume":"136","author":"Gagnon","year":"2010","journal-title":"J. Gen. Physiol."},{"key":"2023072622462018200_bib11","doi-asserted-by":"publisher","first-page":"1204","DOI":"10.1016\/S0006-3495(97)78768-X","article-title":"Slow inactivation differs among mutant Na channels associated with myotonia and periodic paralysis","volume":"72","author":"Hayward","year":"1997","journal-title":"Biophys. J."},{"key":"2023072622462018200_bib12","doi-asserted-by":"publisher","first-page":"1447","DOI":"10.1212\/WNL.52.7.1447","article-title":"Defective slow inactivation of sodium channels contributes to familial periodic paralysis","volume":"52","author":"Hayward","year":"1999","journal-title":"Neurology."},{"key":"2023072622462018200_bib13","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1085\/jgp.116.3.461","article-title":"Immobilizing the moving parts of voltage-gated ion channels","volume":"116","author":"Horn","year":"2000","journal-title":"J. Gen. Physiol."},{"key":"2023072622462018200_bib14","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1085\/jgp.200809962","article-title":"Atomic constraints between the voltage sensor and the pore domain in a voltage-gated K+ channel of known structure","volume":"131","author":"Lewis","year":"2008","journal-title":"J. Gen. Physiol."},{"key":"2023072622462018200_bib15","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1038\/nature06265","article-title":"Atomic structure of a voltage-dependent K+ channel in a lipid membrane-like environment","volume":"450","author":"Long","year":"2007","journal-title":"Nature."},{"key":"2023072622462018200_bib16","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1016\/0005-2736(89)90360-X","article-title":"Use-dependent block of sodium channels in frog myelinated nerve by tetrodotoxin and saxitoxin at negative holding potentials","volume":"985","author":"L\u00f6nnendonker","year":"1989","journal-title":"Biochim. Biophys. Acta."},{"key":"2023072622462018200_bib17","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1126\/science.271.5246.213","article-title":"Direct physical measure of conformational rearrangement underlying potassium channel gating","volume":"271","author":"Mannuzzu","year":"1996","journal-title":"Science."},{"key":"2023072622462018200_bib18","doi-asserted-by":"crossref","first-page":"2","DOI":"10.3389\/neuro.10.002.2009","article-title":"Adaptive transition rates in excitable membranes","volume":"3","author":"Marom","year":"2009","journal-title":"Front Comput Neurosci."},{"key":"2023072622462018200_bib19","doi-asserted-by":"publisher","first-page":"1514","DOI":"10.1124\/mol.106.027177","article-title":"An inner pore residue (Asn406) in the Nav1.5 channel controls slow inactivation and enhances mibefradil block to T-type Ca2+ channel levels","volume":"70","author":"McNulty","year":"2006","journal-title":"Mol. Pharmacol."},{"key":"2023072622462018200_bib20","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1007\/s004240050900","article-title":"A global defect in scaling relationship between electrical activity and availability of muscle sodium channels in hyperkalemic periodic paralysis","volume":"438","author":"Melamed-Frank","year":"1999","journal-title":"Pflugers Arch."},{"key":"2023072622462018200_bib21","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1016\/S0026-895X(24)05648-7","article-title":"Lidocaine: a foot in the door of the inner vestibule prevents ultra-slow inactivation of a voltage-gated sodium channel","volume":"66","author":"Sandtner","year":"2004","journal-title":"Mol. Pharmacol."},{"key":"2023072622462018200_bib22","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1161\/01.RES.81.5.727","article-title":"Ionic mechanisms of propagation in cardiac tissue. Roles of the sodium and L-type calcium currents during reduced excitability and decreased gap junction coupling","volume":"81","author":"Shaw","year":"1997","journal-title":"Circ. Res."},{"key":"2023072622462018200_bib23","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1085\/jgp.115.5.609","article-title":"The role of the putative inactivation lid in sodium channel gating current immobilization","volume":"115","author":"Sheets","year":"2000","journal-title":"J. Gen. Physiol."},{"key":"2023072622462018200_bib24","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1085\/jgp.201210910","article-title":"Voltage-sensor movements describe slow inactivation of voltage-gated sodium channels II: A periodic paralysis mutation in NaV1.4 (L689I)","volume":"141","author":"Silva","year":"2013","journal-title":"J. Gen. Physiol."},{"key":"2023072622462018200_bib25","doi-asserted-by":"publisher","first-page":"1020","DOI":"10.1124\/mol.107.041046","article-title":"Inhibition of sodium channel gating by trapping the domain II voltage sensor with protoxin II","volume":"73","author":"Sokolov","year":"2008","journal-title":"Mol. Pharmacol."},{"key":"2023072622462018200_bib26","first-page":"12","article-title":"History-dependent dynamics in a generic model of ion channels\u2014an analytic study","volume":"4","author":"Soudry","year":"2010","journal-title":"Front Comput Neurosci."},{"key":"2023072622462018200_bib27","doi-asserted-by":"publisher","first-page":"996","DOI":"10.1016\/S0006-3495(94)80881-1","article-title":"Gating of Shaker K+ channels: I. Ionic and gating currents","volume":"66","author":"Stefani","year":"1994","journal-title":"Biophys. J."},{"key":"2023072622462018200_bib28","doi-asserted-by":"publisher","first-page":"4209","DOI":"10.1529\/biophysj.107.104794","article-title":"Speeding the recovery from ultraslow inactivation of voltage-gated Na+ channels by metal ion binding to the selectivity filter: a foot-on-the-door?","volume":"93","author":"Szendroedi","year":"2007","journal-title":"Biophys. J."},{"key":"2023072622462018200_bib29","doi-asserted-by":"crossref","first-page":"1893","DOI":"10.1523\/JNEUROSCI.18-05-01893.1998","article-title":"Interaction between duration of activity and time course of recovery from slow inactivation in mammalian brain Na+ channels","volume":"18","author":"Toib","year":"1998","journal-title":"J. Neurosci."},{"key":"2023072622462018200_bib30","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1085\/jgp.110.1.23","article-title":"Effect of alkali metal cations on slow inactivation of cardiac Na+ channels","volume":"110","author":"Townsend","year":"1997","journal-title":"J. Gen. Physiol."},{"key":"2023072622462018200_bib31","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1385\/CBB:35:2:171","article-title":"Slow inactivation in voltage-gated sodium channels: molecular substrates and contributions to channelopathies","volume":"35","author":"Vilin","year":"2001","journal-title":"Cell Biochem. Biophys."},{"key":"2023072622462018200_bib32","doi-asserted-by":"publisher","first-page":"1384","DOI":"10.1016\/S0006-3495(99)76987-0","article-title":"Structural determinants of slow inactivation in human cardiac and skeletal muscle sodium channels","volume":"77","author":"Vilin","year":"1999","journal-title":"Biophys. J."},{"key":"2023072622462018200_bib33","doi-asserted-by":"publisher","first-page":"17600","DOI":"10.1073\/pnas.0807387105","article-title":"S4-based voltage sensors have three major conformations","volume":"105","author":"Villalba-Galea","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072622462018200_bib34","doi-asserted-by":"publisher","first-page":"755","DOI":"10.1212\/01.wnl.0000265397.70057.d8","article-title":"Cold-induced defects of sodium channel gating in atypical periodic paralysis plus myotonia","volume":"70","author":"Webb","year":"2008","journal-title":"Neurology."},{"key":"2023072622462018200_bib35","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1085\/jgp.200308881","article-title":"Molecular motions of the outer ring of charge of the sodium channel: Do they couple to slow inactivation?","volume":"122","author":"Xiong","year":"2003","journal-title":"J. Gen. Physiol."},{"key":"2023072622462018200_bib36","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1113\/jphysiol.2006.115105","article-title":"A conserved ring of charge in mammalian Na+ channels: a molecular regulator of the outer pore conformation during slow inactivation","volume":"576","author":"Xiong","year":"2006","journal-title":"J. Physiol."}],"container-title":["Journal of General Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jgp\/article-pdf\/141\/3\/309\/1791385\/jgp_201210909.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jgp\/article-pdf\/141\/3\/309\/1791385\/jgp_201210909.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,29]],"date-time":"2025-04-29T20:40:30Z","timestamp":1745959230000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jgp\/article\/141\/3\/309\/43127\/Voltage-sensor-movements-describe-slow"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,2,11]]},"references-count":36,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2013,3,1]]}},"URL":"https:\/\/doi.org\/10.1085\/jgp.201210909","relation":{},"ISSN":["1540-7748","0022-1295"],"issn-type":[{"value":"1540-7748","type":"electronic"},{"value":"0022-1295","type":"print"}],"subject":[],"published":{"date-parts":[[2013,2,11]]}}}