title: Voltage-sensor movements describe slow inactivation of voltage-gated sodium channels I: wild-type skeletal muscle Na(V)1.4.
abstract: The number of voltage-gated sodium (Na(V)) 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. Na(V) channels have four domains (DI-DIV), 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 Na(V)1.4 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 1-160 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 Na(V) channel availability.
authors: Department of Biochemistry, Brandeis University, Waltham, MA 02453, USA.
authors: Jonathan R
authors: JR
authors: Silva
authors: Steve A N
authors: SA
authors: Goldstein
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D015640:Ion Channel Gating / Q000502:physiology; D008564:Membrane Potentials / Q000502:physiology; D009124:Muscle Proteins / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000502:physiology*; D062553:NAV1.4 Voltage-Gated Sodium Channel / Q000378:metabolism*; D009865:Oocytes / Q000378:metabolism / Q000502:physiology; D051381:Rats; D012964:Sodium / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: D009124:Muscle Proteins; D062553:NAV1.4 Voltage-Gated Sodium Channel; D012964:Sodium
references: Neurology. 2002 Apr 23;58(8):1266-72
references: 11971097
references: J Physiol. 2006 Nov 1;576(Pt 3):739-54
references: 16873407
references: J Gen Physiol. 2004 Mar;123(3):217-30
references: 14981134
references: J Gen Physiol. 1997 Jul;110(1):23-33
references: 9234168
references: Mol Pharmacol. 2008 Mar;73(3):1020-8
references: 18156314
references: J Physiol. 1996 Jul 15;494 ( Pt 2):431-42
references: 8842002
references: Pflugers Arch. 1999 Jul;438(2):213-7
references: 10370108
references: J Neurosci. 1998 Mar 1;18(5):1893-903
references: 9465014
references: Neurology. 1999 Apr 22;52(7):1447-53
references: 10227633
references: Cell Biochem Biophys. 2001;35(2):171-90
references: 11892790
references: Neurology. 2008 Mar 4;70(10):755-61
references: 17898326
references: Pharmacol Rev. 2005 Dec;57(4):397-409
references: 16382098
references: Biophys J. 1994 Apr;66(4):996-1010
references: 8038403
references: J Gen Physiol. 2003 Sep;122(3):323-32
references: 12913092
references: J Gen Physiol. 2000 May;115(5):609-20
references: 10779318
references: Neuron. 1999 Jan;22(1):73-87
references: 10027291
references: Biophys J. 1997 Mar;72(3):1204-19
references: 9138567
references: J Gen Physiol. 2013 Mar;141(3):323-34
references: 23401572
references: Science. 1996 Jan 12;271(5246):213-6
references: 8539623
references: Front Comput Neurosci. 2010 Apr 08;4:
references: 20725633
references: Neuron. 1993 Apr;10(4):667-78
references: 8386527
references: J Gen Physiol. 2010 Nov;136(5):555-68
references: 20974773
references: Mol Pharmacol. 2004 Sep;66(3):648-57
references: 15322257
references: Proc Natl Acad Sci U S A. 2008 Nov 18;105(46):17600-7
references: 18818307
references: Biophys J. 2007 Dec 15;93(12):4209-24
references: 17720727
references: Circ Res. 1997 Nov;81(5):727-41
references: 9351447
references: Proc Natl Acad Sci U S A. 2012 Feb 14;109(7):2648-53
references: 22308389
references: Front Comput Neurosci. 2009 Feb 10;3:2
references: 19225576
references: Mol Pharmacol. 2006 Nov;70(5):1514-23
references: 16885209
references: J Gen Physiol. 2000 Sep;116(3):461-76
references: 10962021
references: J Gen Physiol. 2008 Jun;131(6):549-61
references: 18504314
references: Nature. 2007 Nov 15;450(7168):376-82
references: 18004376
references: Biophys J. 1996 Dec;71(6):3098-109
references: 8968581
references: J Gen Physiol. 2002 Nov;120(5):629-45
references: 12407076
references: Biochim Biophys Acta. 1989 Oct 16;985(2):153-60
references: 2553115
references: Biophys J. 1999 Sep;77(3):1384-93
references: 10465750