QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (33) Citing Articles via Google Scholar Google Scholar Articles by Bendahhou, S. Articles by Ptácek, L. J. Search for Related Content PubMed PubMed Citation Articles by Bendahhou, S. Articles by Ptácek, L. J.

 Previous Article  |  Next Article 

The Journal of Neuroscience, June 15, 1999, 19(12):4762-4771

Activation and Inactivation of the Voltage-Gated Sodium Channel: Role of Segment S5 Revealed by a Novel Hyperkalaemic Periodic Paralysis Mutation

Saïd Bendahhou¹, Theodore R. Cummins^{2, 3}, Rabi Tawil⁴, Stephen G. Waxman^{2, 3}, and Louis J. Ptácek¹

¹ Howard Hughes Medical Institute, Eccles Institute of Human Genetics, University of Utah, Salt Lake City, Utah 84112, ² Departments of Neurology and Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510, ³ Neuroscience Research Center, Veterans Administration Medical Center, West Haven, Connecticut 06516, and ⁴ Department of Neurology, University of Rochester, Rochester, New York 14642

Hyperkalaemic periodic paralysis, paramyotonia congenita, and potassium-aggravated myotonia are three autosomal dominant skeletal muscle disorders linked to the SCN4A gene encoding the -subunit of the human voltage-sensitive sodium channel. To date, ~20 point mutations causing these disorders have been described. We have identified a new point mutation, in the SCN4A gene, in a family with a hyperkalaemic periodic paralysis phenotype. This mutation predicts an isoleucine-to-phenylalanine substitution at position 1495 located in the transmembrane segment S5 in the fourth homologous domain of the human -subunit sodium channel. Introduction of the I1495F mutation into the wild-type channels disrupted the macroscopic current inactivation decay and shifted both steady-state activation and inactivation to the hyperpolarizing direction. The recovery from fast inactivation was slowed, and there was no effect on channel deactivation. Additionally, a significant enhancement of slow inactivation was observed in the I1495F mutation. In contrast, the T704M mutation, a hyperkalaemic periodic paralysis mutation located in the cytoplasmic interface of the S5 segment of the second domain, also shifted activation in the hyperpolarizing direction but had little effect on fast inactivation and dramatically impaired slow inactivation. These results, showing that the I1495F and T704M hyperkalaemic periodic paralysis mutations both have profound effects on channel activation and fast-slow inactivation, suggest that the S5 segment maybe in a location where fast and slow inactivation converge.

Key words: Na channel; SCN4A; disorders; activation; slow inactivation; expression

---

Copyright © 1999 Society for Neuroscience  0270-6474/99/19124762-10$05.00/0

This article has been cited by other articles:

				P. L. Sheets, J. O. Jackson II, S. G. Waxman, S. D. Dib-Hajj, and T. R. Cummins A Nav1.7 channel mutation associated with hereditary erythromelalgia contributes to neuronal hyperexcitability and displays reduced lidocaine sensitivity J. Physiol., June 15, 2007; 581(3): 1019 - 1031. [Abstract] [Full Text] [PDF]

				T. P. Harty, S. D. Dib-Hajj, L. Tyrrell, R. Blackman, F. M. Hisama, J. B. Rose, and S. G. Waxman Nav1.7 Mutant A863P in Erythromelalgia: Effects of Altered Activation and Steady-State Inactivation on Excitability of Nociceptive Dorsal Root Ganglion Neurons J. Neurosci., November 29, 2006; 26(48): 12566 - 12575. [Abstract] [Full Text] [PDF]

				W. Xiong, Y. Z. Farukhi, Y. Tian, D. DiSilvestre, R. A. Li, and G. F. Tomaselli A conserved ring of charge in mammalian Na+ channels: a molecular regulator of the outer pore conformation during slow inactivation J. Physiol., November 1, 2006; 576(3): 739 - 754. [Abstract] [Full Text] [PDF]

				P. J. Stocker and E. S. Bennett Differential Sialylation Modulates Voltage-gated Na+ Channel Gating throughout the Developing Myocardium J. Gen. Physiol., February 27, 2006; 127(3): 253 - 265. [Abstract] [Full Text] [PDF]

				S. L. Venance, S. C. Cannon, D. Fialho, B. Fontaine, M. G. Hanna, L. J. Ptacek, M. Tristani-Firouzi, R. Tawil, R. C. Griggs, and the CINCH investigators The primary periodic paralyses: diagnosis, pathogenesis and treatment Brain, January 1, 2006; 129(1): 8 - 17. [Abstract] [Full Text] [PDF]

				W. Ulbricht Sodium Channel Inactivation: Molecular Determinants and Modulation Physiol Rev, October 1, 2005; 85(4): 1271 - 1301. [Abstract] [Full Text] [PDF]

				S. Vicart, D. Sternberg, E. Fournier, F. Ochsner, P. Laforet, T. Kuntzer, B. Eymard, B. Hainque, and B. Fontaine New mutations of SCN4A cause a potassium-sensitive normokalemic periodic paralysis Neurology, December 14, 2004; 63(11): 2120 - 2127. [Abstract] [Full Text] [PDF]

				S. Bendahhou, M. R. Donaldson, N. M. Plaster, M. Tristani-Firouzi, Y.-H. Fu, and L. J. Ptacek Defective Potassium Channel Kir2.1 Trafficking Underlies Andersen-Tawil Syndrome J. Biol. Chem., December 19, 2003; 278(51): 51779 - 51785. [Abstract] [Full Text] [PDF]

				W. Xiong, R. A. Li, Y. Tian, and G. F. Tomaselli Molecular Motions of the Outer Ring of Charge of the Sodium Channel: Do They Couple to Slow Inactivation? J. Gen. Physiol., August 25, 2003; 122(3): 323 - 332. [Abstract] [Full Text] [PDF]

				T.R. Cummins, M. Renganathan, P.K. Stys, R.I. Herzog, K. Scarfo, R. Horn, S.D. Dib-Hajj, and S.G. Waxman The pentapeptide QYNAD does not block voltage-gated sodium channels Neurology, January 28, 2003; 60(2): 224 - 229. [Abstract] [Full Text] [PDF]

				S. Bendahhou, T. R. Cummins, R. W. Kula, Y.-H. Fu, and L. J. Ptacek Impairment of slow inactivation as a common mechanism for periodic paralysis in DIIS4-S5 Neurology, April 23, 2002; 58(8): 1266 - 1272. [Abstract] [Full Text] [PDF]

				F.-F. Wu, M.P. Takahashi, E. Pegoraro, C. Angelini, P. Colleselli, S.C. Cannon, and E.P. Hoffman A new mutation in a family with cold-aggravated myotonia disrupts Na+ channel inactivation Neurology, April 10, 2001; 56(7): 878 - 884. [Abstract] [Full Text] [PDF]

				A. F. Struyk, K. A. Scoggan, D. E. Bulman, and S. C. Cannon The Human Skeletal Muscle Na Channel Mutation R669H Associated with Hypokalemic Periodic Paralysis Enhances Slow Inactivation J. Neurosci., December 1, 2000; 20(23): 8610 - 8617. [Abstract] [Full Text] [PDF]

				R. L. Ruff and S. C. Cannon Defective slow inactivation of sodium channels contributes to familial periodic paralysis Neurology, June 13, 2000; 54(11): 2191 - 2192. [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help