Impairment of slow inactivation as a common mechanism for periodic paralysis in dIIS4-S5

S. Bendahhou, Theodore Cummins, R. W. Kula, Y. H. Fu, L. J. Ptácek

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

Background: Mutations in the human skeletal muscle sodium channels are associated with hyperKPP, hypoKPP, paramyotonia congenita, and potassium-aggravated myotonia. This article describes the clinical manifestations of a patient with hyperKPP carrying a mutation (L689I) occurring in the linker DIIS4-S5 and its functional expression in a mammalian system. Objective: To correlate the clinical manifestations of hyperkalemic periodic paralysis (hyperKPP) with the functional expression of a sodium channel mutation. Methods: The mutation was introduced into a mammalian expression vector and expressed in the human embryonic kidney 293 cells. The functional expression of the L689I and that of the wild-type channels was monitored using the whole cell voltage-clamp technique. Results: There was no change in the kinetics of fast inactivation, and inactivation curves were indistinguishable from that of wild-type channels. However, the L689I mutation caused a hyperpolarizing shift in the voltage dependence of activation and the mutant channels showed an impaired slow inactivation process. In addition, the mutant channels have a larger persistent current at -40 mV where window current may occur. Conclusions: The L689I mutation has similar effects to the T704M mutation and causes hyperKPP in this family. Because both of these hyperKPP mutations cause episodic muscle weakness, and because patients harboring another mutation (I693T) also can have episodic weakness, it is hypothesized that mutations occurring in this region of the sodium channel may cause episodic weakness through an impaired slow inactivation process coupled with enhanced activation.

Original languageEnglish (US)
Pages (from-to)1266-1272
Number of pages7
JournalNeurology
Volume58
Issue number8
StatePublished - Apr 23 2002
Externally publishedYes

Fingerprint

Paralysis
Hyperkalemic Periodic Paralysis
Mutation
Sodium Channels
Myotonic Disorders
Muscle Weakness
Patch-Clamp Techniques
Skeletal Muscle
Kidney

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Bendahhou, S., Cummins, T., Kula, R. W., Fu, Y. H., & Ptácek, L. J. (2002). Impairment of slow inactivation as a common mechanism for periodic paralysis in dIIS4-S5. Neurology, 58(8), 1266-1272.

Impairment of slow inactivation as a common mechanism for periodic paralysis in dIIS4-S5. / Bendahhou, S.; Cummins, Theodore; Kula, R. W.; Fu, Y. H.; Ptácek, L. J.

In: Neurology, Vol. 58, No. 8, 23.04.2002, p. 1266-1272.

Research output: Contribution to journalArticle

Bendahhou, S, Cummins, T, Kula, RW, Fu, YH & Ptácek, LJ 2002, 'Impairment of slow inactivation as a common mechanism for periodic paralysis in dIIS4-S5', Neurology, vol. 58, no. 8, pp. 1266-1272.
Bendahhou S, Cummins T, Kula RW, Fu YH, Ptácek LJ. Impairment of slow inactivation as a common mechanism for periodic paralysis in dIIS4-S5. Neurology. 2002 Apr 23;58(8):1266-1272.
Bendahhou, S. ; Cummins, Theodore ; Kula, R. W. ; Fu, Y. H. ; Ptácek, L. J. / Impairment of slow inactivation as a common mechanism for periodic paralysis in dIIS4-S5. In: Neurology. 2002 ; Vol. 58, No. 8. pp. 1266-1272.
@article{f52dc894246242fe9723a055cfbc0b23,
title = "Impairment of slow inactivation as a common mechanism for periodic paralysis in dIIS4-S5",
abstract = "Background: Mutations in the human skeletal muscle sodium channels are associated with hyperKPP, hypoKPP, paramyotonia congenita, and potassium-aggravated myotonia. This article describes the clinical manifestations of a patient with hyperKPP carrying a mutation (L689I) occurring in the linker DIIS4-S5 and its functional expression in a mammalian system. Objective: To correlate the clinical manifestations of hyperkalemic periodic paralysis (hyperKPP) with the functional expression of a sodium channel mutation. Methods: The mutation was introduced into a mammalian expression vector and expressed in the human embryonic kidney 293 cells. The functional expression of the L689I and that of the wild-type channels was monitored using the whole cell voltage-clamp technique. Results: There was no change in the kinetics of fast inactivation, and inactivation curves were indistinguishable from that of wild-type channels. However, the L689I mutation caused a hyperpolarizing shift in the voltage dependence of activation and the mutant channels showed an impaired slow inactivation process. In addition, the mutant channels have a larger persistent current at -40 mV where window current may occur. Conclusions: The L689I mutation has similar effects to the T704M mutation and causes hyperKPP in this family. Because both of these hyperKPP mutations cause episodic muscle weakness, and because patients harboring another mutation (I693T) also can have episodic weakness, it is hypothesized that mutations occurring in this region of the sodium channel may cause episodic weakness through an impaired slow inactivation process coupled with enhanced activation.",
author = "S. Bendahhou and Theodore Cummins and Kula, {R. W.} and Fu, {Y. H.} and Pt{\'a}cek, {L. J.}",
year = "2002",
month = "4",
day = "23",
language = "English (US)",
volume = "58",
pages = "1266--1272",
journal = "Neurology",
issn = "0028-3878",
publisher = "Lippincott Williams and Wilkins",
number = "8",

}

TY - JOUR

T1 - Impairment of slow inactivation as a common mechanism for periodic paralysis in dIIS4-S5

AU - Bendahhou, S.

AU - Cummins, Theodore

AU - Kula, R. W.

AU - Fu, Y. H.

AU - Ptácek, L. J.

PY - 2002/4/23

Y1 - 2002/4/23

N2 - Background: Mutations in the human skeletal muscle sodium channels are associated with hyperKPP, hypoKPP, paramyotonia congenita, and potassium-aggravated myotonia. This article describes the clinical manifestations of a patient with hyperKPP carrying a mutation (L689I) occurring in the linker DIIS4-S5 and its functional expression in a mammalian system. Objective: To correlate the clinical manifestations of hyperkalemic periodic paralysis (hyperKPP) with the functional expression of a sodium channel mutation. Methods: The mutation was introduced into a mammalian expression vector and expressed in the human embryonic kidney 293 cells. The functional expression of the L689I and that of the wild-type channels was monitored using the whole cell voltage-clamp technique. Results: There was no change in the kinetics of fast inactivation, and inactivation curves were indistinguishable from that of wild-type channels. However, the L689I mutation caused a hyperpolarizing shift in the voltage dependence of activation and the mutant channels showed an impaired slow inactivation process. In addition, the mutant channels have a larger persistent current at -40 mV where window current may occur. Conclusions: The L689I mutation has similar effects to the T704M mutation and causes hyperKPP in this family. Because both of these hyperKPP mutations cause episodic muscle weakness, and because patients harboring another mutation (I693T) also can have episodic weakness, it is hypothesized that mutations occurring in this region of the sodium channel may cause episodic weakness through an impaired slow inactivation process coupled with enhanced activation.

AB - Background: Mutations in the human skeletal muscle sodium channels are associated with hyperKPP, hypoKPP, paramyotonia congenita, and potassium-aggravated myotonia. This article describes the clinical manifestations of a patient with hyperKPP carrying a mutation (L689I) occurring in the linker DIIS4-S5 and its functional expression in a mammalian system. Objective: To correlate the clinical manifestations of hyperkalemic periodic paralysis (hyperKPP) with the functional expression of a sodium channel mutation. Methods: The mutation was introduced into a mammalian expression vector and expressed in the human embryonic kidney 293 cells. The functional expression of the L689I and that of the wild-type channels was monitored using the whole cell voltage-clamp technique. Results: There was no change in the kinetics of fast inactivation, and inactivation curves were indistinguishable from that of wild-type channels. However, the L689I mutation caused a hyperpolarizing shift in the voltage dependence of activation and the mutant channels showed an impaired slow inactivation process. In addition, the mutant channels have a larger persistent current at -40 mV where window current may occur. Conclusions: The L689I mutation has similar effects to the T704M mutation and causes hyperKPP in this family. Because both of these hyperKPP mutations cause episodic muscle weakness, and because patients harboring another mutation (I693T) also can have episodic weakness, it is hypothesized that mutations occurring in this region of the sodium channel may cause episodic weakness through an impaired slow inactivation process coupled with enhanced activation.

UR - http://www.scopus.com/inward/record.url?scp=0037161246&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037161246&partnerID=8YFLogxK

M3 - Article

C2 - 11971097

AN - SCOPUS:0037161246

VL - 58

SP - 1266

EP - 1272

JO - Neurology

JF - Neurology

SN - 0028-3878

IS - 8

ER -