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

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

Research output: Contribution to journalArticlepeer-review

59 Scopus citations


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
Issue number8
StatePublished - Apr 23 2002

ASJC Scopus subject areas

  • Clinical Neurology

Fingerprint Dive into the research topics of 'Impairment of slow inactivation as a common mechanism for periodic paralysis in dIIS4-S5'. Together they form a unique fingerprint.

Cite this