Altered fast and slow inactivation of the N440K Nav1.4 mutant in a periodic paralysis syndrome.

Abstract

OBJECTIVE:

To electrophysiologically characterize the Na(v)1.4 mutant N440K found in a Korean family with a syndrome combining symptoms of paramyotonia congenita, hyperkalemic periodic paralysis, and potassium-aggravated myotonia.

METHODS:

We characterized transiently expressed wild-type and mutant Na(v)1.4 using whole-cell voltage-clamp analysis.

RESULTS:

N440K produced a significant depolarizing shift in the voltage dependence of fast inactivation and increased persistent current and acceleration in fast inactivation recovery, which gave rise to a 2-fold elevation in the dynamic availability of the mutant channels. In addition, the mutant channels required substantially longer and stronger depolarization to enter the slow-inactivated state.

CONCLUSIONS:

N440K causes a gain of function consistent with skeletal muscle hyperexcitability as observed in individuals with the mutation. How the same mutation results in distinct phenotypes in the 2 kindreds remains to be determined.

• Authors: Christoph Lossin, Tai-Seung Nam, Shahab Shahangian, Michael A Rogawski, Seok-Yong Choi, Myeong-Kyu Kim, Il-Nam Sunwoo
• Journal: Neurology (Neurology) Vol. 79 Issue 10 Pg. 1033-40 (Sep 04 2012) ISSN: 1526-632X [Electronic] United States
• PMID: 22914841 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• NAV1.4 Voltage-Gated Sodium Channel
• SCN4A protein, human

Topics

• Adolescent
• Adult
• Electromyography
• Female
• Humans
• Ion Channel Gating (genetics)
• Male
• Membrane Potentials (genetics)
• Middle Aged
• Muscle, Skeletal (physiopathology)
• Mutation
• Myotonic Disorders (genetics, physiopathology)
• NAV1.4 Voltage-Gated Sodium Channel (genetics)
• Paralysis, Hyperkalemic Periodic (genetics, physiopathology)