Altered fast and slow inactivation of the N440K Nav1.4 mutant in a periodic paralysis syndrome.
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.
Department of Neurology, University of California, Davis, School of Medicine, USA.
Christoph
C
Lossin
Tai-Seung
TS
Nam
Shahab
S
Shahangian
Michael A
MA
Rogawski
Seok-Yong
SY
Choi
Myeong-Kyu
MK
Kim
Il-Nam
IN
Sunwoo
D000293:Adolescent; D000328:Adult; D004576:Electromyography; D005260:Female; D006801:Humans; D015640:Ion Channel Gating / Q000235:genetics*; D008297:Male; D008564:Membrane Potentials / Q000235:genetics*; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000503:physiopathology; D009154:Mutation; D020967:Myotonic Disorders / Q000235:genetics / Q000503:physiopathology*; D062553:NAV1.4 Voltage-Gated Sodium Channel / Q000235:genetics*; D020513:Paralysis, Hyperkalemic Periodic / Q000235:genetics / Q000503:physiopathology*
D062553:NAV1.4 Voltage-Gated Sodium Channel; C106251:SCN4A protein, human