Cold induces shifts of voltage dependence in mutant SCN4A, causing hypokalemic periodic paralysis.
BACKGROUND
The authors reported a mutation, P1158S, of the human skeletal muscle sodium channel gene (SCN4A) in a family with cold-induced hypokalemic periodic paralysis (hypoKPP) and myotonia.


OBJECTIVE
To identify mechanisms of temperature dependency in this channelopathy.


METHODS
Using the amphotericin B perforated patch clamp method, sodium currents were recorded at 22 and 32 degrees C from the wild-type (WT) and P1158S mutant SCN4A expressed in tsA201 cells. Computer simulation was performed, incorporating the gating parameters of the P1158S mutant SCN4A.


RESULTS
P1158S mutant SCN4A exhibited hyperpolarizing shifts in voltage dependence of both activation and inactivation curves at a cold temperature and a slower rate of inactivation than the WT. Computer simulation reproduced the abnormal skeletal muscle electrical activities of both paralysis at a low potassium concentration in the cold and myotonia at a normal potassium concentration.


CONCLUSIONS
Both paralysis and myotonia are attributable to the biophysical properties of the SCN4A mutation associated with hypoKPP. This is the first report of an SCN4A mutation that exhibits temperature-dependent shifts of voltage dependence in sodium channel gating.
Sugiura
Y
Y
Department of Neurology, Fukushima Medical University School of Medicine, Japan. sugiura@fmu.ac.jp
Makita
N
N
Li
L
L
Noble
P J
PJ
Kimura
J
J
Kumagai
Y
Y
Soeda
T
T
Yamamoto
T
T
D000200:Action Potentials / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D003080:Cold Temperature / Q000009:adverse effects*; D003198:Computer Simulation; D006801:Humans; D020514:Hypokalemic Periodic Paralysis / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology*; D015640:Ion Channel Gating / Q000235:genetics / Q000502:physiology; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D062553:NAV1.4 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D013696:Temperature; D014162:Transfection
D062553:NAV1.4 Voltage-Gated Sodium Channel; C106251:SCN4A protein, human; D015222:Sodium Channels; D012964:Sodium