The human skeletal muscle Na channel mutation R669H associated with hypokalemic periodic paralysis enhances slow inactivation.
Missense mutations of the human skeletal muscle voltage-gated Na channel (hSkM1) underlie a variety of diseases, including hyperkalemic periodic paralysis (HyperPP), paramyotonia congenita, and potassium-aggravated myotonia. Another disorder of sarcolemmal excitability, hypokalemic periodic paralysis (HypoPP), which is usually caused by missense mutations of the S4 voltage sensors of the L-type Ca channel, was associated recently in one family with a mutation in the outermost arginine of the IIS4 voltage sensor (R669H) of hSkM1 (Bulman et al., 1999). Intriguingly, an arginine-to-histidine mutation at the homologous position in the L-type Ca(2+) channel (R528H) is a common cause of HypoPP. We have studied the gating properties of the hSkM1-R669H mutant Na channel experimentally in human embryonic kidney cells and found that it has no significant effects on activation or fast inactivation but does cause an enhancement of slow inactivation. R669H channels exhibit an approximately 10 mV hyperpolarized shift in the voltage dependence of slow inactivation and a twofold to fivefold prolongation of recovery after prolonged depolarization. In contrast, slow inactivation is often disrupted in HyperPP-associated Na channel mutants. These results demonstrate that, in R669H-associated HypoPP, enhanced slow inactivation does not preclude, and may contribute to, prolonged attacks of weakness and add support to previous evidence implicating the IIS4 voltage sensor in slow-inactivation gating.
Struyk
A F
AF
Departments of Neurology, Massachusetts General Hospital, and Neurobiology, Harvard Medical School, Boston, Massachusetts 02114, USA.
Scoggan
K A
KA
Bulman
D E
DE
Cannon
S C
SC
D019943:Amino Acid Substitution; D002460:Cell Line; D004558:Electric Stimulation; D004594:Electrophysiology; D006801:Humans; D020514:Hypokalemic Periodic Paralysis / Q000235:genetics* / Q000378:metabolism; D015640:Ion Channel Gating / Q000235:genetics / Q000502:physiology; D018482:Muscle, Skeletal / Q000378:metabolism*; D009154:Mutation / Q000235:genetics*; D018408:Patch-Clamp Techniques; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
D026941:Sodium Channel Blockers; D015222:Sodium Channels