C.,The human skeletal muscle Na channel mutation R669H associated with hypokalemic periodic paralysis enhances slow inactivation, J.Neurosci

Missense mutations of the human skeletal muscle voltage-gated Na channel (hSkM1) underlie a variety of diseases, including hyperkalemic periodic paralysis (HyperPP), paramyotonia con-genita, and potassium-aggravated myotonia. Another disorder of sarcolemmal excitability, hypokalemic periodic paralysis (Hy-poPP), which is usually caused by missense mutations of the S4 voltage sensors of the L-type Ca channel, was associated re-cently 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 Ca21 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 acti-vation or fast inactivation but does cause an enhancement o